Neutropenic Enterocolitis

Background

Neutropenic enterocolitis, also known as typhlitis (from Greek typhlon ["blind"], referring to the cecum), is an acute life-threatening condition classically characterized by transmural inflammation of the cecum, often with involvement of the ascending colon and ileum, in patients who are severely myelosuppressed.^{[1, 2, 3, 4, 5, 6, 7, 8, 9]}

The clinical presentation of neutropenic enterocolitis can be dramatic, and the outcome may be devastating. Mortality is high, and the treatment is controversial, with options ranging from conservative medical management to surgical intervention.^{[1, 2, 3, 4, 5, 6, 7, 8]} Early recognition of neutropenic enterocolitis is paramount for potentially achieving a good outcome.

Although initially described in children undergoing chemotherapy for leukemia, over the past three decades,^[10] neutropenic enterocolitis has increasingly been reported in adults with a variety of myeloproliferative disorders or solid malignant tumors, as well as in the setting of immunosuppression with solid organ and bone marrow transplantation. Some cases in adults are due to the increasing use of myelotoxic chemotherapeutic regimens that have a high potential to induce mucosal damage.^[11]

For patient education resources, see the Digestive Disorders Center, as well as Colitis, Abdominal Pain in Adults, and Complete Blood Count (CBC).

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Pathophysiology

Although the exact pathogenesis and progression of neutropenic enterocolitis are unknown, profound neutropenia appears to be the common denominator, in conjunction with intestinal mucosal injury and immune compromise.^[9] Many factors have been described that may potentially play a role in the pathogenesis of neutropenic enterocolitis, including the following:

• Mucosal injury caused by cytotoxic drugs – However, mucosal injury can occur in the absence of cytotoxic drug therapy, and neutropenia itself can cause mucosal ulcerations
• Cecal distention – Whether primary or secondary to vinca alkaloids, cecal distention may compromise the blood supply, leading to further mucosal damage
• The use of antibiotics and steroids – These agents may contribute to an altered enteric bacterial flora and overgrowth of fungi
• Bacterial, and sometimes fungal, invasion of the impaired bowel wall – These may result in transmural inflammation, leading to perforation and peritonitis; bacteremia is a frequent complication, with less frequent fungemia^[12]

The pathologic process of neutropenic enterocolitis may involve the cecum alone, or it may extend to the ileum, the ascending colon, or both. It is felt that cecal distensibility and limited blood supply may predispose the cecum to injury more often than other areas.

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Etiology

Although cytotoxic chemotherapeutic agents account for most cases of neutropenic enterocolitis, other conditions may also predispose some patients to develop this condition.

The cytotoxic chemotherapeutic agents include cytosine arabinoside, vinca alkaloids, and doxorubicin. Other drugs that have been implicated anecdotally include paclitaxel, docetaxel, procainamide, sulfasalazine, 5-fluorouracil, vinorelbine, carboplatin, cisplatin, gemcitabine, leucovorin, and pemetrexed.^[13]

There have been described cases of neutropenic enterocolitis associated with the monoclonal antibody alemtuzumab,^[14] as well as with pegylated interferon (PEG-INF) in combination with ribavirin.^{[15, 16]}

Other predisposing conditions for neutropenic enterocolitis include the following:

• Myelodysplastic syndromes, multiple myeloma, and aplastic anemia
• Solid organ and bone marrow transplantation
• Acquired immunodeficiency syndrome (AIDS)
• Cyclic neutropenia
• Solid malignant tumors
• Lymphomas

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Epidemiology

United States statistics

The exact incidence and prevalence of neutropenic enterocolitis are unknown, because many patients survive and are never diagnosed with this condition. In addition, because there is no gold standard of diagnosis for neutropenic enterocolitis, the inclusion criteria differ among studies.

An autopsy study in children reported a prevalence of 24%,^[17] whereas a cohort study in children treated for acute myelogenous leukemia (AML) reported a frequency of 33%.^[18] A retrospective review of 1224 children treated for malignancy showed an incidence of only 1.4%, 53% of whom were treated for leukemia.^[19] Data regarding neutropenic enterocolitis in adults are sparse. In one systematic review, a 5.3% pooled incidence was reported in adults.^[12]

International statistics

An even greater paucity of information regarding the international incidence and prevalence rates of neutropenic enterocolitis exists in the published literature.

