Neutropenic enteropathy: A 10-year review

Neutropenic Enteropathy: By Joanne

Baerg,

James

J. Murphy,

Vancouver,

Ron

British

Purpose: With the advent of more aggressive chemotherapy, the incidence of neutropenic enteropathy is increasing. This review was performed to (1) determine which children are affected, (2) identify predisposing factors, and (3) assess efficacy of treatment. Methods: A IO-year (1988 to 1997) review identified 33 children who had 38 episodes of neutropenic enteropathy. Each presented with fever, abdominal pain, and chemotherapy-induced neutropenia. All were treated with fluid resuscitation, bowel rest, and broad-spectrum antibiotics. Surgical intervention was reserved for children with bowel perforation. Results: Neutropenic enteropathy with hematologic malignancies This disease developed in three transplantation for leukemia. All rent episodes developed were

occurred in 24 children and nine with solid tumors. children after bone marrow five patients in whom recurreceiving chemotherapy for

N

EUTROPENIC ENTEROPATHY (typhilitis) is a disease process involving mucosal damage to the bowel, most commonly involving the terminal ileum and cecum. It occurs in the setting of malignancy and cytotoxic chemotherapy. The diagnosis is based on a symptom complex of fever, abdominal pain, and chemotherapy-induced neutropenia.lA Pediatric surgeons are frequently called on to evaluate children with this disease entity. The decision to operate on these high-risk patients can be extremely difficult. There is no consensus in the literature regarding treatment of these children. This prompted us to review our experience with these patients. MATERIALS

AND

METHODS

A retrospective chart review was performed on all cases of neutropenit enteropathy seen by the surgical service at British Columbia’s Children’s Hospital between January 1988 and May 1997. The patient’s medical record was reviewed to obtain age, sex, diagnosis, and

From the B.C. Children’s Hospital, Vancouver; British Columbia, Canada. Presented at the 30th Annual Meeting of the Canadian Association of Paediatric Surgeons, Toronto, Ontario, Cano& September 25-28, 1998. Address reprint requests to James J. Murphy, MD, FRCS, B.C. Children’s Hospital, 4800 Oak St, Room A242B, Vancouvel; British Columbia, Canada, V6H 3V4. Copyright 0 1999 by WB. Saunders Company 0022-3468/99/3407-0005$03.00/0

A lo-Year Review Anderson,

and

J. Fergall

Magee

Columbia

Burkitt’s lymphoma. Cytosine most commonly implicated children required laparotomy all survived. Overall survival

arabinoside and VP16 were the chemotherapeutic agents. Four and right hemicolectomy, and was 94%.

Conclusions: Although previously described in children receiving chemotherapy for hematologic malignancies, neutropenic enteropathy also occurs in children who have solid tumors and after bone marrow transplantation. The use of cytosine arabinoside and VP16 may predispose patients to this disease. Children receiving chemotherapy for Burkitt’s lymphoma are at increased risk for recurrent episodes. Excellent survival rate was attained with supportive care being used as the primary treatment modality.

J Pediatr Surg 34:1068-1071. Saunders Company. INDEX litis.

WORDS:

Neutropenic

Copyright

enteropathy,

o 1999 by W.B.

typhlitis,

enteroco-

chemotherapeutic regime. Number of days between administration of chemotherapy and onset of neutropenia, onset of neutropenic enteropathy, resolution of neutropenia, and resolution of neutropenic enteropathy was recorded. Neutropenia was defined as an absolute neutrophil count of less than 1,000 cells/mm3,4 Radiological workup and clinical course were recorded. Surgical and autopsy reports as well as pathology and autopsy specimens were reviewed to examine indications for surgery and outcome. Recovery with supportive care describes patients who did not require operation and were alive and tolerating a diet 30 days after the initial consultation. Deaths were defined as in-hospital mortalities.

