Clin Rheumatol DOI 10.1007/s10067-014-2521-6
CASE BASED REVIEW
Eosinophilic granulomatosis with polyangiitis complicated by cholecystitis: a case report and review of the literature Lu Ye & Xiaoyong Lu & Jing Xue
Received: 15 January 2014 / Revised: 28 January 2014 / Accepted: 29 January 2014 # Clinical Rheumatology 2014
Abstract The objectives are to report an atypical case of eosinophilic granulomatosis with polyangiitis (EGPA) associated with cholecystitis and to review the main clinical features, therapy, and prognosis of it. We present a 49-year-old male with non-classic clinical manifestations of EGPA and EGPArelated cholecystitis. EGPA was diagnosed by histology of the gallbladder after cholecystectomy. In addition, 11 cases of EGPA-associated cholecystitis have been reported and were described in details in this article. Gallbladder involvement is very uncommon in EGPA. All cases reviewed showed multiple organs involved as well as obviously elevated eosinophilic granulocyte proportion with inflammatory index, although antineutrophil cytoplasmic antibody may be negative. All patients in this cohort that showed gallbladder involvement were eventually confirmed with EGPA by histology examination after cholecystectomy. The pathological change could be infiltration of inflammatory mononuclear cells of small- and medium-sized vessels. Of the cases, 91.7 % responded well to steroid and immunosuppressant therapy. Gallbladder involvement is a very rare comorbid condition in EGPA. However, it is an important symptom or secondary condition to alert physicians the diagnosis of EGPA. Moreover, timely diagnosis and correct administration in the early stage of this disease could obviously improve the prognosis.
Keywords Characteristics . Cholecystitis . Eosinophilic granulomatosis with polyangiitis . Histology
L. Ye : X. Lu : J. Xue (*) Department of Rheumatology, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, 310009 Hangzhou, Zhejiang Province, People’s Republic of China e-mail: [email protected]
Introduction Eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg-Strauss syndrome, is an autoimmune systemic vasculitis with peripheral eosinophilic infiltration of unknown origin [1–4]. American College of Rheumatology (ACR) proposed diagnostic criteria as four of the following six features being necessary for EGPA: allergic asthma, transient pulmonary infiltrates, hypereosinophilia, neuropathy, paranasal sinus abnormality, and extravascular eosinophils on biopsy [5]. However, some cases can manifest atypical symptoms or uncommon complications (e.g., cholecystitis [6], refractory otitis media [7]), which make the diagnosis of EGPA rather difficult to be established. Here, we present an atypical case of EGPA associated with cholecystitis, which was diagnosed by histology of the gallbladder after cholecystectomy.
A case report A 49-year-old male presented to us with recurrent fever, occasional abdominal pain, and multiple subcutaneous nodules on his scalp, forehead, and right forearm. His hemogram showed white blood cell count (WBC) 20.9×109/L, with 57.2 % eosinophils. Bone marrow aspiration revealed activating hematopoiesis with significantly increased eosinophils at the level of 42.5 %. Endoscopy demonstrated multiple ulcers in gastric antrum. He was diagnosed as eosinophilic gastroenteritis before his admission in our hospital and treated with low dose of oral prednisone and omeprazole for 1 month. Thereafter, his body temperature rapidly decreased to the normal level, and the subcutaneous nodules obviously improved at that time. However, after withdrawal of prednisone, his abdominal pain and subcutaneous nodules recurred with the development
Clin Rheumatol
of slight numbness in his feet; therefore, he visited our department. Physical examination revealed multiple subcutaneous nodules with 1∼2×1∼2 cm size on his scalp, forehead, and right forearm. The nodules were moderately firm, moveable, poorly defined, and non-tender. In routine clinical investigations, his hematologic test showed WBC 17.0×109/L, with 43.6 % eosinophils. Creactive protein (CRP) was elevated to 62.0 mg/L. Antineutrophil cytoplasmic antibody (ANCA), anti-nuclear antibodies, erythrocyte sedimentation rate (ESR), and all tumor markers were negative. Therefore, these signs indicate the suspicious of eosinophilic gastroenteritis, idiopathic hypereosinophilic syndrome, EGPA, as well as Kimura’s disease (a rare, benign lymphoproliferative and chronic inflammation disorder) [8]. Interestingly, he had experienced slight rhinitis, but without steroid or anti-allergy medication, he sustained complete clinical remission for over 4 years. Therefore, sinonasal CT scan was carried out for detailed information, and the result demonstrated the inflammatory lesions of paranasal sinus. In addition, electromyogram analysis of his extremities demonstrated