Typhlitis complicating autologous blood stem cell transplantation for breast cancer

Abstract

Three cases of typhlitis occurring during autologous blood stem cell transplantation (ABSCT) for metastatic breast cancer are described. Typhlitis is a rare complication of neutropenia and has uncommonly been reported in the autologous transplant setting. Although it has been most commonly described in children with leukemia, typhlitis has increasingly been reported in adult leukemias and in association with neutropenia secondary to chemotherapy for a number of solid tumors. Only five previous cases of typhlitis in the setting of ABSCT have been described. Whereas diarrhea and fever are common toxicities associated with high-dose chemotherapy, it is likely that many cases of typhlitis go unrecognized. Bone Marrow Transplantation (2000) 25, 321–326.

Main

Typhlitis was initially described in 1970 as a life-threatening condition occurring in children with leukemia.1 This condition is characterized by a necrotizing colitis usually localized to the cecum. Although most reports involve children with leukemia or aplastic anemia,234567 in recent years cases involving adults with hematologic malignancies have been described.8910111213 In addition, reports of typhlitis in patients with solid tumors treated with myelosuppressive doses of chemotherapy have appeared in the literature.141516 To date there have been five reported cases of typhlitis occurring in patients undergoing high-dose chemotherapy with autologous blood stem cell transplant (ABSCT), three from Hadassah University Hospital171819 and two from the Beth Israel-Deaconess Medical Center.20 We describe our experiences with three additional cases of typhlitis complicating ABSCT for metastatic breast cancer. The frequency of typhlitis is likely to be underestimated given that diarrhea and fever are common side-effects of high-dose chemotherapy.

Case 1

A 33-year-old athletic white female with stage IV carcinoma of the breast was treated with three cycles of adriamycin and cyclophosphamide (AC) chemotherapy with good response. She was randomized to receive GM-CSF (Immunex, Seattle, WA, USA) 375 μg/m2/day after cyclophosphamide for mobilization of peripheral blood progenitor cells (PBPC). Given the marginal numbers of total CD34+ cells that were collected with two attempts at mobilization, a bone marrow harvest was performed to serve as a backup in the event of engraftment failure. She then received the STAMP V high-dose regimen (carboplatin, cyclophosphamide, thiotepa) with daily itraconazole and acyclovir for infection prophylaxis. After infusion of the PBPC, the patient received PIXY321 (Immunex) (a recombinant GM-CSF/IL3 fusion protein) 375 μg/m2 twice a day.

On day +2, she was noted to be neutropenic and febrile (38.3°C) with loose stools, and was placed on broad spectrum antibiotics. On day +3, she developed abdominal pain with copious diarrhea (3 liters/day). Physical examination revealed diminished bowel sounds and a diffusely tender abdomen without rebound tenderness. A radiograph of the abdomen (Figure 1) on day +4 demonstrated a distended small bowel with a thickened wall, consistent with typhlitis. Despite aggressive supportive care, she developed functional gastrointestinal obstruction on day +7 requiring a nasogastric tube. Stool cultures were negative for C. difficile but blood cultures grew methacillin-resistant Staphylococcus aureus. Due to her continued neutropenia, her back-up bone marrow harvest was infused on day +9. On day +14, a stool culture was positive for Blastocystis hominis for which amphotericin was given. Stools were also positive for C. difficile toxin and metronidazole was prescribed. The patient symptomatically improved with good oral intake, only one to two loose stools per day, and no abdominal pain. She continued to be febrile (38.5°C), however, with an absolute neutrophil count (ANC) of 500/μl on day +19. On day +20 she defervesced, her abdominal symptoms improved, and stool and blood cultures were negative for pathogens. On day +21 she was noted to be bradycardic. She subsequently suffered a respiratory arrest followed by ventricular fibrillation and expired.

Figure 1
figure1

Patient 1. Abdominal upright radiograph demonstrating multiple air-fluid levels and markedly distended loops of large and small bowel.

