A Pediatric Patient with Severe Churg-Strauss Syndrome Tohoku J. Exp. Med., 2011, 225, 117-121
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Successful Multidrug Treatment of a Pediatric Patient with Severe Churg-Strauss Syndrome Refractory to Prednisolone Shojiro Watanabe,1 Tomomi Aizawa-Yashiro,1 Kazushi Tsuruga,1 Toru Takahashi,1 Etsuro Ito1 and Hiroshi Tanaka1,2 1
Department of Pediatrics, Hirosaki University Hospital, Hirosaki, Japan Department of School Health Science, Hirosaki University Faculty of Education, Hirosaki, Japan
2
Churg-Strauss syndrome (CSS), which is characterized by systemic small-vessel vasculitis of unknown etiology, is associated with a history of asthma. Although reports of CSS occurring in children are limited, effective treatment of pediatric patients with severe CSS remains challenging. A 10-year-old Japanese boy with a 6-month history of asthma treated with a leukotriene modifier, pranlukast, developed high fever, pleural infiltration, and pericarditis that were associated with marked hypereosinophilia (10,350 eosinophils/ μl). Owing to his persistent high fever, mononeuritis multiplex, and severe abdominal pain that was refractory to prednisolone, his general condition progressively deteriorated thereafter. Although intravenous high-dose immunoglobulin administration was transiently effective for mononeuritis multiplex, the recurrent high fever and severe abdominal pain remained refractory. An endoscopic study revealed ulcerative lesions of the total colon. In this context, we treated the patient with an aggressive multidrug immunosuppressive regimen consisting of a high-dose methylprednisolone pulse plus short-course intravenous cyclophosphamide pulse therapy, followed by oral tacrolimus combined with prednisolone. After the rescue multidrug treatment, his severe clinical signs dramatically subsided within a short time, and the concomitantly administered prednisolone was successfully tapered without flare. At present, 12 months after the presentation, he is free from CSS signs or therapy-related toxicity except for an occasional mild asthma attack. Although further close observation should be needed to draw a long-term outcome in this patient, we believe that aggressive multidrug immunosuppressive treatment should be considered as an alternative rescue treatment in selected patients with severe CSS, even with pediatric-onset disease, that is refractory to prednisolone. Keywords: Churg-Strauss syndrome; colon ulcer; multidrug therapy; pranlukast; severe abdominal signs Tohoku J. Exp. Med., 2011, 225 (2), 117-121. © 2011 Tohoku University Medical Press developed typical CSS signs and severe gastrointestinal involvement that was refractory to prednisolone (PDN). Because of the rapid deterioration of his general condition, we initiated the aggressive immunosuppressive treatment consisting of intravenous high-dose methylprednisolone pulse therapy (MPT) plus a short-course cyclophosphamide pulse (IVCY), followed by oral tacrolimus (Tac) combined with PDN. This rescue treatment resulted in a dramatic remission without therapy-related clinical toxicity. Aggressive multidrug immunosuppressive treatment should be considered immediately in cases of severe CSS, even in pediatric patients.