mononeuritis multiplex. Skin biopsy was initially performed, and it showed infiltration of many eosinophils. Abdominal ultrasonography revealed a thickened gallbladder wall and a hypoechoic mass inside the gallbladder, which could be an implication of cancer. Consistent with ultrasonography findings, abdominal CT images could not exclude gallbladder cancer (Fig. 1). Indeed, paraneoplastic syndrome caused by cholecystic carcinoma could be a reasonable explanation for any clinical manifestation in the present patient. Therefore, cholecystectomy was performed, and histological changes of the gallbladder were analyzed. Finally, histopathologic results were consistent with EGPA which demonstrated peri-vascular, focally granulomatous inflammation with many eosinophils and eosinophil-rich necrotizing vasculitis (Fig. 2). Given his history of eosinophilia, mononeuritis multiplex, paranasal sinus abnormality, and histology-proven eosinophilic granulomatous necrotizing vasculitis, the patient fulfilled the ACR’s diagnostic criteria for EGPA. Because his response to the low dose of steroid was dramatically good according to his medical record, oral methylprednisolone (16 mg daily for 7 days, then 12 mg daily for 1 month, and gradually reduced to 4 mg daily within 2 months) was applied. His subcutaneous nodules disappeared, and limb numbness was gradually improved, without recurrent fever and abdominal pain. His WBC was reduced to 12.2×109/L, with a decreased EO to below 1.55×109/L.
Fig. 1 Abdominal CT found thickening in the gallbladder wall and a 1.8 cm×1.6 cm sized mass inside the gallbladder
articles from 1951 to December 2013. The articles were restricted to English language only. Articles with important data missing or without full texts were excluded. Finally, the search criteria identified 8,513 articles, of which 11 full-text articles presenting EGPA patients complicated by cholecystitis with detailed clinical and laboratory data were reviewed. Twelve patients [6, 9–18] (including our case) were analyzed including age, disease onset, gender, disease duration, clinical features, pathologic changes, radiological images, therapies, and prognosis (Table 1). The age range of disease onset in the reviewed articles was from 21 to 65 years, with the mean age of 43.75±14 years. The male to female ratio was 6:6, and disease duration was from 2 to 240 days, with the average duration of 87.38± 105.87 days. Of the patients, 83.3 % (10 /12) had follow-up information, and the mean duration was 16.98±24.75 months. All the 12 patients were diagnosed by histological examination of the gallbladder after cholecystectomy. Pathologic changes varied in these studies, including eosinophilic with/without other inflammatory mononuclear cells infiltration, granulomatous vasculitis, necrotizing vasculitis of smalland medium-sized vessels, and necrosis of the gallbladder. Associated clinical manifestations for the 12 cases were described in details. Besides abdominal pain, respiratory symptom was the most common clinical feature, including
Literature review A systematic review of the literature was performed by using the subject term “Cholecystitis” in PubMed database to search
Fig. 2 Histological examination of the gallbladder revealed eosinophilrich necrotizing vasculitis with organized thrombi
Clin Rheumatol Table 1 Comparison of the case reports on eosinophilic granulomatosis with polyangiitis-induced cholecystitis Author
Age/ gender
Organ involved
ANCA
CRP (mg/L)
ESR (mm/h)
Eosinophil (%)
Histology-proven cholecystic vasculitis
Therapy
Imai et al. [9] Boggi et al. [10] Kalyoncu et al. [11] Nishie et al. [6]
51/F 29/F 36/M 36/M
B, M, N B, G, J, S B, G, L, M, N, P, R G, L, M, P
NA NA NA −
29 NA NA 4.7
50 NA 75 47
58 40.60 15.80 70.98
+ + + +
Steroid Steroid CYC Steroid Steroid
Tatsukawa et al. [12] Suzuki et al. [13] Rolla et al. [14] Francescutti et al. [15] Yüksel et al. [16] Sironen et al. [17] Lenders et al. [18] Present case
50/F 21/F 55/M 38/F 65/M 64/M 31/F 49/M
B, G, M, N, R B, G, L, P B, N, P B, G, P G, L, S B, G, L, U B, H, P G, N, P, S
+ NA NA − NA + − −
3 2.5 0.11 17.5 NA NA NA 62
NA NA 75 59 NA NA NA 15
35 56 12 42.70 39 3.57 50 43.60
+ + + + + + + +
Steroid Steroid Steroid CYC Steroid Steroid Steroid AZA Steroid Steroid
B bronchial asthma, G gastrointestinal tract, H heart, J joint, L lung, M muscle, N nervous system, P pansinusitis/sinusitis, R renal, S skin, U hematuria, AZA azathioprine, CYC cyclophosphamide, NA not available
asthma (9/12), sinusitis (6/12), and lung involvement (5/12). Other systems involved included skin (1/12), heart (1/12), nervous system (4/12), renal (3/12), as well as joint (1/12) and muscle (4/12). Abnormalities in laboratory findings including eosinophilia, ANCA-positive ratio, and elevated levels of ESR and CRP were 100 % (12/12), 33.3 % (2/6), 83.3 % (5/6), and 100 % (7/7), respectively.
