The term typhlitis (from the Greek word typhlon, for cecum) was first used by Wagner and colleagues (1970) to describe a necrotizing inflammation of the cecum that was diagnosed in leukemic children undergoing chemotherapy who were in the terminal stages of the disease (Abramson et al., 1983). Also known as neutropenic enterocolitis and ileocecal syndrome, typhlitis is a potentially life-threatening necrotizing inflammation of the cecum, terminal ileum, or colon. It initially was recognized at autopsy as a complication of childhood leukemia, but it now is known to occur in both adults and children with a variety of hematologic and solid tumor malignancies, in individuals with acquired immunodeficiency syndromes, and as a complication of bone marrow transplantation (McCarville et al., 2005). The appendix usually is only secondarily involved in the inflammatory process (Abramson et al., 1983).

The exact pathogenesis of typhlitis remains unclear and is likely multifactorial. It is believed to begin with mucosal damage, followed by inflammation and edema of the bowel wall, which progresses to ulceration, necrosis, and perforation (Paulino et al., 1994). The cecum is the portion of the lower gastrointestinal tract most vulnerable to developing neutropenic enterocolitis because it is the least vascularized and most distensible region of the colon (Wang & Fadare, 2004). The cecum normally is an area of relative stasis, and chemotherapeutic agents themselves have direct toxic effects on the bowel that may cause vascular changes and ileus (Ikard, 1981; Slavin et al., 1978).

Because most cases of typhlitis have occurred in patients with leukemia who received chemotherapy, one hypothesis of the pathologic etiology of this process is that cytotoxic chemotherapeutic agents are a significant factor in its development. Chemotherapy medications may predispose the cecum to breaks in the mucosal layers of the bowel wall. These interruptions in the cecal wall integrity may serve as portals of entry into the bowel wall for bacteria and fungi (Wang & Fadare, 2004). Chemotherapeutic agents such as cytosine arabinoside, topotecan, atovaquone, PEG-asparaginase, idarubicin, daunorubicin, methotrexate, vincristine, paclitaxel, doxorubicin, and steroids have been implicated in the development of typhlitis (McCarville et al., 2005; Wang & Fadare, 2004).

In addition to mucosal damage, chemotherapeutic drugs induce profound neutropenia. Together, ileal stasis and the resultant distention lead to relative mucosal ischemia which, in the presence of chemotherapeutically induced mucosal damage and agranulocytopenia, allow bacterial, fungal, or viral overgrowth (Abramson et al., 1983). Bacterial or fungal invasion of the cecal mucosa may progress from inflammation to full-thickness infarction and perforation. Pseudomonas species, Escherichia coli, and other gram-negative bacteria, Staphylococcus aureus, alpha-hemolytic streptococci, and Clostridium species are common bacterial pathogens. Necrosis of the mucosal surface of the ileocecal region provides a favorable environment for the spores of Clostridium species to germinate and may be the portal of entry into the bloodstream (Wang & Fadare, 2004). Candida and Aspergillus species are the major fungal pathogens, and Cytomegalovirus organisms may also be present in large numbers (Pizzo & Poplack, 2002; Newbold et al., 1987; Abramson et al., 1983).

In a systematic review of adults with neutropenic enterocolitis, Cardona and colleagues (2005) found that most blood cultures from these patients were negative; 31% grew gram-negative organisms, 9% grew gram-positive organisms, 7.2% grew anaerobes, and 0.9% grew Candida organisms. Of reported stool cultures, 59.6% were negative, 18.8% showed gram-negative organisms, 11.7% showed anaerobes, 7.4% showed Candida organisms, and 3.2.% showed gram-positive organisms (Cardona et al., 2005). McCarville and coworkers (2005) reported that blood cultures obtained from 89 episodes of typhlitis in pediatric patients were positive only 8% of the time; isolated organisms included E. coli, Klebsiella and Enterococcus species, staphylococci, and streptococci. Of 92 stool cultures done, 20% were positive for Clostridium difficile.

Although typhlitis has been reported in adults, it is more commonly reported in children (Varki et al., 1979; Exelby et al., 1975; Wagner et al., 1970; Bierman, 1960). It is difficult to determine accurate prevalence rates for typhlitis and necrotizing enterocolitis. This uncertainty stems from the nonspecific features of the illness and similarities to other acute abdominal syndromes in immunocompromised patients. Also, because few accurate clinical tests are available, pathologic confirmation of the diagnosis may be lacking (Urbach & Rotstein, 1999).

