Fever in a Woman With an Abnormal White Blood Cell Count

HISTORY

The patient has a small-fiber sensory neuropathy that is managed with lamotrigine. She is a physical therapy student who has frequent patient contact. She drinks alcohol occasionally but denies smoking and illicit drug use; she says she is not sexually active.

PHYSICAL EXAMINATION

This uncomfortable-appearing woman has a heart rate of 116 beats per minute and an oral temperature of 39.6°C (103.2°F); all other vital signs are normal. Her face is flushed, but no cervical or axillary lymphadenopathy is noted. Heart rhythm is regular, with no murmurs, and lungs are clear. Abdomen is normal. No neurological deficits are noted, and she is oriented to time and place.

LABORATORY AND IMAGING STUDIES

White blood cell count is 1100/μL, with 40% neutrophils, 3% band forms, and 50% lymphocytes. Hemoglobin level is 12.2 g/dL, and platelet count is 116 x 10³/μL. Results of a basic metabolic panel, liver function tests, and urinalysis are unremarkable. A chest radiograph is normal.

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CORRECT ANSWER: C

This woman has neutropenic fever, which is defined as a single oral temperature of 38.3°C (101°F) or higher-or a temperature of 38°C (100.4°F) or higher for more than 1 hour-in a patient whose absolute neutrophil count (ANC) is less than 500/μL or less than 1000/μL but predicted to decrease to less than 500/μL.¹ Causes of neutropenia include disorders of production that are related to cytotoxic medications, immunosuppressive agents, hematological malignancies, or a number of infrequently seen congenital disorders; and disorders that affect neutrophil turnover and distribution, including immune-mediated and drug-induced disorders and neutropenia associated with infectious diseases.²

Initial evaluation. This should include a detailed history and a physical examination that involves careful inspection of the skin and mucous membranes, the perirectal area (although a digital rectal examination should be avoided), and any indwelling catheters and lines. Recommended initial laboratory studies include a complete blood cell count with differential count and levels of transaminases, bilirubin, amylase, and electrolytes. Obtain at least 2 blood samples for culture; a sputum sample for Gram staining and culture; and a urine sample for urinalysis, urine Gram staining, and culture. Obtain a chest radiograph in all patients; consider ordering a chest CT scan-even if the chest film is normal-if another source of infection is not found.¹

Risk stratification. Fever in a patient with neutropenia is a medical emergency: the mortality rate is extremely high if treatment is delayed. On the basis of the initial evaluation, the patient can be classified as being either at low risk or at higher risk for complications. Factors associated with low risk include ANC greater than 100/μL; a normal chest radiograph; age younger than 60 years; no chronic obstructive pulmonary disease; normal renal and hepatic function; neutropenia duration of less than 7 days; resolution of neutropenia expected in less than 10 days; no intravenous catheter site infection; temperature under 39°C (102.2°F); no neurological or mental changes; no abdominal pain; and no shock, hypoxia, vomiting, or diarrhea.^3,4

Antibiotic selection. Ciprofloxacin in combination with amoxicillin/clavulanate is appropriate for patients at low risk⁴; monotherapy with oral moxifloxacin is also effective.⁵ Patients at higher risk need intravenous antibiotics, usually either a cephalosporin (cefepime or ceftazidime [choice C]) or a carbapenem (meropenem or imipenem/cilastatin).¹ This patient’s high temperature classifies her as high risk; thus, oral monotherapy (choice B) is insufficient.

The routine addition of antibiotic therapy with gram-positive coverage has not been associated with clinical benefit or a reduction in mortality.⁶ The addition of vancomycin to empirical therapy is recommended for patients with suspected serious catheter-related infection, known colonization with penicillin-resistant and cephalosporin-resistant pneumococci or methicillin- resistant Staphylococcus aureus, blood culture positive for gram-positive bacteria before final identification and susceptibility testing, or hypotension or other evidence of cardiovascular impairment.¹

The risk of fungal infection rises if fever persists and neutropenia lasts more than 7 days. After 5 days of neutropenia in patients with persistent fever, the addition of antifungal agents can be considered. Although amphotericin B (choice A) is recommended, newer agents have become available, including caspofungin and voriconazole, and these appear to be as effective as amphotericin B.^7,8 However, this patient has not yet reached the threshold for antifungal therapy, and so choice A is not correct.

No mortality benefit has been reported for the use of colony-stimulating factors (CSFs) (choice D) in patients with neutropenia. Thus, these agents are not recommended for routine use in this setting.⁹ However, CSFs may be considered for critically ill patients and for patients in whom bone marrow recovery is expected to be prolonged.

In patients who remain febrile for more than 3 days after initiation of antibiotic treatment, diagnostic reassessment is recommended. If the fever persists for more than 5 days, options include continued administration of the same regimen (in clinically stable patients in whom the neutropenia is expected to resolve in 5 days), switching antibiotics if disease progression or drug toxicity is evident, or antifungal therapy when indicated.¹

Generally, if an infectious source is identified, continue antibiotics for the standard duration for that particular pathogen. Patients who have an unidentifiable source of infection but whose condition improves can be switched to oral antibiotics and complete a 14-day course with careful follow-up.

Outcome of this case. The patient was admitted, and intravenous ceftazidime monotherapy was started. Blood, urine, and sputum cultures produced no microbial growth, and the HIV screen was negative. Defervescence occurred after 36 hours. The lamotrigine was withheld. By the morning of the fifth hospital day, her ANC had risen to more than 1200/μL and she was discharged. She was sent home with a 14-day course of oral moxifloxacin.

References:

REFERENCES:

1

. Hughes WT, Armstrong D, Bodey GP, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer.

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2002;34:730-751.

2

. Marshall A, Lichtman, Beutler E, et al, eds.

Williams Hematology.

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3

. Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients.

J Clin Oncol.

2000;18:3038-3051.

4

. 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.

N Engl J Med.

1999;341:305-311.

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. Chamilos G, Bamias A, Efstathiou E, et al. Outpatient treatment of low-risk neutropenic fever in cancer patients using oral moxifloxacin.

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6

. Aoun M. Review: additional anti-gram-positive antibiotics do not reduce all-cause mortality in cancer and febrile neutropenia.

ACP J Club.

2006;144:3.

7

. Walsh TJ, Pappas P, Winston DJ, 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.

N Engl J Med.

2002;346:225-234.

8

. Walsh TJ, Teppler H, Donowitz GR, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia.

N Engl J Med.

2004;351:1391-1402.

9

. Clark OA, Lyman GH, Castro AA, et al. Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials.

J Clin Oncol.

2005;23:4198-4214.