Discussion EGPA is a rare granulomatous necrotizing vasculitis characterized by diffuse involvement of small- to medium-sized vessels and multiple organs with eosinophilic infiltration, which was first described by Churg and Strauss in 1951 [2]. It was reported that 41 % of patients with EGPA could develop abdominal pain due to gastroduodenal/colorectal ulcers, gastritis, intestinal occlusion, appendicitis, or pancreatitis [20]. Cholecystitis has been reported to be a possible association with systemic vasculitis in recent case series, such as polyarteritis nodosa (PAN), with the incidence of 10–40 % of PAN patients that may have vascular lesions in the gallbladder at autopsy [19]. In a large cohort of EGPA patients, which was reported by Guillevin et al. [20] in 1999, only 1 in 96 patients developed cholecystitis during 32 years of follow-up. Similar prevalence (1/62) was also reported in another cohort of 62 EGPA patients [21]. More recently, Lenders et al. [18] described a patient with hypereosinophilia presenting cardiac tamponade and acalculous cholecystitis; subsequently, EGPA was diagnosed by histology. However, cholecystitis is an extremely rare complication in EGPA, as only 14 cases had been reported previously.
Besides clinical features, radiological images and histology are both key points in confirming the diagnosis. In these patients reviewed, abdominal ultrasonography during routine clinical investigation may provide important indication of gallbladder involvement, with the characteristic Doppler signals as a thickened gallbladder wall, with or without solitary calculus, sludge, or pericholecystic fluid in the gallbladder [17]. In addition, the most common finding of abdominal CT scan is usually consistent with ultrasonography detection. To date, histological examination remains the gold standard to confirm a diagnosis of EGPA. Pathological changes with typical description are eosinophilic infiltration, granulomatous inflammation, and necrotizing vasculitis. It was considered the classic pathological features of the gallbladder as eosinophilic infiltration and necrotizing vasculitis of small- to mediumsized vessels by some authors [14, 17, 18], whereas Boggi et al. [10] described the pathological change as mononuclear inflammatory infiltration without eosinophils. Moreover, in the present case, the presence of eosinophil-rich necrotizing vasculitis was found, and some of the affected vessels also show organized thrombi. Therefore, histological analysis of gallbladder involvement differs in EGPA patients, with the most common observation of small- to medium-sized vessel vasculitis, although eosinophil-rich infiltration may not exist. Intriguingly, all of the previous studies indicated that a good prognosis was based on effective therapy in the early stage, and prednisolone administration for patients with vasculitis in the end stage was shown to be non-sensitive [22, 23]. Therefore, the important role of prompt diagnosis and correct administration in the early stage of patients with atypical symptoms should be emphasized, which may significantly change the fatal outcome and prognosis.