A study from India performed by Jain et al reported a frequency of 6.1% in 180 children undergoing chemotherapy for acute lymphocytic leukemia (ALL).^[20]

A retrospective study of data from 20 patients in Turkey reported an incidence of 6.5% for neutropenic enterocolitis in acute myeloid leukemia and 4.6% for neutropenic enterocolitis in acute lymphoblastic leukemia.^[21] Another Turkish study, involving prospective data from 215 adults, showed an incidence of 3.5%, which was significantly associated with acute leukemias and anthracycline administration in adults.^[22]

Polish investigators of a prospective study that examined 297 adult patients following hematopoietic stem cell transplantation diagnosed neutropenic enterocolitis in 12% of patients using the criteria of abdominal pain, diarrhea, and bowel-wall thickening greater than 4 mm on abdominal ultrasonography.^[23]

A lower incidence, 0.22%, was reported in another study from the UK in the treatment of malignancy, not specifically leukemia.^[24]

Race-, sex-, and age-related demographics

No predilection for neutropenic enterocolitis in any specific race or in either sex has been reported in the literature.

On the basis of the published literature, no frequency differences in age groups are known to exist for neutropenic enterocolitis. It has been noted, however, that although neutropenic enterocolitis was initially described in children, it is increasingly reported in adults.

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Prognosis

The prognosis of neutropenic enterocolitis is generally poor and is highly dependent on the rapidity of restoration of the white blood cell (WBC) count. The potential for recovery from neutropenic enterocolitis may be improved by early, accurate diagnosis along with aggressive and meticulous medical and supportive therapy.^[25]

Mortality figures in the range of 5-100% have been reported with conservative management of neutropenic enterocolitis; average mortality is about 40-50%.

In a collective review of 178 published cases, mortality for neutropenic enterocolitis was reported as 48% with conservative management and 21% with surgical management^[26] ; however, these numbers cannot be compared with each other because of selection bias. No known prospective randomized trials comparing surgery with medical management have been performed.

Complications

Complications of neutropenic enterocolitis include the following:

• Bowel perforation and peritonitis
• Gastrointestinal bleeding^[27]
• Gastrointestinal obstruction
• Intra-abdominal abscess
• Sepsis
• Death

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History

Most patients who are affected with neutropenic enterocolitis are receiving antineoplastic drugs and are profoundly neutropenic (ie, < 1000 cells/μL).

The time course and severity of the clinical presentation of neutropenic enterocolitis is variable. Symptoms usually occur within 10-14 days after the initiation of cytotoxic chemotherapy. The typical presentation mimics that of acute appendicitis.

Symptoms include the following:

• Right-lower-quadrant abdominal pain, which may be cramping and intermittent or a continuous dull ache
• Fever
• Watery or bloody diarrhea,^[22] which occurs in about 25-45% of patients
• Nausea
• Vomiting
• Abdominal distention

Oral and pharyngeal mucositis (see the image below) may manifest before the onset of colonic symptoms

View Image

Ulcerative oral mucositis lesion on the lateral and ventral surfaces of the tongue.

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Physical Examination

Physical findings in patients with neutropenic enterocolitis vary according to the severity of the disease and the presence or absence of complications. The following may be noted:

• Abdominal distention, hypoactive bowel sounds, and a tympanitic abdomen may suggest ileus
• The abdomen may be markedly tender, especially in the right lower quadrant
• The cecum may be palpated as a boggy mass
• Rebound tenderness and rigidity may suggest colonic perforation
• Shock may be present as a consequence of sepsis

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Laboratory Studies

A complete blood cell (CBC) count is used to confirm neutropenia. A serum bicarbonate level and pH value should be obtained to rule out acidosis.

Obtain stool studies for the following:

• Clostridium difficile toxin to rule out pseudomembranous colitis
• Culture for enteric pathogens to rule out infectious causes of enterocolitis

Obtain blood cultures for aerobic/anaerobic bacteria and fungus to rule out bacterial and fungal sepsis.

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Imaging Studies

Radiography

Plain abdominal radiographs rarely help in the diagnosis of neutropenic enterocolitis. Radiographic findings usually are nonspecific and may even be normal. Nonspecific findings may include the following:

• Right-side colonic and small-bowel dilatation
• Thumbprinting (see the image below) of the right colon
• Paucity of air in the right colon because of a fluid-filled colon
• Intramural air or pneumatosis
• Soft-tissue mass displacing the small bowel

View Image

Plain abdominal radiograph in a 44-year-old man known to have a long history of ulcerative colitis. The patient presented with an acute exacerbation o....