Autopsy revealed mucosal hyperemia at the ileocecal valve. All evidence of colitis had resolved. Microscopically there was autolysis of the intestinal mucosa but no inflammatory reaction. Examination of the heart demonstrated biventricular hypertrophy (athlete's heart) with pulmonary edema.

Case 2

A 42-year-old white female was diagnosed with node negative, ER/PR positive breast cancer in 1990. She underwent a mastectomy and six cycles of cyclophosphamide, methotrexate, 5-flourouracil chemotherapy. In 1994 she was noted to have recurrence of her breast cancer. She received three cycles of AC with good response. She was randomized to receive PIXY321 375 μg/m2 twice a day after cyclophosphamide for mobilization of PBPC. After PBPC harvest, she received the STAMP V high-dose regimen with daily itraconazole and acyclovir for infection prophylaxis. The patient again received PIXY321 375 μg/m2 twice a day beginning after infusion of PBPC.

She was neutropenic by day +3 with severe nausea, vomiting, and diarrhea of 2 liters per day. At that time, physical examination revealed increased bowel sounds and diffuse abdominal tenderness with no guarding or rebound. She developed a fever (38.4°C) on day +5 with Klebsiella pneumonia bacteremia sensitive to ceftazidime and amikacin, with which she was treated. She had abdominal pain and distension, decreased bowel sounds, guarding, and right lower quadrant tenderness without rebound. A CT scan on day +4 did not show any abnormality initially, but a repeat CT 4 days later when her ANC was 1080/μl revealed a thickened small bowel wall with edema and a fluid filled, dilated cecum and colon. She developed severe abdominal distension requiring nasogastric tube placement. Multiple stool cultures did not reveal any evidence of C. difficile.

Despite these measures, she became hypotensive requiring pressors, and on day +9 required intubation. On day +10 bilateral pleural effusions and ascitic fluid were aspirated. Although her ANC was 7200/μl, she continued to be febrile (39.4°C) with diarrhea of 2 liters per day. Abdominal examination was remarkable only for distension with normal bowel sounds and no tenderness. Supportive measures were without effect and she expired. The next day, cultures of blood from the time of expiration grew E. coli, E. faecium, and Staph. aureus, and the ascitic fluid grew Citrobacter freundii and E. coli.

Gross findings at autopsy included diffuse transmural hemorrhage, necrosis in the small and large intestine, and a patchy fibropurulent exudate in the small intestine. Microscopically, both the small and large intestine had mucosal and submucosal edema and hemorrhage. There was a diffuse, intense neutrophilic polymorphonuclear fibropurulent exudate of the mucosa with bacterial colonies and focal mucosal necrosis (Figure 2). Focal fibropurulent serositis of the large intestine was present.

Figure 2
figure2

(a) Gross photograph of the small intestine from patient 2 with (1) hemorrhage, necrosis, and serositis; and (2) mucosal hemorrhage and necrosis. (b) Detail of panel a (1) Marked mucosal and mural necrosis, neutrophilic inflammation and hemorrhage (hematoxylin and eosin, ×100). (2) Acute necrotizing serostis with abundant neutrophilic polymorphonuclear leukocytes in the serosal adipose tissue (hematoxylin and eosin, ×200).

Case 3

A 57-year-old woman was diagnosed with stage 2, ER positive breast cancer in 1994. She underwent a right mastectomy and was treated with AC for four cycles followed by tamoxifen. In 1996 she developed a biopsy-proven recurrence and received six cycles of standard dose paclitaxel without complications. A CT prior to paclitaxel demonstrated cecal thickening. Prior to transplant the thickening was still present and a colonoscopy with biopsy showed an area of fatty infiltration without carcinoma. Her PBPC were mobilized per protocol with G-CSF 5 μg/kg/day. She then received high-dose thiotepa, cyclophosphamide, and dose escalated paclitaxel (325 mg/m2) with daily valcyclovir and alternate day amphotericin for infection prophylaxis. On the day of PBPC infusion, she was started on G-CSF 5 μg/kg/day.

