Neutropenic Enterocolitis Gastrointestinal Infection

chemotherapy McCarville et al. 2005 ; Sundell et al. 2012 . Case series suggest that patients with acute myelogenous leukemia AML are at high risk for typhlitis in any phase of therapy Gray et al. 2010 . Symptoms of neutropenic enterocolitis are nonspecifi c and highly variable and include abdominal pain, vomiting, diarrhea and GI bleed- ing McCarville et al. 2005 ; Sundell et al. 2012 . Signs can include fever, abdominal distension, tachycardia, hypotension, sepsis, and peritoneal irritation that can be diffuse or localized to the right lower quadrant Sundell et al. 2012 . Uncommonly a cecal mass is palpable Haut 2005 ; Gray et al. 2010 . Appendicitis, pancreati- tis, pseudomembranous colitis, intussusception, and pelvic or peritoneal abscess should be con- sidered in the differential diagnosis. In the neutropenic patient with acute abdomi- nal pain, a two-view plain radiograph should fi rst be obtained as it may show an appendicolith, pneumatosis, or free air. Plain radiographs may support the diagnosis of enterocolitis with fi nd- ings of pneumatosis and bowel wall thickening although most fi ndings are nonspecifi c Fisher and Rheingold 2011 ; Pizzo 2011 ; Sundell et al. 2012 . Presence of free air will require immedi- ate surgical consultation and intervention. Contrast enema is contraindicated if neutropenic enterocolitis is suspected as it may lead to perfo- ration Arul and Spicer 2008 ; Morgan et al. 2011 . Ultrasound US is the preferred imaging modality for demonstrating bowel wall thicken- ing McCarville et al. 2005 . A diagnosis of enterocolitis consists of bowel wall thickening 3 mm, and mortality rates increase when bowel wall thickening exceeds 10 mm Pizzo 2011 ; Sundell et al. 2012 . If US results are inconclu- sive, computed tomography CT is the current defi nitive imaging study Cloutier 2010 ; Pizzo 2011 . CT is very sensitive for identifying cecal wall thickening, transmural infl ammation, soft tissue masses and pneumatosis. A characteristic feature of typhlitis on CT is necrosis localized to the cecum. Both US and CT may reveal a target sign, an echogenic center with a wide hypoecho- genic periphery, at the cecum in typhlitis. CT may overestimate bowel wall thickening leading to false- positive diagnoses of enterocolitis and typhlitis. Magnetic resonance imaging MRI for the diagnosis of neutropenic enterocolitis has not been reported in the medical literature. Supportive management of enterocolitis has typically included complete gut rest NPO dur- ing the acute phase of symptomatic pain, paren- teral nutrition while NPO and nasogastric suctioning for decompression Sundell et al. 2012 . However, evidence regarding the benefi t of these interventions is lacking. Narcotics should be utilized for anal gesia. Vasopressor support may be required; hypotension is associated with poor outcome. Patients may require packed red blood cell and platelet transfusions Albano and Sandler 2004 ; Pizzo 2011 . The utility of granu- locyte colony- stimulating factor GCSF in patients with enterocolitis is unclear, and the use of GCSF is discussed in more detail in Chap. 15 . A non-evidence- based argument to support GCSF use is generally that resolution of neutro- penia parallels resolution of typhlitis Fisher and Rheingold 2011 . On the other hand, GCSF could theoretically increase infl ammation and cause obstruction. Early imaging and rapid initiation of antimi- crobials are vital, as these interventions may decrease mortality in neutropenic enterocolitis. Antibacterial therapy should be broad to cover for enteric pathogens, especially Gram-negative and anaerobic microbes in addition to Gram- positive enterococcal species. Cloutier 2010 suggests that monotherapy with piperacillin- tazobactam or imipenem-cilastatin or dual ther- apy with either ceftazidime or cefepime with metronidazole is suffi cient initial coverage for neutropenic enterocolitis. Metronidazole is the generally preferred anaerobic coverage given the similar clinical features of typhlitis and pseudo- membranous enterocolitis due to C. diffi cile Sundell et al. 2012 . Such regimens have not been specifi cally studied in pediatric neutropenic enterocolitis. Typhlitis is an oncologic emergency because it may lead to bowel obstruction or perforation requiring surgical intervention Haut 2005 . Consultation with surgery should be requested early, even if surgery is not anticipated. Surgery should be deferred until supportive therapy has clearly failed or the following complications develop: perforation, hemorrhage despite correc- tion of thrombocytopenia and coagulopathies, obstruction, necrosis, abscess or peritonitis requiring drainage, fi stula, toxic megacolon, or septic shock Gray et al. 2010 ; Morgan et al. 2011 ; Sundell et al. 2012 . Surgery consists of visualization and management of bleeding, resecting necrotic portions of the bowel, and possible transient diversion via colostomy Pizzo 2011 .