Clin Rheumatol
The 1-year survival rate is 90 % for the general population of EGPA patients [24], and the major factors related to poor clinical outcomes are severe cardiac involvement, such as myocardial infarction as well as cardiac insufficiency, and gastrointestinal involvement including hemorrhage, perforation, and pancreatitis [20, 21, 25–29]. Consistent with these data, the prognosis was also encouraging in the limited number of patients reviewed, with a 1-year survival rate of 91.7 %. Moreover, the majority of them achieved sustained remission after corticosteroid administration, and only 25 % (3/12) combined with immunosuppressants (including cyclophosphamide and azathioprine), excluding one patient who died due to cardiac arrest. Although the limited number of subjects attributed to the difficulties in making a firm conclusion, we hypothesize EGPA individual associated with cholecystitis without involvement of other vital organs receives good outcomes. However, the necessity of gastrointestinal involvement is ignored in current classification criteria. Moreover, in these patients reviewed, all the subjects underwent cholecystectomy to draw a firm evidence of EGPA, whereas in most previous large cohort studies, gastrointestinal manifestations were listed, but without further detail for which kind of gastrointestinal involvement that was. Thus, further studies are needed to classify the features and subtypes of gastrointestinal involvement, to comment the need of cholecystectomy, to evaluate whether gallbladder involvement could be treated only medically, and to determine whether EGPA individuals or patients with a high suspicion of EGPA, who have cholecystitis, could start steroids with or without immunosuppressors under close observation during clinical follow-up, therefore, avoiding overtreatment especially operations in these patients to improve life quality and prognosis. In summary, diagnosis of EGPA was often delayed due to a lack of classic symptom recognition. EGPA should be suspicious when cholecystitis is associated with hypereosinophilia. Radiological and pathological examinations are important means to confirm the diagnosis. Moreover, timely diagnosis and correct administration in the early stage of EGPA could significantly change the prognosis. Acknowledgments This work was supported by Dr. Liang Zhu, MD, Department of Rheumatology, Second affiliated hospital, School of medicine, Zhejiang University, Hangzhou, China, who revised the data. Disclosures All authors declare that there are no conflicts of interest.
References 1. Wolf M, Rose H, Smith RN (2005) Case records of the Massachusetts General Hospital. Case 28-2005. A 42-year-old man with weight loss, weakness, and a rash. N Engl J Med 353(11):1148– 1157 2. Churg J, Strauss L (1951) Allergic angiitis and periarteritis nodosa. Am J Pathol 27:277–301
3. Noth I, Strek ME, Leff AR (2003) Churg-Strauss syndrome. Lancet 361:587–594 4. Pagnoux C, Guillevin L (2010) Churg-Strauss syndrome: evidence for disease subtype? Curr Opin Rheumatol 22:21 5. Masi AT, Hunder GG, Lie JT, Michel BA, Bloch DA, Arend WP et al (1990) The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 33:1094–1100 6. Nishie M, Tomiyama M, Kamijo M, Kannari K, Tanosaki M, Baba M (2003) Acute cholecystitis and duodenitis associated with Churg-Strauss syndrome. Hepatogastroenterology 50: 998–1002 7. Saka N, Seo T, Shimano K, Kashiba K, Mori T, Sakagami M (2009) A case of Churg-Strauss syndrome with refractory otitis media. Auris Nasus Larynx 36(1):79–81 8. Ben-Chetrit E, Amir G, Shalit M (2005) Cetirizine: an effective agent in Kimura’s disease. Arthritis Rheum 53(1):117–118 9. Imai H, Nakamoto Y, Nakajima Y, Sugawara T, Miura AB (1990) Allergic granulomatosis and angiitis (Churg-Strauss syndrome) presenting as acute acalculous cholecystitis. J Rheumatol 17: 247–249 10. Boggi U, Mosca M, Giulianotti PC, Naccarato AG, Bombardieri S, Mosca F (1997) Surviving catastrophic gastrointestinal involvement due to Churg-Strauss syndrome: report of a case. Hepatogastroenterology 44(16):1169–1171 11. Kalyoncu A, Karakaya G, Sahin A, Artvinli M (2001) Experience of 10 years with Churg-Strauss syndrome: an accompaniment to or a transition from aspirin-induced asthma? Allergol Immunopathol (Madr) 29(5):185–190 12. Tatsukawa H, Nagano S, Umeno Y, Oribe M (2003) Churg-Strauss syndrome with cholecystitis and renal involvement. Intern Med 42: 893–896 13. Suzuki M, Nabeshima K, Miyazaki M, Yoshimura H, Tagawa S, Shiraki K (2005) Churg-Strauss syndrome complicated by colon erosion, acalculous cholecystitis and liver abscesses. World J Gastroenterol 11(33):5248–5250 14. Rolla G, Tartaglia N, Motta M, Ferrero N, Bergia R, Guida G et al (2007) Warning nonrespiratory symptoms in asthma: catastrophic abdominal involvement in a case of a Churg-Strauss syndrome. Ann