兒童急性淋巴性白血病患者於前導性化學治療期間發生由侵襲性麴菌症所造成的小腸穿孔

Transcription

1 台灣癌症醫誌 (J. Cancer Res. Pract.) 7(5),7-3, 0 Case Report journal homepage: Invasive Aspergillosis Causing Small Bowel Perforation During Induction Chemotherapy for Acute Lymphoblastic Leukemia in Children Yu-Wei Fu, Nien-Lu Wang *, Jin-Cherng Sheu, His-Che Liu, Ting-Chi Yeh, Yi-Chen Du, Chin-Hung Wei Division of Pediatric Surgery, Mackay Memorial Hospital, Taipei, Taiwan Division of Pediatric Hematology, Mackay Memorial Hospital, Taipei, Taiwan Abstract. We report on two pediatric patients suffering from acute lymphoblastic leukemia with small bowel perforation caused by invasive aspergillosis during their induction course of chemotherapy. A 4-year-old girl presented with neutropenic fever who developed massive gastrointestinal bleeding with shock 30 days after chemotherapy. Another -year-old boy had neutropenic fever and peritonitis which developed days after chemotherapy. Both patients underwent urgent laparotomies, and small bowel perforation was found in each child. Segmental resection of the involved intestine with primary anastomosis was performed. Microscopic examination revealed transmural necrosis and fungal invasion of the bowel. The two patients recovered uneventfully under intensive postoperative care, manifesting a good response to anti-fungal agents and further chemotherapies. Invasive intestinal aspergillosis is rare but life threatening, and should be kept in mind when neutropenic patients present with gastrointestinal symptoms and fever during chemotherapy. Prompt surgical intervention is required in case of intestinal perforation whereafter timely postoperative administration of anti-fungal therapy may decrease patient mortality. 病例報告 Keywords : aspergillosis, intestinal perforation, leukemia, chemotherapy 兒童急性淋巴性白血病患者於前導性化學治療期間發生由侵襲性麴菌症所造成的小腸穿孔 傅玉瑋 王念陸 * 許錦城 劉希哲 葉庭吉 杜奕成 魏晉弘 馬偕紀念醫院小兒外科 馬偕紀念醫院小兒血液腫瘤科 中文摘要我們報告兩例小兒急性淋巴性白血病患者, 皆於接受前導性化學治療期間, 發生由侵襲性麴菌症造成的小腸穿孔 一位十四歲少女以嗜中性白血球低下併發燒為初期表現, 在接受化療後第三十天, 發展成大量消化道出血併休克 另一位二歲的男孩, 亦患嗜中性白血球低下併發燒及在第二十一天產生腹膜炎 兩位病患皆接受緊急剖腹探查並發現小

2 8 Y. W. Fu et al./jcrp 7(0) 7-3 腸穿孔, 手術將穿孔小腸段切除後行直接吻合腸道 病理檢查下, 顯現全壁式壞死和肌層真菌侵犯 兩位患者術後在重症照顧之下都恢復順利, 對於抗黴菌藥物及後續化學治療都有良好的反應 侵襲性麴菌病發生在腸道相當罕見且危及生命 若嗜中性白血球低下患者, 於化療期間出現胃腸道症狀並發燒時, 需高度懷疑侵襲性麴菌症造成腸穿孔 如果發生腸穿孔, 需要及時手術治療 術後持續使用抗黴菌藥物治療可降低死亡率 關鍵字 : 麴菌病 腸道穿孔 白血病 化學治療 INTRODUCTION Invasive aspergillosis (IA) is a lethal fungal infection. It is a rare clinical entity with a high mortality rate that usually affects immunocompromised patients with malignancies undergoing chemotherapy (C/T). In recent years, the incidence of IA in these patients has risen, which is likely attributable to the growing use of increasingly effective but also increasingly cytotoxic C/T [,]. There is limited information about IA in children, and treatment outcomes in these pediatric patients are often unfavorable []. We herein report the successful management of IA causing small-bowel perforation in two children with neutropenia during induction C/T for acute lymphoblastic leukemia (ALL). CASE A 4-year-old girl with ALL was admitted for induction C/T. She received vincristine.5 mg/m, and epirubicin 0 mg/m intravenously, with each infusion five minutes in duration on days, 7, 4 and. She was also administered a total of nine doses of leunase 5,000 IU/m, given intramuscularly, every other day. On day 4 after this regimen, she exhibited remittent fevers up to 38 C. Her white blood cell (WBC) count was 500/µl and her neutrophil count was 0/µl. Broad spectrum antibiotics with meropenem, piperacillin/ *Corresponding author: Nien-Lu Wang M.D. * 通訊作者 : 王念陸醫師 Tel: Fax: nienlu.wang@msa.hinet.net tazobactam, amikacin, and teicoplanin and anti-fungal agent with amphotricin B IV were administrated. On day 6, methotrexate (MTX), hydrocortisone, and cytarabine (Ara-C) were given. On day 0, gastrointestinal (GI) bleeding and a high fever of 38.5 C developed. Microbiological studies were taken on day 0, including fungal cultures of blood, and both urine and stool were positive for Candida tropicalis infection. By this time the patient s WBC count and neutrophil count was 300/µl and 30/µl, respectively. Granulocyte colony-stimulating factor (G-CSF) 300 µg/day subcutaneously was then given for the neutropenia. Her platelet count was,000/µl after transfusion therapy. There was no specific finding on abdominal X-ray and ultrasound examinations. Initially, we treated the patient conservatively with empiric antibiotics, vasopressin, nitroglycerin, and anti-fungal agents with voriconazole and caspofungin, in addition to amphotricin B. But her condition had not improved after 0 days and a septic response was becoming more severe. Because of persistent GI bleeding with septic shock and a poor response to medical treatment, surgical intervention was indicated even if there was a high operative risk. An urgent laparotomy revealed necrosis with several perforations at the jejunum. We performed segmental resection of the necrotic jejunum with primary anastomosis. There was no blood transfusion during the operation. Postoperatively, G-CSF 00 µg/day was continued for 7 days. Macroscopically, there were several patches of necrosis with perforation on the jejunum. Pathological examination revealed transmural necrosis with perforations and branching hyphae invading the intestinal

