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35-Year-Old Man With Fever and Abdominal Pain

      A 35-year-old man came to our emergency department with fever (temperature, 38.4°C), a 2-day history of crampy intermittent abdominal pain localized to the right lower quadrant, and loose nonbloody stools. His medical history was notable for acute promyelocytic leukemia, for which he was receiving induction chemotherapy. The abdominal pain was not associated with positional changes, eating, bowel movements, or other factors. The patient had last received chemotherapy 10 days previously. A review was negative for mouth sores, nausea, or vomiting or for recent travel. The patient had no history of abdominal surgery, and family history was noncontributory.
      On physical examination, the patient was febrile (temperature, 38.4°C), with pulse rate of 132/min, supine blood pressure of 108/56 mm Hg, and respiratory rate of 20 breaths/min. He appeared fatigued but in no acute distress. Skin was without rashes, and the port-a-catheter site did not seem to be infected. Abdominal examination revealed normoactive bowel sounds and moderate tenderness to palpation in the right lower quadrant, without guarding or rigidity. The perirectal area was without lesions, and digital rectal examination was not performed. Results of the remainder of the complete multisystem examination were unremarkable.
      Laboratory studies revealed the following values (reference ranges shown parenthetically): hemoglobin, 12.3 g/dL (13.5-17.5 g/dL); leukocyte count, 0.1 × 109/L (3.5-10.5 × 109/L); absolute neutrophil count (ANC), 91 cells/μL (1500-8000 cells/μL); platelet count, 127 × 109/L (150-450 ×109/L); sodium, 138 mEq/L (135-145 mEq/L); potassium, 3.6 mEq/L (3.6-5.2 mEq/L); chloride, 105 mEq/L (100-108 mEq/L); bicarbonate, 27 mEq/L (22-29 mEq/L); serum urea nitrogen, 22 mg/dL (8-24 mg/dL); creatinine, 0.8 mg/dL (0.8-1.3 mg/dL); calcium, 8.3 mg/dL (8.9-10.1 mg/dL); aspartate aminotransferase, 76 U/L (8-48 U/L); alanine aminotransferase, 51 U/L (7-55 U/L); alkaline phosphatase, 47 U/L (52-144 U/L); and total bilirubin, 0.7 mg/dL (0.1-1.0 mg/dL).
      • 1.
        Which one of the following would be the most appropriate initial medical therapy in this patient with fever and neutropenia?
        • a.
          Antipseudomonal β-lactam plus vancomycin plus metronidazole
        • b.
          Antipseudomonal β-lactam plus vancomycin
        • c.
          Antipseudomonal β-lactam plus voriconazole
        • d.
          Ciprofloxacin plus amoxicillin-clavulanate
        • e.
          Antipseudomonal β-lactam plus granulocyte colony-stimulating factor (G-CSF)
      Because of risk of serious life-threatening infection in all patients with neutropenic fever, empiric broad-spectrum antibiotic therapy should be initiated within 60 minutes of presentation. Initiation of antipseudomonal β-lactam monotherapy with meropenem, cefepime, or piperacillin-tazobactam is appropriate to empirically cover gram-positive and gram-negative infections. Vancomycin should be added if there is suspected catheter-associated infection; skin and soft tissue infection such as severe mucositis; or hypotension, as in this patient.
      • Freifeld A.G.
      • Bow E.J.
      • Sepkowitz K.A.
      • et al.
      Infectious Diseases Society of America
      Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America.
      Metronidazole may be added in patients with suspected Clostridium difficile infection. Antifungal therapy is typically added in patients with persistent neutropenic fever after more than 4 to 7 days of appropriate antimicrobial therapy and if the duration of neutropenia is expected to be longer than 7 days. Amphotericin B, voriconazole, and caspofungin are acceptable alternatives.
      • Walsh T.J.
      • Pappas P.
      • Winston D.J.
      • et al.