7.2.2 Appendicitis

Incidence of appendicitis in pediatric leukemia and lymphoma is the same as the general popula- tion, ranging from 0.5–1.5 Hobson et al. 2005 ; Fisher and Rheingold 2011 . Signs and symptoms of appendicitis may overlap with neu- tropenic colitis; in the patient who does not improve with medical management for enteroco- litis, the physician should consider appendicitis Albano and Sandler 2004 . In the review by Hobson et al. 2005 , they found that pediatric oncology patients had inconsistent clinical signs and symptoms of appendicitis, routinely lacked fever and often lacked localizing signs on abdom- inal exam. However, in a similar cohort, Chui et al. 2008 reported that fever was common and the majority presented with localizing abdominal signs prior to surgery. In both cohorts, a delay in diagnosis was common Hobson et al. 2005 ; Chui et al. 2008 . Although a KUB may show an appendicolith to diagnosis appendicitis, a staged protocol with US followed by CT in those patients with an equivocal US has been found accurate and cost- effi cient in the regular pediatric population while reducing radiation exposure Wan et al. 2009 ; Krishnamoorthi et al. 2011 . Whether this meth- odology is effective for pediatric oncology patients is unknown. Hobson et al. 2005 noted that CT evaluation was not accurate in their cohort of pediatric oncology patients, with only 2 of 7 patients having classic CT fi ndings. Again, Chui et al. 2008 reported dissimilar results as 8 of 10 patients had CT imaging consistent with appendicitis. Additionally, patients with typhlitis have been noted to have appendiceal thickening of uncertain signifi cance in a small percentage of cases and not correlated with development of appendicitis McCarville et al. 2004 . Isolated appendiceal typhlitis has also been noted in case reports McAteer et al. 2014 . Management of acute appendicitis during neu- tropenic episodes remains somewhat controver- sial. Small case series have shown that medical management with broad spectrum antibiotics has resulted in resolution of symptoms without recur- rence Wiegering et al. 2008 . Others suggest that surgery remains the defi nitive treatment modality even in the presence of neutropenia, with the ante- cedent potential for infectious complications and delayed wound healing, given the potential risks of ruptured appendicitis Hobson et al. 2005 ; Chui et al. 2008 . It is unclear if those patients who were medically managed had appendicitis or rather isolated appendiceal typhlitis. It has also been argued that pediatric oncology patients undergoing a primary abdominal operation have incidental appendectomy to decrease future risk of appendicitis especially during periods of neu- tropenia Steinberg et al. 1999 .

7.2.3 Perirectal Abscess

Prolonged severe neutropenia can also lead to the development of perirectal abscess. Most abscesses are polymicrobial, including Gram- negative, Gram-positive and anaerobic organ- isms. Commonly seen microbes are E. coli , P. aeruginosa , and staphylococcal and strepto- coccal species Pizzo 2011 . Perirectal abscesses are often occult. Patients infrequently complain of anorectal pain, which can be independent of defecation. Since neutropenia precludes the development of purulence, exam may yield only erythema, tenderness to anorectal palpation, edema or cellulitis Pizzo 2011 . Perianal exami- nation is essential in the neutropenic patient to monitor for this potential complication; rectal examination should be avoided due to concern for damaging friable mucosa and introducing bacteria Büyükaşik et al. 1988 ; Wolfe and Kennedy 2011 ; Mercer-Falkoff and Lacy 2013 . Initial medical management of perirectal abscess includes sitz baths to provide symptom- atic relief as well as laxatives and stool softeners to minimize painful defecation and prevent fi s- sures and tears. As with enterocolitis, broad- spectrum parenteral antibiotics should be utilized. GCSF can be considered in the neutropenic patient although there is no evidence to support its usage. Surgical management may include incision and drainage, debridement, or further intervention but only if there is a fl uctuant mass, large amounts of necrotic tissue, progression to necrotizing fasciitis, or a persistent fi stula Arul and Spicer 2008 ; Pizzo 2011 .