Barium enema is usually contraindicated, especially if a potential for perforation exists. Water-soluble contrast may demonstrate rigidity and thickening of the cecum.

Abdominal ultrasonography

Abdominal ultrasonography is one of the most important diagnostic studies for neutropenic enterocolitis, and it is preferable to contrast enemas. Ultrasonography may be also useful as a follow-up tool to assess the gradual decrease in bowel-wall thickening.

Findings include thickening of the bowel wall that produces a target or halo sign. However, this is a nonspecific finding and may be observed in other conditions listed under the differential diagnosis (see DDx).

Bowel-wall thickness has also been suggested as a significant prognostic factor regarding patient outcome in individuals with neutropenic enterocolitis.^{[29, 30]} A retrospective study using ultrasonography showed that mortality was higher in patients with a bowel-wall thickness greater than 5 mm (29%) than in those without bowel-wall thickening (0%).^[31] If the bowel-wall thickness cutoff was set at greater than 10 mm, the mortality was 60%, as compared with 4.2% in those without bowel-wall thickening.

Bowel-wall thickening has also been associated with the duration of illness and neutropenia in neutropenic enterocolitis.^[32]

Ultrasonography also allows follow-up imaging without repeated exposure to ionizing radiation, an especially important consideration in children and younger adults.^[28]

Abdominal computed tomography (CT) scanning

CT scanning of the abdomen (see the images below) is the diagnostic procedure of choice in neutropenic enterocolitis,^[28]  because it has a lower false-negative rate (15%) than ultrasonography (23%) or plain abdominal radiography (48%). CT scanning is also the test of choice for diagnosing alternative causes of abdominal pain, such as megacolon, appendicitis, and small-bowel obstruction.^{[14, 33, 34, 35]}

View Image

Typhlitis. Marked asymmetric cecal wall thickening (arrow) in a 64-year-old patient whose status is postchemothery for lymphoma.

View Image

Typhlitis. Marked circumferential cecal and ascending colon wall thickening (large arrows) with mild pericolonic inflammatory stranding (small arrows)....

CT scan findings include the following:

• Symmetrical thickening of the cecum
• Fluid-filled cecum
• Pericecal inflammation
• Free air if an underlying perforation exists
• Portal venous gas

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Procedures

Endoscopic procedures that may be considered in the setting of neutropenic enterocolitis include colonoscopy and flexible sigmoidoscopy (see the images below.) However, these procedures are relatively contraindicated in patients with neutropenic enterocolitis because of an increased risk of complications (eg, perforation),^[28]  especially in the context of underlying neutropenia and thrombocytopenia. They are usually unnecessary, except in rare circumstances in which a gentle sigmoidoscopy may aid in the diagnosis of pseudomembranous colitis.

View Image

Colonic pseudomembranes of pseudomembranous colitis. Photographs courtesy of Eric M. Osgard, MD.

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Histologic Findings

Gross and microscopic findings of neutropenic enterocolitis include diffuse bowel-wall thickening with mucosal and intramural edema and necrosis, mucosal ulcerations, and intramural or intraluminal hemorrhage. The bowel-wall specimens obtained during colectomy or at autopsy demonstrate an abundance of bacteria, a striking lack of lymphoid inflammatory cells, and a virtual absence of neutrophils.

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Approach Considerations

The ongoing growth in chemotherapy for hematologic and solid-organ malignancies has resulted in increased neutropenia-related perianal and intra-abdominal infections. Joint management between medical and surgical teams is extremely important for a good outcome in patients with neutropenic enterocolitis.^{[28, 36]}

Patients with neutropenic enterocolitis must be monitored in an intensive care unit (ICU) with serial abdominal examinations. Management of these patients often is not straightforward. A wide range of diagnostic and therapeutic approaches have been proposed for neutropenic enterocolitis. To date, most large-scale studies and recommendations on this condition have involved hematologic patients; they will require further validation in ICU patients.^[37]  A key determinant of infection resolution is the degree and duration of neutropenia.