Allergy Asthma Immunol 98(6):595–597 15. Francescutti V, Ellis AK, Bourgeois JM, Ward C (2008) Acute acalculous cholecystitis: an unusual presenting feature of ChurgStrauss vasculitis. Can J Surg 51(6):E129–E130 16. Yüksel I, Ataseven H, Başar O, Köklü S, Ertuğrul I, Ibiş M et al (2008) Churg-Strauss syndrome associated with acalculous cholecystitis and liver involvement. Acta Gastroenterol Belg 71(3):330–332 17. Sironen RK, Seppä A, Kosma VM, Kuopio T (2010) Churg-Strauss syndrome manifested by appendicitis, cholecystitis and superficial micronodular liver lesions—an unusual clinicopathological presentation. J Clin Pathol 63(9):848–850 18. Lenders G, Goethals M, Verstreken S, Dierckx R, Vanderheyden M (2011) Acalculous cholecystitis and tamponade: an unusual combination? Acta Cardiol 66(3):383–385 19. LiVolsi VA, Perzin KH, Porter M (1973) Polyarteritis nodosa of the gallbladder, presenting as acute cholecystitis. Gastroenterology 65(1):115–123 20. Guillevin L, Cohen P, Gayraud M, Lhote F, Jarrousse B, Casassus P (1999) Churg-Strauss syndrome: clinical study and long-term followup of 96 patients. Medicine (Baltimore) 78:26–37 21. Pagnoux C, Mahr A, Cohen P, Guillevin L (2005) Presentation and outcome of gastrointestinal involvement in systemic necrotizing vasculitides: analysis of 62 patients with polyarteritis nodosa, microscopic polyangiitis, Wegener granulomatosis, Churg-Strauss syndrome, or rheumatoid arthritis-associated vasculitis. Medicine (Baltimore) 84(2):115–128
Clin Rheumatol 22. Cohen P, Pagnoux C, Mahr A, Arene JP, Mouthon L, Le Guern V et al (2007) Churg-Strauss syndrome with poor-prognosis factors: a prospective multicenter trial comparing glucocorticoids and six or 12 cyclophosphamide pulses in 48 patients. Arthritis Rheum 57:686–693 23. Baldini C, Talarico R, Della Rossa A, Bombardieri S (2010) Clinical manifestations and treatment of Churg-Strauss syndrome. Rheum Dis Clin North Am 36(3):527–543. doi:10.1016/j.rdc.2010.05.003, Epub 2010 Jun 20 24. Alfaro TM, Duarte C, Monteiro R, Simão A, Calretas S, Nascimento Costa JM (2012) Churg-Strauss syndrome: case series. Rev Port Pneumol 18(2):86–92 25. Della Rossa A, Baldini C, Tavoni A, Tognetti A, Neglia D, Sambuceti G et al (2002) Churg-Strauss syndrome: clinical and serological features of 19 patients from a single Italian centre. Rheumatology (Oxford) 41:1286–1294
26. Solans R, Bosch JA, Perez-Bocanegra C, Selva A, Huguet P, Alijotas J et al (2001) Churg-Strauss syndrome: outcome and long-term follow-up of 32 patients. Rheumatology (Oxford) 40:763–771 27. Oh MJ, Lee JY, Kwon NH, Choi DC (2006) Churg-Strauss syndrome: the clinical features and long-term follow-up of 17 patients. J Korean Med Sci 21(2):265–271 28. Comarmond C, Pagnoux C, Khellaf M, Cordier JF, Hamidou M, Viallard JF et al (2013) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study Group cohort. Arthritis Rheum 65(1):270–281. doi:10.1002/art.37721 29. Ribi C, Cohen P, Pagnoux C, Mahr A, Arene JP, Lauque D et al (2008) Treatment of Churg-Strauss syndrome without poorprognosis factors: a multicenter, prospective, randomized, openlabel study of 72 patients. Arthritis Rheum 58:586–594
CASE BASED REVIEW
Eosinophilic granulomatosis with polyangiitis complicated by cholecystitis: a case report and review of the literature Lu Ye & Xiaoyong Lu & Jing Xue
Received: 15 January 2014 / Revised: 28 January 2014 / Accepted: 29 January 2014 # Clinical Rheumatology 2014
Abstract The objectives are to report an atypical case of eosinophilic granulomatosis with polyangiitis (EGPA) associated with cholecystitis and to review the main clinical features, therapy, and prognosis of it. We present a 49-year-old male with non-classic clinical manifestations of EGPA and EGPArelated cholecystitis. EGPA was diagnosed by histology of the gallbladder after cholecystectomy. In addition, 11 cases of EGPA-associated cholecystitis have been reported and were described in details in this article. Gallbladder involvement is very uncommon in EGPA. All cases reviewed showed multiple organs involved as well as obviously elevated eosinophilic granulocyte proportion with inflammatory index, although antineutrophil cytoplasmic antibody may be negative. All patients in this cohort that showed gallbladder involvement were eventually confirmed with EGPA by histology examination after cholecystectomy. The pathological change could be infiltration of inflammatory mononuclear cells of small- and medium-sized vessels. Of the cases, 91.7 % responded well to steroid and immunosuppressant therapy. Gallbladder involvement is a very rare comorbid condition in EGPA. However, it is an important symptom or secondary condition to alert physicians the diagnosis of EGPA. Moreover, timely diagnosis and correct administration in the early stage of this disease could obviously improve the prognosis.