RESULTS

Thirty-three children had 38 episodes of neutropenic enteropathy. They ranged in age from 15 months to 16 years of age. Twenty-four (73%) had hematologic malignancy, and nine (27%) had solid neoplasms. Seventy-one percent of those with hematologic malignancy and 89% of those with solid tumors were receiving intensive (induction, reinduction, intensification) chemotherapy. The solid tumor patients were all either stage III or IV Neutropenic enteropathy developed in three children with leukemia after bone marrow transplant. Five patients (15%) had a second episode of neutropenit enteropathy, and all were receiving treatment for Burkitt’s lymphoma. They ranged in age from 4 to 15 years, and four were receiving induction or intensification therapy. Cytosine arabinoside and VP16 were administered in all cases. In three cases, the second episode

Journaloff’ediatric

Surgery,

Vol34,

No 7 (July),

1999: pp 1068-1071

NEUTROPENIC

ENTEROPATHV

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Table 1. Presenting

Signs

and Symptoms

Signs and Symptoms

Fever Abdominal paln Nausea and vomiting Diarrhea Abdominal

Table 3. Positive

Frequency

distension

(%I

Chemotherapeutic

Cytosine

Agents Agent

arabinoside

Used

epidermidis

100 67 56

Staphylococcus 6 fragilis

aureus

(Hematologic

P aeruginosa Klebsiella Candida

Frequency

60 53 37

Prednisone

33

Wncristine

33 27 23

Daunorubicin

Y/b)

At Diagnosis

Enterococcus

Surgery,

survwed

Survwed Survived Survived

S epidermidis S epidermidis Escherichia

Outcome

Died

Klebsietla Klebsiella

Malignancy)

VP16 Methotrexate

Cyclophosphamide

Cultures

Staphylococcus

occurred during the subsequent round of chemotherapy, which was administered 1 month after the initial illness. One child’s second episode presented with bowel perforation and required laparotomy. All five children have survived. All children presented with the triad of fever, abdominal pain, and chemotherapy-induced neutropenia. On average, symptoms developed 9 days after the chemotherapy was administered and 6 days after the onset of neutropenia. Most children localized their pain to the right lower quadrant and experienced signs and symptoms of gastrointestinal ileus (nausea, vomiting, abdominal distension). Fifty-six percent had diarrhea, and 21% had bloody stools. Eighteen percent required intensive care unit admission and inotropic support (Table 1). Sixty percent of children with hematologic malignancy received cytosine arabinoside, and 53% were treated with VP16 (Table 2). The most common cytotoxic agents administered in solid tumor patients were VP16 (67%) and ifosfamide (56%). Findings on blood cultures drawn on the first day of illness were positive in only eight (21%) cases. Six of these grew enteric organisms. Of the three who grew multiple organisms, one died, one required surgery and survived, and one recovered without operation. All five with just a single organism on blood culture survived, including two who had undergone bone marrow transplant (Table 3). Plain abdominal radiographs were obtained in all cases. Three showed pneumatosis intestinalis, and two showed free intraperitoneal air. Thirty-three were consistent with an ileus. Other findings included absent right lower quadrant gas, dilated loops of small bowel with air-fluid levels, ascites, and bowel wall edema. In fifteen Table 2. Chemotherapeutic

Blood Organism

100

38 21 18

Gastrointestinal bleeding lnotropic support

Patlent No.

cloacae

Survived Survived Survived

cases, the radiologist reported that the findings were consistent with neutropenic enteropathy. Abdominal ultrasonography was performed in 14 patients. In twelve (86%), thick-walled bowel and free intraperitoneal fluid were seen. Two computed tomography (CT) scans were performed for persistence of abdominal symptoms after resolution of neutropenia. Results of each of these studies showed an occult retroperitoneal colonic perforation that was confirmed at laparotomy. Overall survival rate was 94% (31 of 33 children). Twenty-five of 29 (86%) patients with hematologic malignancy (including three who underwent bone marrow transplant), and seven of nine (77%) with solid tumors recovered with supportive care. The treatment regime included bowel rest (nasogastric decompression and total parenteral nutrition), broad-spectrum antibiotics, and serial abdominal examinations. All patients were treated with a standard antibiotic regime for febrile neutropenia (piperacillin, cloxacillin, tobramycin, and metronidazole). Amphotericin was added after 4 days if no clinical improvement was seen. Only four children (12%) required surgery, and all survived. Two had hematologic neoplasms, and two had solid tumors. The only indication for surgery was radiological evidence of bowel perforation. All four were treated with right hemicolectomy, end ileostomy, and mucus fistula formation (Table 4). Review of surgical pathology specimens showed a range of disease. Bowel ulceration varied in depth from focal areas of mucosal involvement, to deep muscularis ulcers, to hemorrhagic, necrotic bowel. Overgrowth of bacteria was present in two specimens and pneumatosis intestinalis in one. No specimen showed leukemic infiltrates of the bowel. Perforation of the bowel was present in all four cases. The two leukemic patients who died were never surgical candidates. Neutropenic enteropathy developed in both patients 2 days after the onset of neutropenia. This is much earlier than the average of 6.3 days seen in the