Use of recombinant granulocyte colony-stimulating factor (GCSF) may be considered in individual patients, depending on the clinical progression.^[11] Controlled trials using GCSF in this specific entity are lacking, although several case reports of a successful outcome have been reported in the literature. Moreover, a better understanding and definition of specific subsets of patients that may benefit from treatment or prevention of neutropenic enterocolitis is needed.

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Medical Care

Although there are practice guidelines available,^[38] no published randomized control trials comparing conservative medical therapy with surgical intervention in neutropenic enterocolitis exist; however, both types of therapy have their advocates.

The outcome appears to reflect the state of the underlying disease and other comorbidities at the time of the clinical presentation rather than the treatment modality. Accordingly, a uniform management strategy for neutropenic enterocolitis cannot be recommended. Individualize the approach to each patient. Early recognition of neutropenic enterocolitis in a patient who is neutropenic is paramount for achieving a good outcome.

Conservative management includes the following:

• Bowel rest and nasogastric suction
• Close monitoring of patients using serial abdominal examinations in an intensive care unit (ICU)
• Intravenous fluids, blood, and platelet transfusions as necessary
• Parenteral broad-spectrum antibiotics – Antibiotics should include agents covering enteric gram-negative and anaerobic organisms, including Clostridium and Enterococcus species, Enterobacteriaceae, and Pseudomonas aeruginosa^[28] ; metronidazole may also be considered if pseudomembranous colitis cannot immediately be excluded
• Cultures – Obtain blood cultures for fungi, and consider early use of antifungal agents if the disease does not respond to antibiotics^{[28, 39]}
• Avoidance of certain medications – Anticholinergic agents, antidiarrheal drugs, and narcotics may worsen the condition or further confuse the clinical picture of neutropenic enterocolitis

Withhold further chemotherapy until complete recovery from neutropenic enterocolitis occurs.

Diet and activity

Because the patient is fasting and on bowel rest, consider parenteral nutrition. Patients with neutropenic enterocolitis are usually extremely ill and in the ICU on complete bed rest.^[28]

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Surgical Care

Immediate surgery was proposed by Shamberger et al in patients with neutropenic enterocolitis with the following indications^[18] :

• Free intra-abdominal perforation
• Clinical deterioration during conservative medical therapy
• Differentiation from other acute abdominal conditions for which surgery is indicated
• Unrelenting intra-abdominal sepsis or abscess formation
• Continued hemorrhage with a platelet count and coagulation parameters within the reference range

Tailor the surgical procedure to the operative findings.

Surgical options include the following:

• Cecostomy and drainage
• Two-stage right hemicolectomy or total abdominal colectomy, with or without a primary anastomosis
• Defunctioning of the colon with a loop ileostomy

Normal-appearing serosal surfaces may conceal mucosal breakdown and necrosis. Therefore, resection should be extensive to assure removal of the diseased bowel.

Consider elective right hemicolectomy in patients who have required repeated courses of chemotherapy and who have responded to initial conservative medical therapy. Recurrent episodes of neutropenic enterocolitis have been reported in such patients.

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Prevention

Consider antibiotic prophylaxis in neutropenic patients. A meta-analysis by Gafter-Gvili suggested an overall mortality benefit with antibiotic prophylaxis, although this is not specific to neutropenic enterocolitis.^[40]  Another meta-analysis suggested a mortality benefit in primary prophylaxis with granulocyte colony-stimulating factors (GCSFs) in adult cancer patients, but it was also not specific to neutropenic enterocolitis.^[41]

Consider an elective right hemicolectomy in patients with neutropenic enterocolitis who have successfully recovered and may require repeated courses of chemotherapy in the near future.^[1]

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Medication Summary

Because patients with neutropenic enterocolitis have often received numerous courses of antibiotics previously for other indications, a specific agent or regimen cannot be recommended, and the decision must be made on an individual basis. However, a few possible choices of antibiotics and antifungals are listed below. The author favors a combination of amikacin plus imipenem or cefepime/ceftazidime plus metronidazole in addition to vancomycin.

Consider adding antifungal agents if clinical improvement does not occur with antibiotics.

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Metronidazole (Flagyl)

• Dosing, Interactions, etc.

Clinical Context:  Synthetic antibacterial with good activity against gram-negative anaerobes, including Bacteroides species, and gram-positive anaerobes, including Clostridium species.

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Cefepime (Maxipime)

• Dosing, Interactions, etc.