      National Institute of Allergy and Infectious Diseases Mycoses Study Group
      Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever.
      • Cornely O.A.
      • Maertens J.
      • Winston D.J.
      • et al.
      Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia.
      In patients at low risk, initial oral empiric antibiotic therapy may be given; the combination of ciprofloxacin and amoxicillin-clavulanate is commonly recommended.
      • Freifeld A.
      • Marchigiani D.
      • Walsh T.
      • et al.
      A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy.
      Colony-stimulating factors such as G-CSF are not generally recommended for treatment of febrile neutropenia but can be considered as adjuvant therapy in selected cases in which prolonged duration of neutropenia is expected.
      • Ozer H.
      • Armitage J.O.
      • Bennett C.L.
      • et al.
      American Society of Clinical Oncology
      2000 Update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines; American Society of Clinical Oncology Growth Factors Expert Panel.
      Meropenem, vancomycin, and metronidazole were initiated to treat neutropenic fever in this patient with leukemia, an indwelling catheter, and diarrhea. The patient remained hemodynamically stable but continued to experience crampy right lower quadrant abdominal discomfort.
      • 2.
        Which one of the following would be the least appropriate test for evaluating the symptoms in this patient?
        • a.
          Blood cultures
        • b.
          C difficile stool toxin
        • c.
          Computed tomography (CT) of the abdomen
        • d.
          Colonoscopy
        • e.
          Ultrasonography of the abdomen
      Blood cultures should be obtained from each lumen of a central venous catheter and peripheral blood in any patient with febrile neutropenia, ideally before administration of antibiotic therapy. Bacteremia occurs in only 10% to 25% of patients with neutropenic fever.
      • Freifeld A.G.
      • Bow E.J.
      • Sepkowitz K.A.
      • et al.
      Infectious Diseases Society of America
      Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America.
      Our patient had gastrointestinal symptoms including abdominal pain and diarrhea, which is considered a comorbid medical condition that placed him at high risk of serious complications. A stool specimen should be evaluated for C difficile toxin because this infection can be catastrophic in the setting of neutropenia. Computed tomography affords a detailed assessment of bowel integrity to assist in the differential diagnosis of fever and abdominal pain, with high specificity for related diagnoses including appendicitis, typhlitis, diverticulitis, C difficile–associated disease, obstruction, and intra-abdominal abscess. Colonoscopy and other invasive tests such as barium enema are relatively contraindicated in the presence of neutropenia. Manipulation of the rectal and colonic mucosa may provoke bacteremia, and air insufflation may result in perforation if mucosal integrity is compromised. Ultrasonography is a useful diagnostic tool for abdominal pain because it is relatively inexpensive, can be performed at the bedside, and may enable identification of cholecystitis, appendicitis, or ovarian torsion.
      Contrast-enhanced CT revealed mural thickening and edema of the right colon and a moderate volume of liquid stool in the distal sigmoid colon and rectum. Stool was negative for C difficile toxin.
      • 3.
        On the basis of available information, which one of the following conditions is the most likely diagnosis at this point?
        • a.
          Ischemic colitis
        • b.
          Typhlitis
        • c.
          Appendicitis
        • d.
          Colonic obstruction
        • e.
          Pseudomembranous colitis
      Ischemic colitis is an unlikely diagnosis in this patient. It classically occurs in older patients with a history of comorbidities including atrial fibrillation, myocardial infarction, or evidence of atherosclerosis. In addition, pain was not out of proportion with examination findings, which can be a sign of ischemic bowel. Among the diagnoses listed, typhlitis is most likely and should be included in the differential diagnosis. Typhlitis, also known as neutropenic enterocolitis, is an inflammation of the bowel with a predilection for the cecum that occurs in the setting of neutropenia. Clinical criteria for the diagnosis include the triad of fever, abdominal pain, and neutropenia. Our patient met all 3 of these criteria and had characteristic CT findings of right-sided colonic thickening and intramural edema. Typhlitis mimics acute appendicitis in that both may cause pain localized to the right lower quadrant. Differentiating the 2 conditions is crucial for management, and CT usually enables differentiation of cecal vs appendiceal inflammation.