Churg-Strauss syndrome (CSS) shows protean clinical manifestations due to systemic vasculitic syndrome. It has been reported that pulmonary, cardiac, and gastrointestinal involvements are predominant in pediatric CSS cases compared to that seen in adult cases, and these clinical signs are hallmarks of a worse prognosis (Boyer et al. 2006; Zwerina et al. 2008). Since CSS is an uncommon disease entity in children, the treatment of pediatric patients with CSS, especially in severe cases, remains challenging (Ikemoto et al. 2001; Boyer et al. 2006; Zwerina et al. 2008; Domircin et al. 2010). Regarding the etiology of CSS, some case reports have suggested an association between the onset of CSS and the use of leukotriene modifiers for the treatment of pre-existing asthma (Kobayashi et al. 2003; Boyer et al. 2006; Salerno et al. 2010), although this remains speculative (Harrold 2007). We experienced an informative case of severe CSS with a relatively short-term history of asthma treated with a leukotriene modifier, pranlukast. The patient
Clinical Report A 10-year-old Japanese boy with a 6-month history of mild asthma and allergic rhinitis was referred to our hospital because of persistent high fever, numbness of the right lower extremity, and subsequent development of severe
Received August 9, 2011; revision accepted for publication August 31, 2011. doi: 10.1620/tjem.225.117 Correspondence: Hiroshi Tanaka, M.D., Ph.D., Department of Pediatrics, Hirosaki University Hospital, Hirosaki, 036-8563, Japan. e-mail:
[email protected]
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abdominal pain. A chest X-ray revealed an enlarged cardiothoracic ratio (64%) with pulmonary infiltration. A peripheral blood examination showed a white blood cell (WBC) count of 23,000 cells/μl with 45% eosinophils and C-reactive protein (CRP) levels of 8.0 mg/100 ml. A bone marrow examination revealed no signs of malignancy. Thus, hypereosinophilic syndrome (HES) complicated with pericarditis was suspected at a regional hospital. His family history was unremarkable. He had experienced an asthma attack 6 months before the presentation, and treatment with a leukotriene modifier, pranlukast, was started at that time. At the time of first asthma attack, his serum IgE and CRP levels were 560 IU/ml (normal, < 250 IU/ml) and 0.1 mg/100 ml (normal, < 0.3 mg/100 ml), respectively, and a peripheral WBC count was 10,280 cells/μl without eosinophils. A month before the presentation, he experienced another asthma attack with a peripheral WBC count of 20,100 cells/μl with 16% eosinophils and serum CRP level of 0.67 mg/100 ml. Thereafter, a peripheral eosinophil count progressively increased to 51% of total WBC count. Except for asthma attack, he had experienced occasional pain on the posterior surface of his right thigh, which diminished spontaneously. Upon admission to our hospital, the patient showed body temperature of 37.9°C, heart rate of 120/min, respiratory rate of 20/min, and blood pressure of 120/80 mmHg. A physical examination revealed tenderness in the middle of the abdomen, and numbness and pain of the right foot and hand. Skin lesions and sinusitis were absent. Laboratory examinations revealed a significantly increased eosinophil count of 15,400/μl (46% on differential WBC count of 33,480 cells/μl) and serum immunoglobulin E levels of 3,773 IU /ml. Serum CRP levels were increased to 11.3 mg/100 ml. Neither serum anti-neutrophil cytoplasmic antibodies (ANCA, anti-proteinase 3 or anti-myeloperoxidase antibodies) nor anti-dsDNA antibody were present. A urine analysis was unremarkable. Serum soluble interleukin-2 receptor levels were increased to 2,980 U/ml (normal, 145-519 U/ml), suggesting the presence of residual hyper proinflammatory cytokinemia. An echocardiogram revealed pericardial effusion with an ejection fraction of 64%. A nerve conduction study showed the presence of axonopathy of the right median, tibial and sural nerves. The patient was diagnosed with CSS in accordance with the American College of Rheumatology classification criteria (history of asthma, eosinophilia greater than 10% on differential WBC count, pulmonary infiltrates and neuropathy). Treatment with pranlukast was discontinued, and PDN at a dose of 30 mg (1.5 mg/kg) daily was initiated. However, his severe abdominal and left leg pain persisted. Since he was in around near-pubertal age, we avoided the use of IVCY at that time. The patient was, therefore, initially treated with high-dose immunoglobulin therapy (IVIG, 1 g/kg daily for 2 consecutive days), which was combined with a dose escalation of PDN to 40 mg daily (2 mg/kg). This regimen proved to be transiently effective for the mononeuritis mul-