Keywords Characteristics . Cholecystitis . Eosinophilic granulomatosis with polyangiitis . Histology
L. Ye : X. Lu : J. Xue (*) Department of Rheumatology, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, 310009 Hangzhou, Zhejiang Province, People’s Republic of China e-mail: [email protected]
Introduction Eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg-Strauss syndrome, is an autoimmune systemic vasculitis with peripheral eosinophilic infiltration of unknown origin [1–4]. American College of Rheumatology (ACR) proposed diagnostic criteria as four of the following six features being necessary for EGPA: allergic asthma, transient pulmonary infiltrates, hypereosinophilia, neuropathy, paranasal sinus abnormality, and extravascular eosinophils on biopsy [5]. However, some cases can manifest atypical symptoms or uncommon complications (e.g., cholecystitis [6], refractory otitis media [7]), which make the diagnosis of EGPA rather difficult to be established. Here, we present an atypical case of EGPA associated with cholecystitis, which was diagnosed by histology of the gallbladder after cholecystectomy.
A case report A 49-year-old male presented to us with recurrent fever, occasional abdominal pain, and multiple subcutaneous nodules on his scalp, forehead, and right forearm. His hemogram showed white blood cell count (WBC) 20.9×109/L, with 57.2 % eosinophils. Bone marrow aspiration revealed activating hematopoiesis with significantly increased eosinophils at the level of 42.5 %. Endoscopy demonstrated multiple ulcers in gastric antrum. He was diagnosed as eosinophilic gastroenteritis before his admission in our hospital and treated with low dose of oral prednisone and omeprazole for 1 month. Thereafter, his body temperature rapidly decreased to the normal level, and the subcutaneous nodules obviously improved at that time. However, after withdrawal of prednisone, his abdominal pain and subcutaneous nodules recurred with the development
Clin Rheumatol
of slight numbness in his feet; therefore, he visited our department. Physical examination revealed multiple subcutaneous nodules with 1∼2×1∼2 cm size on his scalp, forehead, and right forearm. The nodules were moderately firm, moveable, poorly defined, and non-tender. In routine clinical investigations, his hematologic test showed WBC 17.0×109/L, with 43.6 % eosinophils. Creactive protein (CRP) was elevated to 62.0 mg/L. Antineutrophil cytoplasmic antibody (ANCA), anti-nuclear antibodies, erythrocyte sedimentation rate (ESR), and all tumor markers were negative. Therefore, these signs indicate the suspicious of eosinophilic gastroenteritis, idiopathic hypereosinophilic syndrome, EGPA, as well as Kimura’s disease (a rare, benign lymphoproliferative and chronic inflammation disorder) [8]. Interestingly, he had experienced slight rhinitis, but without steroid or anti-allergy medication, he sustained complete clinical remission for over 4 years. Therefore, sinonasal CT scan was carried out for detailed information, and the result demonstrated the inflammatory lesions of paranasal sinus. In addition, electromyogram analysis of his extremities demonstrated mononeuritis multiplex. Skin biopsy was initially performed, and it showed infiltration of many eosinophils. Abdominal ultrasonography revealed a thickened gallbladder wall and a hypoechoic mass inside the gallbladder, which could be an implication of cancer. Consistent with ultrasonography findings, abdominal CT images could not exclude gallbladder cancer (Fig. 1). Indeed, paraneoplastic syndrome caused by cholecystic carcinoma could be a reasonable explanation for any clinical manifestation in the present patient. Therefore, cholecystectomy was performed, and histological changes of the gallbladder were analyzed. Finally, histopathologic results were consistent with EGPA which demonstrated peri-vascular, focally granulomatous inflammation with many eosinophils and eosinophil-rich necrotizing vasculitis (Fig. 2). Given his history of eosinophilia, mononeuritis multiplex, paranasal sinus abnormality, and histology-proven eosinophilic granulomatous necrotizing vasculitis, the patient fulfilled the ACR’s diagnostic criteria for EGPA. Because his response to the low dose of steroid was dramatically good according to his medical record, oral methylprednisolone (16 mg daily for 7 days, then 12 mg daily for 1 month, and gradually reduced to 4 mg daily within 2 months) was applied. His subcutaneous nodules disappeared, and limb numbness was gradually improved, without recurrent fever and abdominal pain. His WBC was reduced to 12.2×109/L, with a decreased EO to below 1.55×109/L.