      • Ullery B.W.
      • Pieracci F.M.
      • Rodney J.R.
      • Barie P.S.
      Neutropenic enterocolitis.
      Computed tomography did not reveal a colonic mass or evidence of obstruction. Our patient lacked signs of obstruction such as nausea, vomiting, or inability to pass gas or stool and was younger than expected for colon cancer. Pseudomembranous colitis is less likely in the absence of recent antibiotic exposure or hospitalization. Stool C difficile polymerase chain reaction assay was negative for toxins A and B, with up to 93% sensitivity and 97% specificity for the diagnosis.
      • Peterson L.R.
      • Manson R.U.
      • Paule S.M.
      • et al.
      Detection of toxigenic Clostridium difficile in stool samples by real-time polymerase chain reaction for the diagnosis of C. difficile-associated diarrhea.
      The diagnosis was typhlitis, the most common gastrointestinal infection related to neutropenia, and the patient was admitted to the hospital for further management.
      • 4.
        Which one of the following is most appropriate in the management of this patient’s condition?
        • a.
          Observation
        • b.
          Broad-spectrum antibiotic therapy, bowel rest, and administration of G-CSF
        • c.
          Surgical intervention
        • d.
          Administration of antimotility agents including loperamide
        • e.
          Aggressive pain control with narcotic agents
      Observation is not indicated in patients with typhlitis because of risk of severe complications including sepsis, bowel wall perforation, and gastrointestinal bleeding. Studies performed before the acceptance of early recognition and treatment have cited mortality of 40% to 50%.
      • Ullery B.W.
      • Pieracci F.M.
      • Rodney J.R.
      • Barie P.S.
      Neutropenic enterocolitis.
      Broad-spectrum antibiotic therapy should be promptly initiated in typhlitis because microbial invasion of the bowel wall is thought to be central to its pathogenesis. Similar to the treatment of ileus, supportive care is essential in typhlitis, with bowel rest, nasogastric decompression to relieve obstruction, and fluid resuscitation. The American Society of Clinical Oncology does not routinely recommend G-CSF in febrile neutropenia; however, they consider its use in patients at high risk such as those with expected prolonged or profound neutropenia (ANC <100 cells/μL).
      • Ozer H.
      • Armitage J.O.
      • Bennett C.L.
      • et al.
      American Society of Clinical Oncology
      2000 Update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines; American Society of Clinical Oncology Growth Factors Expert Panel.
      Granulocyte colony-stimulating factor reduces the mortality of typhlitis in retrospective studies and should be considered for reversal of neutropenia.
      • Ullery B.W.
      • Pieracci F.M.
      • Rodney J.R.
      • Barie P.S.
      Neutropenic enterocolitis.
      Early surgery is indicated in typhlitis because of clinical deterioration noted on serial examinations or to treat complications of the disease such as peritonitis, gangrenous bowel, perforation, or severe gastrointestinal bleeding.
      • Wade D.S.
      • Nava H.R.
      • Douglass Jr., H.O.
      Neutropenic enterocolitis: clinical diagnosis and treatment.
      The standard approach is laparotomy and resection of the involved bowel. Antidiarrheal and opioid agents are not indicated because they may potentiate ileus.
      Our patient received supportive measures, meropenem for 7 days, and G-CSF. Metronidazole was discontinued after C difficile toxin assay yielded negative findings. The patient experienced substantial improvement of abdominal pain, and repeated imaging after 2 weeks showed resolution of colonic inflammation. The patient had many questions about the new diagnosis and was educated about the risk factors for severe infection in the setting of neutropenia.
      • 5.
        When counseling this patient about his infectious illness, which one of the following statements would be most appropriate?
        • a.