Diarrhea developed on day −3 and increased to 2.5 liters per day by day 0. On day +2 she was neutropenic and febrile (38.3°C). Blood cultures grew Klebsiella pneumonia sensitive to piperacillin and amikacin and she was started on these antibiotics. Stool cultures were negative for C. difficile. On day +3 she developed right upper quadrant tenderness and continued to have severe diarrhea. A CT scan (Figure 3) on day +6 showed massive thickening of the colon wall with fat stranding and dilated loops of bowel. On day +10 her ANC increased to 1360/μl, but she began to have bloody stools. Abdominal examination revealed decreased bowel sounds, right lower quadrant tenderness, and guarding without rebound. She continued to be febrile with rectal bleeding. By day +14 her abdominal pain improved and fever resolved. G-CSF was discontinued. On day +16 the rectal bleeding decreased and a flexible sigmoidoscopy demonstrated submucosal edema and no evidence of infection. The abdominal symptoms slowly improved and she was discharged home on day +30.

Figure 3
figure3

Patient 3. CT abdomen with thickened wall of large bowel with surrounding fat stranding and dilated bowel loops.

Discussion

Typhlitis is an uncommonly reported complication of neutropenia either due to disease or cytotoxic chemotherapy. Only five other cases of typhlitis, three from Hadassah University Hospital171819 and two from Beth Israel-Deaconess Medical Center20 have been described in ABSCT. In most cases, symptoms include fever, abdominal pain (which is usually generalized), watery diarrhea, and variably, hematochyzia, nausea, vomiting, and abdominal bloating.21 All of our patients had at least three of these symptoms (fever, diarrhea, abdominal pain); two had signs of severe abdominal bloating, and one had hematochezia.

Radiographic findings are variable. Plain films of the abdomen may be unremarkable, but a picture of small bowel obstruction with distension of the distal small bowel or dilatation of the cecum with a thickened bowel wall is commonly seen.12 CT scans are useful when abdominal films are unhelpful. An edematous cecum and/or right colon, spiculation, and inflammation of the pericolic fat, and pneumatosis are diagnostic of typhlitis.14 All of our patients demonstrated radiographic evidence of typhlitis, with the most striking abnormalities occurring in patient 3, with thickened bowel walls and inflammation of the pericolic fat.

Pathology specimens in typhlitis commonly reveal a sharply demarcated area of ulceration, which may be isolated, or part of an extensive process affecting segments of large and small bowel.12 Grossly, the bowel wall is thickened with intramural hemorrhage, ulceration, and necrosis with masses of gram negative organisms.1 There is often a notable absence of an inflammatory response, perhaps attributable to the associated neutropenia.

The cecum is thought to be a primary site of involvement because it has great distensibility, decreased vascular perfusion, and decreased lymphatic drainage. Some have speculated that the pathophysiology involves failure to maintain the integrity of the cecal mucosa related to either the direct cytotoxic effects of chemotherapy or to leukemic infiltration with bacterial invasion of the bowel wall.820 Proliferation of bacteria occurs secondary to decreased immunologic defenses related to neutropenia or steroids. Production of bacterial endotoxins with subsequent bacteremia, necrosis, hemorrhage, and perforation ensues.22

In most patients, at least one blood culture is positive, usually for a gram negative organism.21 Commonly isolated pathogens are Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter taylorae, Morganella morganii, and Streptococcus viridans.7 Clostridium difficile toxin has also been demonstrated in the stool of some patients. Other laboratory abnormalities include a mild elevation of liver enzymes and an elevated bilirubin. Although one patient was positive for C. difficile toxin during the course of her hospital stay, the toxin had been negative at the time her symptoms first appeared. At autopsy, there was no evidence of membranous colitis. It is uncertain if the cecal abnormality in patient 3 had any role in the development of typhlitis and hematochezia. This abnormality could not be characterized as anything other than a variant by evaluation with CT, ultrasound, and colonoscopy with biopsy.