7.3 Gastrointestinal

Hemorrhage Severe GI hemorrhage requires immediate medical, and potentially, surgical intervention. Common etiologies include gastritis or esophagi- tis, ulcers, necrotizing pancreatitis, primary GI tumors, infection, and radiation-induced infl am- mation and micro vascular damage i.e., mucosal telangiectasias. Hemorrhagic gastritis of varying severity may occur in almost half of pediatric oncology patients Kaste et al. 1999 . Common etiologies of ulcer formation include peptic ulcer disease, infection, increased intracranial pressure stimulating the vagal nerve and parietal cells Cushing’s ulcer, and steroids. Esophageal bleeding results from progressive esophageal varices associated with portal hypertension or Mallory-Weiss tears with repeated emesis. Tumors precipitate bleeding by vascular infi ltra- tion or abnormal tumor vessel growth direct damage as well as infarctions and lacerations via mass effect indirect damage. Common infec- tious agents that may trigger signifi cant bleeding include fungi such as Candida spp., viral patho- gens including Herpesviridae , C. diffi cile , and the opportunistic protozoan cryptosporidium Kaste et al. 1999 ; Fisher and Rheingold 2011 . Sepsis and disseminated intravascular coagula- tion can exacerbate bleeding. Anti- angiogenic chemotherapeutic agents such as bevacizumab, sunitinib, and sorafenib can cause severe bleeding, poor wound healing, and gastric perfo- ration; such adverse manifestations should prompt immediate discontinuation. Ginkgo biloba, a commonly utilized nutritional supplement for fatigue, depression and memory loss, has been associated with an increased bleeding risk Demshar et al. 2011 . Oncology patients should avoid aspirin and nonsteroidal anti- infl ammatory drugs NSAIDs to reduce bleeding risk. Signs and symptoms of GI hemorrhage vary. Symptoms include pain, hematemesis, melena or hematochezia, and anemia-induced symptoms and signs such as fatigue, headache, dizziness, syncope, dyspnea, pallor, and oliguria. To pre- vent aspiration, the patient’s head of the bed should be at an angle of 30–45° Fisher and Rheingold 2011 . In the patient with signs or symptoms of volume depletion, immediate bolus intravenous isotonic crystalloid fl uids should be initiated and type O − red blood cells considered while awaiting results of blood counts and for preparation of crossmatched packed red blood cells. If thrombocytopenia is suspected, empiric platelet transfusion can also be considered. If hypotension persists despite appropriate fl uids and blood products, vasopressors are indicated. The initial emergent laboratory workup includes: 1 complete blood count CBC to evaluate severity of anemia and thrombocytopenia; 2 coagulation evaluation with prothrombin, partial thromboplastin time and fi brinogen; and 3 type and cross in preparation for blood products. Setting goals and anticipating blood loss will maximize safety. Goals include: 1 correction of anemia, with maintenance of hemoglobin ≥8 g dL; 2 correction of throm bocytopenia, with maintenance of platelets ≥75 × 10 9 L; and 3 correction of any coagulopathy with either fresh frozen plasma or fi brinogen. Complete gut rest may be augmented with histamine blockers or proton pump inhibitors. The necessity of gastric lavage remains unclear. In non-oncology adult patients, the aspirate results determine an individual’s pre- endoscopic risk stratifi cation. A high-risk lesion consists of a bleeding lesion or visible vessel on endoscopy. A bloody versus “coffee-ground” or bilious aspirate is 75 specifi c for an active