When Wagner and colleagues first described typhlitis in the 1970s, it was considered a terminal disease. This group reported on clinical and autopsy material from 191 cases (children with leukemia) from Texas Children’s Hospital from 1958 to 1970. During that time, there were 19 cases of advanced typhlitis, representing approximately 10% of the studied sample (Wagner et al., 1970).

In 1962 Amromin and Solomon reported the frequency of typhlitis in patients with ALL to be 22% (Amromin & Solomon, 1962). Moir and Bale (1976) reported an autopsy-based descriptive series that suggested an incidence of neutropenic enterocolitis of up to 32% among treated leukemia patients.

Sloas and colleagues (1993) diagnosed typhlitis in 24 of 6911 children treated for cancer between 1962 and 1992, with an overall incidence of 0.35%. The incidence was significantly higher (2.1%) among children treated for acute leukemia (Sloas et al., 1993). Sloas and coworkers also noted an increase in the incidence of typhlitis during the final years of the study; this corresponded to a period when patients with AML were treated with high doses of cytarabine and etoposide.

Cartoni and colleagues (2001) reported a 6% incidence of neutropenic enterocolitis between 1995 and 1998 among 1450 patients, most of whom were adults with acute leukemia or chronic myeloid leukemia in blast crisis, and all of whom were treated with aggressive chemotherapy.

In 2000 Jain and colleagues reported on a series of 180 children treated for ALL between 1990 and 1995. The incidence of typhlitis in this group was 6.1%. The median age at which typhlitis developed was 6 years, with a range of 4 to 12 years. Four of the 11 children with typhlitis were over age 10. Seventy-three percent of the children with typhlitis suffered from severe neutropenia, defined as an absolute neutrophil count (ANC) less than 10⁸/L (Jain et al., 2000).

Similar to the work of Sloas and colleagues, McCarville and coworkers reviewed the records of patients treated for cancer at St. Jude Children’s Research Hospital. This retrospective review of 3171 children showed that 83 (2.6%) had developed typhlitis (McCarville et al., 2005). In this study, the only demographic variable associated with the development of typhlitis was age. On average, patients with leukemia or lymphoma who developed typhlitis were older than those who did not, whereas in the group of children with solid tumors, younger patients were more likely to develop typhlitis. Overall, patients older than 16 years of age were at significantly greater risk than younger patients. Similarly, McCarville and colleagues (2005) found that the duration of typhlitis significantly increased with increasing age (P = 0.04); this suggests that not only are older children at greater risk of developing typhlitis, but also that they may not respond as well as younger children to management.

It generally is believed that the incidence of typhlitis is related to the intensity of chemotherapy and the degree of immunosuppression (Baerg et al., 1999). With this in mind, Otaibi and colleagues (2002) reviewed a 7-year experience with typhlitis in the bone marrow transplantation program at the Alberta Children’s Hospital in Calgary, Alberta. From 1993 to 2000, 142 transplantations were performed at this institution. Of these, 97 patients had abdominal pain, and five patients had radiographically proven typhlitis. In this study, abdominal pain was very common after bone marrow transplantation, and typhlitis was relatively rare (3.5%) (Otaibi et al., 2002).

The exact pathogenesis of typhlitis remains unclear. Cytotoxic chemotherapy may cause intestinal ulcerations which, in the presence of neutropenia, retard healing. Simultaneously, bacterial and fungal invasion may occur, leading to varying degrees of intestinal inflammation. If the inflammation is only mild, it may remain limited to the mucosa. However, it may progress to transmural inflammation, necrosis, and perforation, especially if the neutropenia is severe (ANC less than 10⁸/L) and prolonged (longer than 7 days) (Jain et al., 2000).

Historically typhlitis was considered a terminal event. Although this is no longer the case, the outcome for these patients remains variable. Moir and Bale (1976) reported mortality rates ranging from 50% to 100%. Wade and colleagues (1992) reported a mortality rate of 63% in their series of 22 patients, and Jain and coworkers (2000) reported a rate of 45% in their small series of 11 patients. However, McCarville and colleagues (2005) found a mortality rate of only 2% in their series of 92 patients.