1070

BAERG

Table 4. Children Diagnosis

Osteosarcoma Central nervous system ALL-CNS Relapse Burkitt’s

Age (yr)

sarcoma

lymphoma

14 7 9 4

Requiring

Surgical

Therapy

InductIon Relapse, Relapse,

Intensification

survivors. This was followed by fulminant illness with rapid progression to multisystem organ failure that required inotropic support in the intensive care unit. One child had severe lower gastrointestinal bleeding that required transfusion. Neither showed any bone marrow recovery, and both died 2 weeks after the onset of their illness. Autopsy results confirmed transmural bowel necrosis with bacterial overgrowth in one patient and severe bowel ulceration in the second patient. Recovery of gastrointestinal function was seen in only 7 of 32 episodes (22%) before resolution of neutropenia. In the majority of cases (78%), gastrointestinal function did not return until up to 9 days after resolution of neutropenia. Three children had undergone bone marrow transplantation for dyskeratosis congenita, congenital chronic myelogenous leukemia, and acute myelogenous leukemia. All received similar chemotherapeutic regimens including bisulfan, cyclosporine, cyclophosphamide, and prednisone. Symptoms developed 12.6 days after chemotherapy, 8.3 days after neutropenia, and 6 days after transplant. All three survived with supportive care alone. DISCUSSION

Twenty-two years ago, Moir and Bale5 reported fifty consecutive autopsies of children with leukemia. In patients who died during induction or reinduction therapy, the most frequent “infection” was typhlitis (neutropenic enteropathy). The incidence was 46%, and it was a significant factor in the death of 38%. Between 1970 and 1987, Katz et al6 reported an incidence of typhlitis of 24% in children who died of leukemia and underwent autopsy. Pathological findings ranged from superficial mucosal ulceration to full-thickness necrosis and perforation. Bacterial or fungal overgrowth and invasion was variably present. These postmortem findings led to the identification of clinical findings in patients with this disease process. The clinical triad of fever, abdominal pain, and chemotherapyinduced neutropenia is considered diagnostic of neutropenit enteropathy.1-4*6 With the advent of more aggressive chemotherapy as well as more frequent use of bone marrow transplantation, neutropenic enteropathy is becoming more prevalent in children.7-9 Pediatric surgeons are being called on more frequently to evaluate and treat these patients. The decision to intervene surgically must

Treatment lndlcation

intensification intensification

ET AL

Procedure

Outcome

Perforation Perforation Perforation

R hemicolectomy

Survived

R hemicolectomy R hemicolectomy

Survived Survived

Perforation

R hemicolectomy

Survived

be tempered by the high risk of morbidity and mortality. Some investigators have recommended laparotomy for a number of indications. These have included (1) bowel perforation, (2) severe lower gastrointestinal bleeding, (3) need for inotropic support, and (4) to rule out other surgical problems (ie, appendicitis).1~3,8JoJ1 Reported mortality rates have ranged from 50% to 100%.1-4JoWe have demonstrated that excellent survival rate (93%) can be attained using a conservative approach, reserving laparotomy for children who have radiological evidence of bowel perforation. A high index of suspicion and early initiation of therapy with broad spectrum antibiotics, bowel rest, and close observation allowed us to avoid surgery in 88% of children with neutropenic enteropathy. Of the six children who required pressor support, two only needed it postoperatively. Two had multisystem failure and were not surgical candidates, and two recovered with supportive care. Although lower gastrointestinal bleeding occurred in 21% of patients, it was only significant in one with severe coagulopathy and multisystern failure. Appendicitis or other surgical causes of intraabdominal pathology were not encountered in the clinical scenario of neutropenic enteropathy in this series. The association between Burkitt’s lymphoma and recurrent episodes of neutropenic enteropathy has not been reported previously. Three of the five cases occurred on consecutive rounds of chemotherapy. These children may not have completely recovered from the first bout of neutropenic enteropathy when the subsequent round of chemotherapy was given. The intensity of the chemotherapeutic regime (especially cytosine arabinoside) given to these patients probably contributed to their severity of illness. Children being treated who have Burkitt’s lymphoma should be carefully monitored for the development of recurrent neutropenic enteropathy. They should be fully recovered before receiving any further chemotherapy. Cytosine arabinoside was the most commonly administered chemotherapeutic agent in children with hematologic malignancy (60%). Wade et al4 report a similar incidence in their series (64%). Slavin et all2 demonstrated that this medication induces mucosal alterations in the gastrointestinal tract through clinicopathologic correlation studies. This may predispose children to the development of neutropenic enteropathy. VP16 may also be implicated in the etiology of this disease because it