The chemotherapeutic drugs most commonly associated with typhlitis are vincristine, prednisone, adriamycin, cytarabine, 6-mercaptopurine, cyclophosphamide, and methotrexate.21 These drugs are most commonly used in the treatment of leukemias, the disease in which the majority of cases have been described. Paclitaxel, when combined with adriamycin, has been reported to be associated with typhlitis in as many as 24% of patients.15 In a phase I study evaluating adriamycin (75 mg/m2) and paclitaxel (180 mg/m2), 100% of patients developed typhlitis at that dose.16 One of our patients developed typhlitis while receiving high doses of paclitaxel (325 mg/m2) in combination with thiotepa and cyclophosphamide although she had tolerated conventional doses earlier. The combination of direct bowel toxicity and profound neutropenia, regardless of the chemotherapeutic agent, seems to be the unifying event.

In the past, the condition was universally fatal with terminal events attributed to sepsis, cecal perforation, and peritonitis.147 In recent years survival has improved with aggressive medical management and broad spectrum antibiotics.232425 Recombinant hematopoeitic growth factors have been used to shorten the period of neutropenia which is essential in eradicating infection and restoring bowel mucosal integrity.

The first two patients we describe were enrolled in a randomized trial comparing the investigational agent PIXY321 and GM-CSF for mobilization of hematopoietic progenitor cells and for acceleration of engraftment. PIXY321 is a recombinant protein that contains both IL-3 and GM-CSF domains. Hematopoietic progenitor cells contain a dual IL3-GM-CSF receptor through which PIXY321 exerts its biologic effect. The PIXY321 molecule has been shown in vitro to exert a 10-fold greater effect on the proliferation of hematopoietic progenitors than equimolar amounts of GM-CSF and IL-3 combined.26 The most common side-effect with PIXY321, IL-3, and GM-CSF has been local injection site reactions. Other frequently described side-effects with IL-3 alone are chills, fever, and myalgia. At the highest doses used (4000 μg/m2) diarrhea was infrequently reported.27 Flu-like symptoms and musculoskeletal pain are also commonly reported with GM-CSF.28 There have been no reports of increased gastrointestinal toxicity with PIXY321 and we believe it to be unlikely that this agent was the cause of typhlitis. G-CSF was used for mobilization and acceleration of engraftment in the case of our third patient.

The optimal management for typhlitis is controversial. Definite indications for surgery are free intraperitoneal air, persistent gastrointestinal bleeding, and medical deterioration with bacteremia and hypotension.14 However, proper timing of surgery is difficult, in part due to difficulty in diagnosing an acute abdomen in neutropenic patients, a reluctance to operate on neutropenic patients, and a rapid downhill course which makes patients too unstable for operation. There has been no definite advantage to a surgical approach, especially in recent years with improved supportive care. During the period of time in which our three patients developed typhlitis, 73 patients with breast cancer underwent ABSCT at our center, yielding a rate of 4% for this particular toxicity. Table 1 lists the reported cases of typhlitis in patients neutropenic due to malignancy and chemotherapy. In the non-transplant patients, 42% died (16/38) despite surgical intervention in 62% of the cases. In the ABSCT patients the mortality rate was 50% with supportive care alone. The only patient in this group to receive surgery survived. The majority of cases in both settings have positive blood or fluid cultures. In recent years, the majority of patients have been treated with supportive care and less commonly with surgery. Today, typhlitis is less commonly fatal, which is likely due to early recognition, broad spectrum antibiotics, and the decreased duration of neutropenia.

Table 1  Clinical course of typhlitis in adults

As more diseases are treated by high-dose chemotherapy with ABSCT, the incidence of typhlitis may increase. Methods for prevention such as oral gentamycin for bowel decontamination have been used in an attempt to decrease the gastrointestinal complications of prolonged neutropenia. Fluoroquinolones have been used with more success to eradicate gram negative organisms but have been associated with an increased frequency of gram positive infections.29 During mobilization with cyclophosphamide patients 1 and 2 received ciprofloxacin until recovery of blood counts. None of our patients received prophylaxis with fluoroquinolones during transplant, consistent with an institutional policy that had been established in an attempt to reduce the development of drug resistance as there have been recent reports of strains of E. coli resistant to fluoroquinilones. C. difficile infection is the most common side-effect of antibiotic therapy and may in itself pre-dispose patients to the development of typhlitis.