          Prophylactic antibiotic therapy decreases both episodes of febrile neutropenia and mortality
        • b.
          Fungi are frequently the cause of fever early in the course of neutropenia
        • c.
          Severity and duration of neutropenia are not useful when defining patients at low or high risk
        • d.
          Most neutropenic fever syndromes result from colonizing bacteria rather than newly acquired infection
        • e.
          An infectious source is found in approximately 60% of febrile neutropenic episodes
      Fluoroquinolone prophylaxis should be considered in patients at high risk with neutropenia because it decreases febrile episodes and bacterial infections, although it has no effect on mortality.
      • Bucaneve G.
      • Micozzi A.
      • Menichetti F.
      • et al.
      Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) Infection Program
      Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia.
      Fungal infections are a rare cause of early neutropenic fever, and the risk of invasive fungal infection increases with the duration of neutropenia; therefore, antifungal agents may be added to the treatment of febrile neutropenia after 4 to 7 days. Patients are considered at high risk of severe infection with neutropenia lasting longer than 7 days with an ANC of less than 100 cells/μL and/or comorbidities including hemodynamic instability, new abdominal pain, altered mental status, catheter-related infection, or hepatic or renal insufficiency. Colonizing bacteria are thought to invade mucosal surfaces and seed the bloodstream, resulting in fever in immunocompromised patients. Newly acquired infections due to environmental exposures are less common; thus, patients may use public transportation and interact with friends and family members. In most cases, an infectious source responsible for the episode of neutropenic fever is not identified, and documented infections occur in only 20% to 30% of febrile neutropenic episodes.
      • Freifeld A.G.
      • Bow E.J.
      • Sepkowitz K.A.
      • et al.
      Infectious Diseases Society of America
      Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America.
      Despite resolution of typhlitis, our patient had prolonged neutropenia and subsequently developed invasive fungal sinusitis requiring extensive surgical debridement and a prolonged stay in the intensive care unit.

      Discussion

      Fever may be the earliest and only symptom of infection during chemotherapy-induced neutropenia. The definition of febrile neutropenia is a single oral temperature of higher than 38.3°C (101°F) or a temperature higher than 38.0°C (100.4°F) sustained for an hour in a patient with an ANC level of less than 500 cells/μL. Absolute neutrophil count reaches its nadir at a median of 7 to 14 days after initiation of induction chemotherapy. Nearly 50% of patients with solid tumors and 80% with hematologic malignancies will develop fever during more than 1 chemotherapy cycle associated with neutropenia.
      • Klastersky J.
      Management of fever in neutropenic patients with different risks of complications.
      Physicians are likely to encounter neutropenic fever in their practice and should be comfortable with the initial workup and treatment.
      The diagnostic approach to febrile neutropenia should include a complete blood cell count, electrolyte panel, testing for hepatic and renal function, urinalysis, and at least 2 sets of blood cultures, with a set collected from each lumen of an existing central venous catheter and a set collected from a distant site. Predisposing factors for infection include catheters, skin breakdown, and mucositis throughout the gastrointestinal tract. The history should elucidate specific symptoms, recent antimicrobial use, and infection exposures. The physical examination requires careful attention to skin, oropharynx, lungs, perirectal area, and surgical and catheter sites. Clinical findings may be extremely subtle because of inability of the patient to mount an inflammatory response in the setting of neutropenia; therefore, high clinical suspicion and low threshold to proceed with higher-resolution imaging are warranted.
      The initial assessment should not preclude early initiation of broad-spectrum antibiotic therapy. Bacteremia with gram-positive, gram-negative, and polymicrobial infection occurs in 57%, 34%, and 9% of cases, respectively, although only 23% of episodes are associated with bacteremia.
      • Ozer H.
      • Armitage J.O.
      • Bennett C.L.
      • et al.
      American Society of Clinical Oncology
      2000 Update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines; American Society of Clinical Oncology Growth Factors Expert Panel.