tiplex (Taniguchi et al. 2007). Since he became aphagic and exhibited a deterioration of his general condition thereafter due to the unremitting severe abdominal pain, total parenteral nutrition and pain control with opioids were required. An endoscopic study and biopsy revealed ulcerative lesions of the total colon (Fig. 1A). However, microscopic examination did not confirm the typical lesion of granulomatous angiitis with eosinophil infiltrates in the specimen (Fig. 1B). The lesion might be influenced by the timing of histologic examination and the prolonged PDN treatment. An effect of tumor necrosis factor (TNF)-α blockade using infliximab (5 mg/kg) combined with MPT (25 mg/kg on 3 consecutive days a week for 3 weeks) was only transient, and recurrent fever and severe abdominal pain persisted for approximately 4 months longer. An additional trial of intravenous cyclosporine A (CsA) administration with trough blood levels of the drug around 100 ng/ml did not show any relief for his condition. Because of his long-term bed rest, he progressively exhibited body weight loss and generalized weakness, in addition to steroid-induced hypertension. In order to rescue his condition, another aggressive immunosuppressive therapy consisting of mini-MPT (20 mg/kg for 3 days) plus a short-course of IVCY (0.5 g per 4 weeks on 3 months) followed by oral Tac (0.1 mg/day with trough blood levels of the drug around 5 ng/ml) combined with PDN was initiated. After this rescue regimen, his severe abdominal pain, as well as remittent fever and leg pain, dramatically subsided within a month. Concomitantly administered PDN was successfully tapered without relapse. At present, 12 months after the initial presentation, he is free from CSS signs. He is on Tac, 3 mg (0.1 mg/kg) daily, and PDN, 5 mg (0.17 mg/kg) daily. He is now a very well schoolchild without any therapy-related clinical toxicities except for an occasional mild asthma attack, which is treated with fluticasone/salmeterol inhalation.
Discussion It has been reported that childhood CSS is rare, and the features of the disease in children have not been fully understood (Ikemoto et al. 2001; Kobayashi et al. 2003; Boyer et al. 2006; Zwerina et al. 2008; Kawakami and Soma 2009; Mutsaers et al. 2009; Domircin et al. 2010; Salerno et al. 2010). Regarding serum ANCA positivity, relatively low frequency in children with CSS, about 25%, were reported to be positive for serum ANCA (Zwerina et al. 2008), which is different from that of adults with CSS. This discrepancy suggests that the possible pathogenetic heterogeneity of CSS may exist between children and adults, although this remains to be examined in future studies. Although many aspects of CSS are similar in childhood and adult patients, cardiopulmonary and gastrointestinal involvements are reported to be predominant in pediatric CSS (Zwerina et al. 2008). Moreover, such severe organ involvements are attributable to a worse prognosis and mortality (Zwerina et al. 2008). Like our patient, some cases
A Pediatric Patient with Severe Churg-Strauss Syndrome
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Fig. 1. Endoscopic and microscopic examinations of the ulcerative lesion of the patient. A. An endoscopic study of the sigmoid colon of the patient. Note a multiple ulcerative lesions were seen. B. A microscopic examination of the ulcerative lesion in the rectum of the patient. A region of eosonophilic infiltration associated with possible granulomatous changes (left upper circle), interstitial edema (left arrow) and crypt atrophy (right arrow) were observed. Perivascular infiltrates by inflammatory cells associated with bleeding were also observed (right lower circle). (Hematoxilin & eosin staining, × 40)
exhibiting multiple colonic ulcers associated with CSS have been reported (Shimamoto et al. 1990; Berarducci et al. 1996; Lin et al. 2001). However, the treatment of pediatric patients with CSS, especially in severe cases, remains challenging (Ikemoto et al. 2001; Boyer et al. 2006; Zwerina et al. 2008; Domircin et al. 2010). We have described a pediatric patient with CSS whose symptoms were characterized mainly by unremitting severe abdominal pain that was refractory to PDN combined with several immunosuppressive agents, such as IVIG, MPT combined with infliximab, and CsA. Because of his unfavorable condition, long-term total parenteral nutrition, pain control with opioids, and bed rest were required. Although the efficacy of IVIG for neuritis signs of CSS has been reported (Taniguchi et al. 2007), IVIG showed only transient benefit in our patient. This might be partly because his severe abdominal signs were