Ultimately, optimal outcome results from early diagnosis and appropriate supportive care. Rapid recovery of neutrophil counts is likely to reduce morbidity and mortality although symptoms may initially worsen as the white count increases due to an associated inflammatory response. Treatment with broad spectrum antibiotics and bowel rest provide the best chance for patient survival. Surgical intervention should be reserved for those cases with impending bowel perforation.

References

  1. 1

    Wagner ML, Rosenberg HS, Fernbach DJ et al. Typhlitis: a complication of leukemia in childhood Am J Radiol 1970 109: 341–350

    CAS  Google Scholar 

  2. 2

    Bajwa RPS, Marwaha RK, Garewal G . Neutropenic enterocolitis and cecal perforation in acute lymphatic leukemia Ind J Cancer 1993 30: 31–33

    CAS  Google Scholar 

  3. 3

    Gavan DR, Henry GMA . Colonic complication of acute lymphoblastic leukaemia Br J Rad 1994 67: 449–452

    CAS  Article  Google Scholar 

  4. 4

    Katz JA, Wagner ML, Gresik MV et al. Typhlitis: an 18-year experience and post mortem review Cancer 1990 65: 1041–1047

    CAS  Article  Google Scholar 

  5. 5

    Paulino AFG, Kennedy R, Norman EN et al. Typhlitis in a patient with acute lymphoblastic leukemia prior to the administration of chemotherapy Am J Ped Hematol Oncol 1994 16: 348–351

    CAS  Google Scholar 

  6. 6

    Sherman NJ, Woolley MM . The ileocecal syndrome in acute childhood leukemia Arch Surg 1973 107: 39–42

    CAS  Article  Google Scholar 

  7. 7

    Sloas MM, Flynn PM, Kaste SC et al. Typhlitis in cancer: a 30-year experience Clin Infect Dis 1993 17: 484–490

    CAS  Article  Google Scholar 

  8. 8

    Hiruki T, Fernandes B, Ramsay J et al. Acute typhlitis in an immunocompromised host: report of an unusual case and review of the literature Dig Dis Sci 1992 37: 1292–1296

    CAS  Article  Google Scholar 

  9. 9

    Ikard RW . Neutropenic typhlitis in adults Arch Surg 1981 116: 943–945

    CAS  Article  Google Scholar 

  10. 10

    Kies MS, Luedke DW, Boyd JF et al. Neutropenic enterocolitis Cancer 1979 43: 730–734

    CAS  Article  Google Scholar 

  11. 11

    Musher DR, Amorosi EL, Gouge T et al. Neutropenic typhlitis simulating carcinoma of the cecum Gastro End 1989 35: 449–451

    CAS  Article  Google Scholar 

  12. 12

    Taylor AJ, Dodds WJ, Gonyo JE et al. Typhlitis in adults Gastro Rad 1985 10: 363–369

    CAS  Article  Google Scholar 

  13. 13

    Varki AP, Armitage JO, Feagler JR . Typhlitis in acute leukemia, successful treatment by early surgical intervention Cancer 1979 43: 695–697

    CAS  Article  Google Scholar 

  14. 14

    Keidan RD, Fanning J, Gatenby RA et al. Recurrent typhlitis: a disease resulting from aggressive chemotherapy Dis Colon Rectum 1989 32: 206–209

    CAS  Article  Google Scholar 

  15. 15

    Pestalozzi BC, Sotos GA, Choyke PL et al. Typhlitis resulting from treatment with taxol and doxorubicin in patients with metastatic breast cancer Cancer 1993 71: 1797–1800

    CAS  Article  Google Scholar 

  16. 16

    Fisherman JS, Cowan KH, Noone M et al. Phase I/II study of 72-hour infusional paclitaxel and doxorubicin with granulocyte colony-stimulating factor in patients with metastaticbreast cancer J Clin Oncol 1996 14: 774–782

    CAS  Article  Google Scholar 

  17. 17

    Nagler A, Pavel L, Naparstek E et al. Typhlitis occurring in autologous bone marrow transplantation Bone Marrow Transplant 1992 9: 63–64