      Effective empiric regimens require bactericidal gram-positive and gram-negative activity including antipseudomonal coverage because of the high mortality associated with this infection. Meropenem, cefepime, and piperacillin-tazobactam are appropriate choices. Vancomycin is not included in the initial regimen because randomized studies have found no substantial reduction in either the duration of fever or overall mortality.
      • Paul M.
      • Borok S.
      • Fraser A.
      • Vidal L.
      • Leibovici L.
      Empirical antibiotics against Gram-positive infections for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials.
      Metronidazole is added to treat abdominal symptoms or suspected C difficile infection, as in our patient. Empiric antibiotic therapy is generally continued until an infection directing further treatment is identified or neutropenia and fever resolve.
      • Klastersky J.
      • Ameye L.
      • Maertens J.
      • et al.
      Bacteraemia in febrile neutropenic cancer patients.
      Identification of an infectious source on laboratory, imaging, or clinical evaluation will guide further management. Common sites of infection in febrile neutropenia include the skin, lungs, and intestinal and urinary tracts. In general, central venous catheters are considered infected if blood cultures drawn from those catheters become positive at least 120 minutes before peripheral blood cultures. Central venous catheter removal is indicated in Staphylococcus aureus, Pseudomonas aeruginosa, fungal, and mycobacterial catheter-related blood stream infections.
      • Freifeld A.G.
      • Bow E.J.
      • Sepkowitz K.A.
      • et al.
      Infectious Diseases Society of America
      Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America.
      Unique infections associated with neutropenia include herpes simplex virus– or Candida-associated esophagitis, invasive fungal pneumonia and rhinosinusitis, and typhlitis.
      The incidence of typhlitis, also known as neutropenic enterocolitis, is approximately 5% among patients receiving chemotherapy for solid tumors.
      • Ullery B.W.
      • Pieracci F.M.
      • Rodney J.R.
      • Barie P.S.
      Neutropenic enterocolitis.
      Diagnosis is centered about the classic triad of fever, abdominal pain, and neutropenia and the characteristic CT findings of bowel wall thickening greater than 4 mm and edema. The invasive, infectious process may involve nearly any part of the gastrointestinal tract but, for unknown reasons, has a predilection for the cecum. Pathologic changes include mucosal injury followed by microbial invasion of the bowel wall, leading to inflammation, edema, ulceration, and transmural necrosis. The mainstay of treatment includes bowel rest, fluid resuscitation, nasogastric suction, supplemental nutrition, and antibiotic therapy. Mortality is as high as 30% to 50%, with deaths attributed to bowel necrosis, perforation, and sepsis.
      • Ullery B.W.
      • Pieracci F.M.
      • Rodney J.R.
      • Barie P.S.
      Neutropenic enterocolitis.
      Because neutropenic infections can be life threatening, it is important for clinicians to perform an appropriate diagnostic workup, prescribe appropriate therapy, and perform timely follow-up. Health care professionals, including primary care physicians and specialists, should inform patients and their families that any fever in the setting of recent chemotherapy warrants further medical evaluation and early initiation of appropriate broad-spectrum antibiotic therapy.

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        • Bow E.J.
        • Sepkowitz K.A.
        • et al.
        • Infectious Diseases Society of America
        Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America.
        Clin Infect Dis. 2011; 52: e56-e93
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        • Pappas P.
        • Winston D.J.
        • et al.
        • National Institute of Allergy and Infectious Diseases Mycoses Study Group
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        Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia.
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        • Freifeld A.
        • Marchigiani D.
        • Walsh T.
        • et al.
        A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy.
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        • Armitage J.O.
        • Bennett C.L.
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        • American Society of Clinical Oncology
        2000 Update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines; American Society of Clinical Oncology Growth Factors Expert Panel.
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        • Micozzi A.
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        Management of fever in neutropenic patients with different risks of complications.
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        • Leibovici L.
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