3 Y. W. Fu et al./jcrp 7(0) A B Figure. A PAS 400x, B GMS 00x: Fungal spores and hyphae. The hyphae are thin with septate, and the branches are narrowly angulated. The features are consistent with aspergillosis wall (Figure ). Fungal spores and hyphae could be seen in Periodic acid-schiff (PAS) and Grocott methenamine silver (GMS) stained sections. The hyphae were thin with septate and the branches are narrowly angulated. These features were consistent with that of aspergillosis. The patient started eating on postoperative day (POD) 4. By POD 6, her WBC count and neutrophil count were 6,00/ul and,880/ul, respectively. Later, the follow-up chest computed tomography (CT) revealed a focal lesion in the left lower lung with suspected fungal infection. She also had intermittent stressed ulcer. Medical treatment was continued until full recovery. The patient was discharged uneventfully after finishing the recommended courses of C/T. CASE A year-old boy presented with ALL, and induction C/T was initiated. The patient received vincristine.5 mg/m, and idarubicin 8 mg/m as an i.v. infusion given over 5 minutes on days, 7, 4 and. On day 4 after C/T was begun, MTX, hydrocortison and Ara-C were given, and on day, leunase was given. On day, the patient complained of vague abdominal pain with abdominal distention, and hypoactive bowel sounds were noted. His WBC and neutrophil was,000/ul and 390/ul, respectively. The plain film x-ray and ultrasonography of the abdomen revealed intestinal ileus over the jejunal area and pneumoperitoneum in which intestinal perforation was apparent. On urgent laparotomy, there was significant fibrin coating and two necrotic patches with perforations were found at terminal ileum 0 cm and 5 cm away from the ileocecal valve. Primary anastomosis after resection of the diseased segments was performed and the patient recovered uneventfully with continuing anti-fungal agents with amphotericin B. Microscopically, the perforation tract is coated by fibrino-inflammatory exudate and necrotic tissue. Fungal spores and a few hyphae are seen in PAS and GMS stained sections. The level of serum galactomannan (GM) test for aspergillus antigen was 0.66 ng/ml, which was considered a positive result. However, microbiological cultures from blood, sputum, and urine and CT of the chest were all negative for fungal infection. On POD6, the patient started to eat, and he was discharged home uneventfully after the chemotherapy. Follow-up bone marrow tests disclosed complete remission.