Clinical Context:  Fourth-generation cephalosporin with good gram-negative coverage. Similar to third-generation cephalosporins but has better gram-positive coverage. Covers pseudomonads.

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Ceftazidime (Ceptaz, Fortaz)

• Dosing, Interactions, etc.

Clinical Context:  Semisynthetic, broad-spectrum, third-generation cephalosporin covering predominantly gram-negative aerobes, including pseudomonads. Provides poor coverage against gram-positive organisms and anaerobes.

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Ceftriaxone (Rocephin)

• Dosing, Interactions, etc.

Clinical Context:  Semisynthetic, broad-spectrum, third-generation cephalosporin covering gram-negative aerobes and anaerobes, including Bacteroides and Clostridium species. Not reliable for coverage against pseudomonads.

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Ticarcillin and clavulanate (Timentin)

• Dosing, Interactions, etc.

Clinical Context:  Antipseudomonal penicillin plus beta-lactamase inhibitor that provides coverage against most gram-positive organisms, most gram-negative organisms, and most anaerobes.

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Piperacillin and tazobactam (Zosyn)

• Dosing, Interactions, etc.

Clinical Context:  Antipseudomonal penicillin plus beta-lactamase inhibitor. Inhibits biosynthesis of cell wall mucopeptide and is effective during the stage of active multiplication.

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Vancomycin (Vancocin, Lyphocin)

• Dosing, Interactions, etc.

Clinical Context:  Tricyclic glycopeptide indicated for the treatment of suspected or confirmed serious infection with methicillin-resistant staphylococci, an entity not uncommonly observed in patients who are severely ill and in the intensive care setting.

To avoid toxicity, the current recommendation is to assay vancomycin trough levels after the third dos, drawn 0.5 h before next dosing. Use creatinine clearance to adjust dose in patients diagnosed with renal impairment.

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Imipenem and cilastatin (Primaxin)

• Dosing, Interactions, etc.

Clinical Context:  Potent broad-spectrum combination antibiotic consisting of a thienamycin class of antibiotic and cilastatin, which is an inhibitor of renal dipeptidase. Coverage includes gram-negative aerobes and anaerobes.

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Amikacin (Amikin)

• Dosing, Interactions, etc.

Clinical Context:  For gram-negative bacterial coverage of infections resistant to gentamicin and tobramycin. Effective against Pseudomonas aeruginosa.

Irreversibly binds to the 30S subunit of bacterial ribosomes. Blocks the recognition step in protein synthesis and causes growth inhibition. Use the patient's IBW (ideal body weight) for dosage calculation.

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Gentamicin (Garamycin)

• Dosing, Interactions, etc.

Clinical Context:  Water-soluble aminoglycoside antibiotic with good coverage against gram-negative aerobes. Used in conjunction with other antibiotics for broad-spectrum coverage in intra-abdominal infections. Coadministration with carbenicillin or piperacillin provides synergistic effects against most strains of Pseudomonas aeruginosa. Follow each regimen by at least a trough level drawn on the third or fourth dose (0.5 h before dosing). May draw a peak level 0.5 h after 30-min infusion.

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Tobramycin (Nebcin)

• Dosing, Interactions, etc.

Clinical Context:  Used in bone and skin structure infections caused by Staphylococcus aureus, P aeruginosa, Proteus species, Escherichia coli, Klebsiella species, and Enterobacter species. Indicated in the treatment of staphylococcal infections when penicillin or potentially less toxic drugs are contraindicated and when bacterial susceptibility and clinical judgment justifies its use.

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Class Summary

Empiric broad-spectrum antibiotics are recommended to cover potential primary or secondary infectious causes of neutropenic enterocolitis and to control sepsis. The antibiotics should cover aerobic and anaerobic enteric organisms, including Clostridium species, because anecdotal reports reveal an association between Clostridium septicum and neutropenic enterocolitis.

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Amphotericin B (Amphocil, Fungizone)

• Dosing, Interactions, etc.

Clinical Context:  Produced by a strain of Streptomyces nodosus. Can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak, with subsequent fungal cell death.

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Class Summary

Consider adding antifungal agents if no clinical improvement occurs with broad-spectrum antibiotics. Amphotericin B is the preferred agent because non-albicans candidemia is more likely to be present and is usually fluconazole resistant. Consider liposomal amphotericin B if the infection is refractory to conventional amphotericin or in patients with renal failure.

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