NEUTROPENIC

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ENTEROPATHY

was used in 53% of children with hematologic malignancy and 67% of those with solid tumors. Ifosfamide was used in 56% of children with solid tumors. Radiological studies are helpful in supporting the diagnosis of neutropenic enteropathy. Plain films show an ileus pattern, free fluid, and thick-walled bowel. They are useful in identifying free intraperitoneal air, which necessitates surgical intervention. We have begun using ultrasonography more frequently because it can accurately assessbowel wall thickness and the presence of free fluid. These findings were noted in 12 of 14 cases in our series. The use of CT scan in neutropenic enteropathy has been reported by Alt et al. lo We found it useful in demonstrating occult retroperitoneal colonic perforations in two of our patients. The incidence of bacteremia in children with neutropenit enteropathy is reported to be between 28% and 7.5%.i-3 Stames et al2 report a mortality rate of 63% in bacteremic patients. In our series, only 21% of children were bacteremic, with six of eight growing enteric organisms. Our mortality rate in this group of patients was only 12%. Early treatment with broad-spectrum

antibiotics may have contributed to these results. The growth of multiple organisms on blood culture may be a prognostic marker, because one child died of multisystem failure, one had bowel perforation, and one recovered without surgery. In addition, early development of neutropenic enteropathy after onset of neutropenia may be a marker for fuhninant disease.Both mortalities in this seriesdeveloped neutropenic enteropathy 2 days after the onset of neutropenia, 4 days earlier than the mean of the entire group. However, a larger seriesis necessaryto further assessthis. Recovery of gastrointestinal function appears to correlate with the resolution of neutropenia. Of the children treated nonoperatively, 100% were able to tolerate enteral feeds within 9 days of the resolution of neutropenia. Children receiving chemotherapeutic regimes for both hematologic and solid malignancy are at risk for the development of neutropenic enteropathy. We recommend that children with this disease be treated with a regime of broad-spectrum antibiotics, bowel rest, and close observation. Surgical intervention should be reserved for children with bowel perforation.

REFERENCES 1. Shamberger R, Weinstein HJ, Delorey MJ. et al: The medical and surgical management of typhlitis in children with acute nonlymphocyttc (myelogenous) leukemia. Cancer 57:603-609. 1986 2. Stames HF, Moore FD. Mentzer S, et al: Abdominal pain in neutropemc cancer patients. Cancer 57:616-621, 1986 3. Villar HV, Wameke JA, Peck MD, et al: Role of surgical treatment in the management of complications of the gastrointestinal tract in patients with leukemia. Surg Gynecol Obstet 165:217-22. 1987 4. Wade DS, Nava HR. Douglas HO: Neutropenic enterocolitis. clinical diagnosis and treatment. Cancer 69: 17-23, 1992 5. Moir DH, Bale PM: Necropsy findings in childhood leukemia, emphasizing neutropemc enterocohtis and cerebral calcification. Pathology 8:247-258,1976 6. Katz JA, Wagner ML, Gresik MV, et al: Typhlitis, an eighteen year experience and post-mortem review Cancer 65: 1041-1047. 1990

7. Varki AP, Armitage JO, Feagler JR: Typhlitis in acute leukemia. successful treatment by early intervention. Cancer 43:695-697, 1979 8. Kies MS, Luedke DW, Boyd JF, et al: Neutropenic enterocolitis. two case reports of long-term survival following surgery. Cancer 43:730-734, 1979 9. Gandy W, Greenberg B: Successful medical management of neutropenic enterocohtis. Cancer 51: 1551-1555, 1983 10 Alt B, Glass NR, Sollinger H: Neutropenic enterocohtis m adults, review of the literature and assessment of surgical intervention. Am J Surg 149:405-408, 1985 11. Skibber JM, Matter GJ, Ptzzo PA, et al: Right lower-quadrant abdominal pam m young patients with leukemia: A surgical perspecttve Ann Surg 206:711-716, 1987 12. Slavin RE, Dias MA, Sara1 R: Cytosine arabmoside-induced gastromtestmal toxic alteration in sequential chemotherapy protocols: A clinical-pathologic study of 33 patients. Cancer 42: 1747-1759, 1978