4 30 Y. W. Fu et al./jcrp 7(0) 7-3 DISCUSSION Aspergillus is an inhaled fungus. Patients with a history of C/T, steroid treatment, immunomodulating agents, neutropenia or malignancies are at a high risk to be affected by this opportunistic organism [3]. The fungus is mainly localized in the areas of the lung and cranial sinuses, with secondary dissemination to the brain, GI tract, liver, and heart [3]. Prescott et al. reported that in immunocompromised patients with deep fungal infection, 4% had GI infection, with % of those affecting the lower part of the GI tract [4]. However, a report from Germany which analysed the autopsy records which showed a relatively low percentage of IA in the GI tract [5]. The lung is the most common portal of entry in disseminated aspergillosis. It is rare to find the isolated occurrence of intestinal aspergillosis without pulmonary disease. Most reported GI fungal infections had pulmonary involvement [3,5]. However, Eggimann et al. reported that the GI tract may also represent a portal of entry for immunocompromised patients with primary aspergillosis [6]. Published information about IA in children is rare. In Rubio s single center study, the incidence of IA in pediatric hematology oncology patients was about.96%, with a tendency towards an increasing incidence probably attributable to the use of more intensive cytotoxic C/T [,]. The presence of IA is also a marker of poor prognosis in immunocompromised patients with a global mortality rate as high as nearly 90% []. Early diagnosis of intestinal IA in a neutropenic patient is quite challenging because the presentations are usually insidious and non-specific such as GI bleeding, abdominal pain, and diarrhea [,3]. The blood cell counts or blood chemistry studies provide little information. Besides, the blood and sputum cultures are frequently not useful because they are often negative, with test results often delayed. Bronchoaveolar lavage (BAL), serum GM test and polymerase chain reaction (PCR) assay may provide some assistance for early diagnosis, but need further validation studies to differentiate between colonization and true infection [7]. IA can cause bowel infarction or diffuse peritonitis from a small bowel perforation. Abdominal contrast-enhanced CT is usually indicated in this situation but the findings may still be nonspecific. Findings of small bowel obstruction secondary to segmental mural thickening of the small intestine, diffuse small bowel distention, and inflammation of the perienteric fat may support the diagnosis of intestinal IA [8]. However, the final diagnosis is mostly made by the histopathologic examination of endoscopic biopsies or of the surgically resected bowel [9]. The organisms found in intestinal fungal infection were either Aspergillus with a tendency for transmural invasion or Candida with mucosal location [4]. Aspergillus invades and proliferates in the vessels, becoming an embolism with subsequent hematogenous dissemination. Chemotherapeutic toxicity may alter GI immunity, which allows entry of Aspergillus by disrupting mucosal barriers. Aspergillus invades blood vessels and therefore exhibits vascular occlusion, peripheral areas of hemorrhage and areas of secondary infarction. These areas are usually surrounded by superimposed necrotizing inflammatory tissue reactions. Aspergillus hyphae also proliferate in infarcted tissue and can extend radially into adjacent tissue. These features are identical in the lung, as well as in other organs involved with disseminated disease, including the GI tract [8]. If the small intestine had been a secondary site of disseminated disease, we should have located the primary lesion. Early detection of intestinal IA using adequate empiric anti-fungal agents may lead to successful IA management [6,9]. Reviewing the published literatures, few cases reported patient survival from complicated opportunistic invasive aspergillosis-induced intestinal perforation during C/T [,0,]. In the present report, the patients in both cases survived. Clinically, they developed neutropenic fever after the induction C/T. This

5 Y. W. Fu et al./jcrp 7(0) was followed by progressing GI bleeding and septic shock in the first case, and a sudden onset of abdominal pain and peritonitis in the second case. Furthermore, the first case is affected by disseminated fungal infection and the second by primary intestinal aspergillosis. Fortunately, both patients recovered well with prompt surgical intervention and subsequent anti-fungal therapy. We estimate that the mortality rate arising from intestinal IA will decrease with the early diagnosis and appropriate medical management. Medical teams should be aware of the possibility of IA involvement when taking care of immunocompromised patients with acute GI symptoms and fever even if there is no clinical pulmonary involvement. An early surgical approach is mandatory for diagnosis and removal of the affected bowel. Even if the primary lesion is surgically resected, anti-fungal agents should be continuously administered to improve patient outcomes []. REFERENCES. Rubio PM, Sevilla J, Gonzalez-Vicent M, et al. Increasing incidence of invasive aspergillosis in pediatric hematology oncology patients over the last decade: a retrospective single centre study. J Pediatr Hematol Oncol 3: , Tresallet C, Nguyen-Thanh Q, Aubriot-Lorton MH, et al. Small-bowel infarction from disseminated aspergillosis. Dis Colon Rectum 47: 55-58, Catalano L, Picardi M, Anzivino D, et al. Small bowel infarction by Aspergillus. Haematologica 8: 8-83, Prescott RJ, Harris M, Banerjee SS. Fungal infections of the small and large intestine. J Clin Pathol 45: 806-8, Schwesinger G, Junghans D, Schroder G, et al. Candidosis and aspergillosis as autopsy findings from 994 to 003. Mycoses 48: 76-80, Eggimann P, Chevrolet JC, Starobinski M, et al. Primary invasive aspergillosis of the digestive tract: Report of two cases and review of the literature. Infection 34: , Lopes da Silva R, Ribeiro P, Abreu N, et al. Early diagnosis of invasive aspergillosis in neutropenic patients comparison between serum galactomannan and polymerase chain reaction. Clin Med Insights Oncol 4: 8-88, Shah SS, Birnbaum BA, Jacobs JE. Disseminated aspergillosis inciting intestinal ischaemia and obstruction. Br J Radiol 74: 45-47, Kayiran P, Urganci N, Cetinkaya F, et al. Two children with invasive gastrointestinal aspergillosis. Indian Pediatr 44: , Enjoji M, Ohtsukasa S, Nagano H, et al. Localized small-bowel infarction caused by Aspergillus during chemotherapy for acute myeloid leukemia: report of a case. Surg Today 38: , Hayden JT, Wood KM, Pedler S, et al. Invasive aspergillosis of the small bowel in an infant with acute myeloid leukemia and intestinal obstruction. Pediatr Hematol Oncol 6: 84-9, Cohen R, Heffner JE. Bowel infarction as the initial manifestation of disseminated aspergillosis. Chest 0: , 99.