Fig. 1 Abdominal CT found thickening in the gallbladder wall and a 1.8 cm×1.6 cm sized mass inside the gallbladder
articles from 1951 to December 2013. The articles were restricted to English language only. Articles with important data missing or without full texts were excluded. Finally, the search criteria identified 8,513 articles, of which 11 full-text articles presenting EGPA patients complicated by cholecystitis with detailed clinical and laboratory data were reviewed. Twelve patients [6, 9–18] (including our case) were analyzed including age, disease onset, gender, disease duration, clinical features, pathologic changes, radiological images, therapies, and prognosis (Table 1). The age range of disease onset in the reviewed articles was from 21 to 65 years, with the mean age of 43.75±14 years. The male to female ratio was 6:6, and disease duration was from 2 to 240 days, with the average duration of 87.38± 105.87 days. Of the patients, 83.3 % (10 /12) had follow-up information, and the mean duration was 16.98±24.75 months. All the 12 patients were diagnosed by histological examination of the gallbladder after cholecystectomy. Pathologic changes varied in these studies, including eosinophilic with/without other inflammatory mononuclear cells infiltration, granulomatous vasculitis, necrotizing vasculitis of smalland medium-sized vessels, and necrosis of the gallbladder. Associated clinical manifestations for the 12 cases were described in details. Besides abdominal pain, respiratory symptom was the most common clinical feature, including
Literature review A systematic review of the literature was performed by using the subject term “Cholecystitis” in PubMed database to search
Fig. 2 Histological examination of the gallbladder revealed eosinophilrich necrotizing vasculitis with organized thrombi
Clin Rheumatol Table 1 Comparison of the case reports on eosinophilic granulomatosis with polyangiitis-induced cholecystitis Author
Age/ gender
Organ involved
ANCA
CRP (mg/L)
ESR (mm/h)
Eosinophil (%)
Histology-proven cholecystic vasculitis
Therapy
Imai et al. [9] Boggi et al. [10] Kalyoncu et al. [11] Nishie et al. [6]
51/F 29/F 36/M 36/M
B, M, N B, G, J, S B, G, L, M, N, P, R G, L, M, P
NA NA NA −
29 NA NA 4.7
50 NA 75 47
58 40.60 15.80 70.98
+ + + +
Steroid Steroid CYC Steroid Steroid
Tatsukawa et al. [12] Suzuki et al. [13] Rolla et al. [14] Francescutti et al. [15] Yüksel et al. [16] Sironen et al. [17] Lenders et al. [18] Present case
50/F 21/F 55/M 38/F 65/M 64/M 31/F 49/M
B, G, M, N, R B, G, L, P B, N, P B, G, P G, L, S B, G, L, U B, H, P G, N, P, S
+ NA NA − NA + − −
3 2.5 0.11 17.5 NA NA NA 62
NA NA 75 59 NA NA NA 15
35 56 12 42.70 39 3.57 50 43.60
+ + + + + + + +
Steroid Steroid Steroid CYC Steroid Steroid Steroid AZA Steroid Steroid
B bronchial asthma, G gastrointestinal tract, H heart, J joint, L lung, M muscle, N nervous system, P pansinusitis/sinusitis, R renal, S skin, U hematuria, AZA azathioprine, CYC cyclophosphamide, NA not available
asthma (9/12), sinusitis (6/12), and lung involvement (5/12). Other systems involved included skin (1/12), heart (1/12), nervous system (4/12), renal (3/12), as well as joint (1/12) and muscle (4/12). Abnormalities in laboratory findings including eosinophilia, ANCA-positive ratio, and elevated levels of ESR and CRP were 100 % (12/12), 33.3 % (2/6), 83.3 % (5/6), and 100 % (7/7), respectively.