not attributable to intestinal neuritis but to ulcerative lesions of the total colon. However, a regimen of MPT combined with infliximab plus CsA was, unexpectedly, not effective in relieving his condition. In addition, the patient developed steroid-induced hypertension. In this context, we chose mini-MPT plus short-course IVCY followed by Tac for the treatment of this refractory CSS patient. To decrease clinical toxicity, MPT was performed only on the initial consecutive 3 days followed by 3 times of IVCY, and then, Tac, as maintenance therapy, was initiated, since we have previously experienced the efficacy and safety of Tac for the treatment of children with systemic-onset juvenile idiopathic arthritis and lupus nephritis (Tanaka et al. 2007, 2009). Also, Niiyama et al. (2010) recently reported the efficacy of Tac in a patient with CSS. As a result, his abdominal signs dramatically subsided, leading to a signifi-
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cant improvement of his general condition. Also, concomitantly administered PDN was successfully tapered without flare. His steroid-induced hypertension gradually subsided. Although gastrointestinal involvement is reported to be higher in children with CSS than that in adults with CSS (Zwerina et al. 2008), long-lasting severe abdominal signs, as observed in our patient, have rarely been reported. Since massive use of corticosteroids increases the risk of intestinal perforation (Venditti et al. 2011), we suggest that an aggressive immunosuppressive regimen including Tac is beneficial for children with refractory CSS like our case, although further studies are needed. Some previous reports have suggested a potentially causal relationship between treatment with leukotriene modifiers and the onset of CSS (Kobayashi et al. 2003; Boyer et al. 2006; Kanda et al. 2010; Salerno et al. 2010,). It has been postulated that the occurrence of CSS in some patients treated with leukotriene modifiers may be related to a residual underlying vasculitic syndrome (Boyer et al. 2006; Salerno et al. 2010). However, some case reports have suggested clear causal association between the use of leukotriene modifiers and CSS (Kobayashi et al. 2003; Kanda et al. 2010). In our patient, CSS occurred following significant hypereosinophilia, which developed after a 6-month course of pranlukast treatment, which is similar to a previous report by Kobayashi et al. (2003). From the clinical course of our patient, marked eosinophilia emerged 5 months after the start of pranlukast, as described in the case presentation. Recently, Kanda et al. reported on an interesting adult patient with CSS, which occurred following a 15-month course of montelukast treatment (Kanda et al. 2010). They speculated that leukotriene modifiers block the effects of the cysteinyl leukotrienes but not the effects of leukotriene B4, which is a chemoattractant for eosinophils and neutrophils, and this theory may be attributable to the onset of CSS in their patient (Kanda et al. 2010). Since our patient presented with HES/CSS possibly due to pranlukast administration, we postulate that the same mechanism may be applicable in our patient, although this remains speculative. Also, the reason why this patient developed CSS in a short time, only 6 months, from the start of pranlukast remains speculative. Although CSS is rare in children, some pediatric patients may develop very severe CSS. Thus, it is essential to be aware of this disease entity, and prompt immunosuppressive therapy should be considered for a favorable outcome. However, further studies involving similar cases of CSS are needed to draw any conclusions.
Acknowledgments We thank Dr. H. Mizuno, Section of Pediatrics, Hiranai Chuo Hospital, for medical care of the patient at his hospital, Dr. N. Hanabata, Department of Gastroenterology, Hirosaki University Hospital for performing the endoscopic studies, Dr. M. Tanaka Department of Laboratory Medicine, Hirosaki City Hospital and Prof. H. Kijima, Department of Pathology Hirosaki University Graduate School of Medicine for the pathologic
examination.
Conflict of Interest The authors have no conflict of interest.
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