    CAS  PubMed  Google Scholar 

  18. 18

    Mehta J, Nagler A, Or R et al. Neutropenic entercolitis and intestinal perforation associated with carboplatin-containing conditioning regimen for autologous bone marrow transplantation Acta Oncol 1992 31: 591 (letter)

    Article  Google Scholar 

  19. 19

    Or R, Mehta J, Nagler A et al. Neutropenic enterocolitis associated with autologous bone marrow transplantation Bone Marrow Transplant 1992 9: 383–385

    CAS  PubMed  Google Scholar 

  20. 20

    Avigan D, Richardson P, Elias A et al. Neutropenic enterocolitis as a complication of high dose chemotherapy with stem cell rescue in patients with solid tumors Cancer 1998 83: 409–414

    CAS  Article  Google Scholar 

  21. 21

    Dosik GM, Luna M, Valdivieso M et al. Necrotizing colitis in patients with cancer Am J Med 1979 67: 646–656

    CAS  Article  Google Scholar 

  22. 22

    Prolla JC, Kirsner JD . The gastrointestinal lesions and complication of leukemias Ann Int Med 1964 61: 1084–1103

    CAS  Article  Google Scholar 

  23. 23

    Asnis DS, Seligman BR, Cohen RI et al. Neutropenic entercolitis: an often unrecognized syndrome J Diarrh Dis Res 1993 11: 252–254

    CAS  Google Scholar 

  24. 24

    Millward MJ, Zalcbert J, Bishop JF et al. Phase I trial of docetaxel and cisplatin in previously untreated patients with advanced non-small-cell lung cancer JCO 1997 15: 750–758

    CAS  Article  Google Scholar 

  25. 25

    Pouwels MJM, Donnelly JP, Raemaekers JMM et al. Clostridium septicum sepsis and neutropenic enterocolitis in a patient treated with intensive chemotherapy for acute myeloid leukemia Ann Hematol 1997 74: 143–147

    CAS  Article  Google Scholar 

  26. 26

    Curtis BM, Williams DE, Broxmeyer HE et al. Enhanced hematopoietic activity of a human granulocyte/macrophage colony-stimulating factor-interleukin 3 fusion protein Proc Natl Acad Sci USA 1991 88: 5809–5813

    CAS  Article  Google Scholar 

  27. 27

    Bukowski RM, Olencki T, Gunn H et al. Phase I trial of subcutaneous interleukin 3 in patients with refractory malignancy: hematological, immunological, and pharmacodynamic findings Clin Cancer Res 1996 2: 347–357

    CAS  PubMed  Google Scholar 

  28. 28

    Fischmeister G, Jurz M, Haas OA et al. G-CSF vs GM-CSF for stimulation of peripheral blood progenitor cells (PBPC) and leukocytes in healthy volunteers: comparison of efficacy and tolerability Ann Hematol 1999 78: 117–123

    CAS  Article  Google Scholar 

  29. 29

    Patrick CC . Use of flouroquinolones as prophylactic agents in patients with neutropenia Pediatr Infect Dis J 1997 16: 135–139

    CAS  Article  Google Scholar 

  30. 30

    Sadullah S, Nagesh K, Johnston D et al. Recurrent septicaemia in a neutropenic patient with typhlitis Clin Lab Haem 1996 18: 215–217

    CAS  Article  Google Scholar 

  31. 31

    Kunkel JM, Rosenthal D . Management of the ileocecal syndrome: neutropenic enterocolitis Dis Colon Rectum 1986 29: 196–199

    CAS  Article  Google Scholar 

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Correspondence to JN Winter.

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Boggio, L., Pooley, R., Roth, S. et al. Typhlitis complicating autologous blood stem cell transplantation for breast cancer. Bone Marrow Transplant 25, 321–326 (2000). https://doi.org/10.1038/sj.bmt.1702134

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Keywords

  • typhlitis
  • neutropenic enterocolitis
  • breast cancer
  • stem cell transplantation

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