Discussion EGPA is a rare granulomatous necrotizing vasculitis characterized by diffuse involvement of small- to medium-sized vessels and multiple organs with eosinophilic infiltration, which was first described by Churg and Strauss in 1951 [2]. It was reported that 41 % of patients with EGPA could develop abdominal pain due to gastroduodenal/colorectal ulcers, gastritis, intestinal occlusion, appendicitis, or pancreatitis [20]. Cholecystitis has been reported to be a possible association with systemic vasculitis in recent case series, such as polyarteritis nodosa (PAN), with the incidence of 10–40 % of PAN patients that may have vascular lesions in the gallbladder at autopsy [19]. In a large cohort of EGPA patients, which was reported by Guillevin et al. [20] in 1999, only 1 in 96 patients developed cholecystitis during 32 years of follow-up. Similar prevalence (1/62) was also reported in another cohort of 62 EGPA patients [21]. More recently, Lenders et al. [18] described a patient with hypereosinophilia presenting cardiac tamponade and acalculous cholecystitis; subsequently, EGPA was diagnosed by histology. However, cholecystitis is an extremely rare complication in EGPA, as only 14 cases had been reported previously.
Besides clinical features, radiological images and histology are both key points in confirming the diagnosis. In these patients reviewed, abdominal ultrasonography during routine clinical investigation may provide important indication of gallbladder involvement, with the characteristic Doppler signals as a thickened gallbladder wall, with or without solitary calculus, sludge, or pericholecystic fluid in the gallbladder [17]. In addition, the most common finding of abdominal CT scan is usually consistent with ultrasonography detection. To date, histological examination remains the gold standard to confirm a diagnosis of EGPA. Pathological changes with typical description are eosinophilic infiltration, granulomatous inflammation, and necrotizing vasculitis. It was considered the classic pathological features of the gallbladder as eosinophilic infiltration and necrotizing vasculitis of small- to mediumsized vessels by some authors [14, 17, 18], whereas Boggi et al. [10] described the pathological change as mononuclear inflammatory infiltration without eosinophils. Moreover, in the present case, the presence of eosinophil-rich necrotizing vasculitis was found, and some of the affected vessels also show organized thrombi. Therefore, histological analysis of gallbladder involvement differs in EGPA patients, with the most common observation of small- to medium-sized vessel vasculitis, although eosinophil-rich infiltration may not exist. Intriguingly, all of the previous studies indicated that a good prognosis was based on effective therapy in the early stage, and prednisolone administration for patients with vasculitis in the end stage was shown to be non-sensitive [22, 23]. Therefore, the important role of prompt diagnosis and correct administration in the early stage of patients with atypical symptoms should be emphasized, which may significantly change the fatal outcome and prognosis.
Clin Rheumatol
The 1-year survival rate is 90 % for the general population of EGPA patients [24], and the major factors related to poor clinical outcomes are severe cardiac involvement, such as myocardial infarction as well as cardiac insufficiency, and gastrointestinal involvement including hemorrhage, perforation, and pancreatitis [20, 21, 25–29]. Consistent with these data, the prognosis was also encouraging in the limited number of patients reviewed, with a 1-year survival rate of 91.7 %. Moreover, the majority of them achieved sustained remission after corticosteroid administration, and only 25 % (3/12) combined with immunosuppressants (including cyclophosphamide and azathioprine), excluding one patient who died due to cardiac arrest. Although the limited number of subjects attributed to the difficulties in making a firm conclusion, we hypothesize EGPA individual associated with cholecystitis without involvement of other vital organs receives good outcomes. However, the necessity of gastrointestinal involvement is ignored in current classification criteria. Moreover, in these patients reviewed, all the subjects underwent cholecystectomy to draw a firm evidence of EGPA, whereas in most previous large cohort studies, gastrointestinal manifestations were listed, but without further detail for which kind of gastrointestinal involvement that was. Thus, further studies are needed to classify the features and subtypes of gastrointestinal involvement, to comment the need of cholecystectomy, to evaluate whether gallbladder involvement could be treated only medically, and to determine whether EGPA individuals or patients with a high suspicion of EGPA, who have cholecystitis, could start steroids with or without immunosuppressors under close observation during clinical follow-up, therefore, avoiding overtreatment especially operations in these patients to improve life quality and prognosis. In summary, diagnosis of EGPA was often delayed due to a lack of classic symptom recognition. EGPA should be suspicious when cholecystitis is associated with hypereosinophilia. Radiological and pathological examinations are important means to confirm the diagnosis. Moreover, timely diagnosis and correct administration in the early stage of EGPA could significantly change the prognosis. Acknowledgments This work was supported by Dr. Liang Zhu, MD, Department of Rheumatology, Second affiliated hospital, School of medicine, Zhejiang University, Hangzhou, China, who revised the data. Disclosures All authors declare that there are no conflicts of interest.
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