Epidemiology

As the population ages, cancer prevalence is expected to increase.¹ In 2010, the United States population had more than 1.5 million new cancer diagnoses and more than 569,000 cancer deaths.² The American Cancer Society estimated that the number of new cancer cases will double from 2000 to 2050.¹ At the same time, aggressive treatment strategies, whether involving surgery, chemotherapy, or radiation, are helping oncology patients to live longer and at times overcome their cancer. In fact, U.S. cancer death rates decreased by 1% per year from 2001 through 2006.² Since the 1970s, the 5-year survival rate for all cancers has increased from 50% to 68% in the United States.² Declines in cancer deaths are the result of many factors, including better screening, early detection strategies, public health risk reduction programs, and improved medical and surgical treatment. Emergency physicians (EPs) are routinely called on to recognize and treat emergency complications of cancer and cancer therapies. Interventions that the EP makes to keep a patient alive acutely may allow the patient’s chemotherapy or radiation therapy to work for an overall cure. Today, oncology patients treated in the emergency department (ED) are increasingly more likely to survive to hospital discharge, even if they are admitted to an intensive care unit.³

Epidemiology

Neutropenic fever is the most common emergency indication for hospital admission among oncology patients. The in-hospital mortality rate in patients with neutropenic fever is approximately 9.5%, and it increases if the patient has any associated comorbidities.⁵ Patients with neutropenic fever have a mean (median) length of stay of 11.5 (6) days, at a mean cost of more than $19,000 per case.⁵

Pathophysiology

Chemotherapy can severely damage a patient’s normal defense mechanisms, including both humoral and cellular immunity, thus leaving the patient defenseless to combat infection. Chemotherapy can weaken or destroy neutrophils, T lymphocytes, macrophages, monocytes, and immunoglobulin production. Radiation and chemotherapy also affect the patient’s mechanical barriers against infection. In particular, they damage the integrity of the mucous membranes and skin. All this injury to the patient’s immune system takes place in an individual who already has cancer and therefore may already have either a weakened immune system or compromised physiologic factors.

Differential Diagnosis and Medical Decision Making

Although the prudent approach is to assume that fever in an oncology patient is from an infectious source, infection is not the only reason that oncology patients may have a fever. Fever can sometimes be a manifestation of the underlying malignant process itself or a side effect of a chemotherapeutic agent. Chemotherapeutic agents such as bleomycin and cytosine arabinoside have been noted to cause fevers. Lymphomas, leukemias, and renal cell carcinoma have been recognized as sources of fever without any concurrent infection, and at times, fever can be their initial presenting symptom. Thrombophlebitis, medications, and transfusion reactions can also be rare causes of fever.

Diagnostic Testing

The EP should search for an infectious source of the fever. A minimum evaluation should include at least two blood cultures, a urinalysis and urine culture, a chest radiograph, a complete blood count with differential (to confirm neutropenia), and baseline chemistry studies including kidney and liver function. Blood cultures should be obtained from all indwelling vascular catheters that are present. At least one blood culture should be drawn from a peripheral vein. Further diagnostic testing should be driven by the patient’s symptoms or physical examination findings. For example, an abdominal and pelvic computed tomography (CT) scan should be ordered if an intraabdominal source of the fever is possible. Other sources to consider culturing in the appropriate clinical setting are the oropharynx, cerebrospinal fluid, peritoneal fluid, pleural fluid, stool, and any purulent skin lesions.

Treatment

Empiric, broad-spectrum antibiotics should be started as early as possible for patients in the ED who have neutropenic fever. Antibiotics should not be delayed while awaiting confirmation of the neutropenia but rather should be started on all febrile patients at high risk (e.g., recent chemotherapy).⁶ Additionally, antibiotics should not be delayed while the EP looks for an infectious source. An obvious source is very often not identifiable in the ED. Rapid antibiotic administration is the likely reason for substantial mortality reductions among bacteremic patients with cancer. With the incorporation of this early antibiotic strategy, a large European research group found an overall mortality decrease from 21% to 7% over a 16-year period.⁷

Patients should be started empirically on antibiotics that reflect the resistance patterns and bacterial profiles of the treating institution. Most institutions have antibiotic protocols based on these bacterial patterns. Gram-positive organisms such as Staphylococcus aureus, Staphylococcus epidermidis, and viridans streptococci are currently more predominant than gram-negative organisms as the source of neutropenic fever. However, gram-negative organisms can be more virulent (e.g., Pseudomonas), and therefore the patient must always be empirically treated for these pathogens.

Single-agent intravenous antibiotics regimens are currently recommended for hemodynamically stable patients whose medical condition is uncomplicated.^6,8 Potential monotherapy regimens include cefepime, piperacillin-tazobactam, or a carbapenem (e.g., imipenem-cilastatin, meropenem).^6,8 Double coverage with an aminoglycoside (e.g., gentamicin, tobramycin) or a fluoroquinolone (e.g., levofloxacin) should be considered if antibiotic resistance is strongly suspected, if the patient is in shock, or if this approach is needed to manage other complications. Vancomycin should not be started empirically for neutropenic fever.^6,8 No significant difference in morbidity or mortality was found in a meta-analysis of 13 randomized control trials when a standard neutropenic antibiotic regimen was compared with the same regimen plus a glycopeptide (e.g., vancomycin).⁹ However, one should consider starting vancomycin if the infection is suspected to originate from an indwelling central venous catheter, a soft tissue infection, or hospital-associated pneumonia or if the patient is in septic shock.^6,8 A lower threshold for adding vancomycin should be used if the institution has a high rate of methicillin-resistant S. aureus (MRSA) or resistant viridans streptococcal strains.

Long indwelling catheters should generally be left in place and not removed in the ED. Many catheters in this patient population are buried subcutaneously and are not easily removed. Removal of the catheter in the ED should be considered if the tunnel is grossly infected or if the infected catheter has produced septic emboli or endocarditis.

Granulocyte colony-stimulating factors (G-CSFs) are used by oncologists with certain chemotherapy regimens to decrease the incidence of neutropenic episodes. Current guidelines recommend the prophylactic administration of a G-CSF with chemotherapy to patients who, based on age, past medical history, chemotherapy toxicity, and tumor characteristics, have a greater than 20% chance of developing febrile neutropenia.^8,10 This G-CSF prophylaxis regimen with chemotherapy has been shown to be effective; for example, in patients with small cell lung cancer, it decreases the incidence, duration, and severity of neutropenic fever.¹¹ Commonly used G-CSFs for prophylaxis are daily injections of filgrastim or lenograstim or a once per chemotherapy cycle injection of pegfilgrastim. Adverse side effects of G-CSF use include bone, joint and musculoskeletal pain and flulike symptoms.¹²

The use of a G-CSF in the acute setting of neutropenic fever is controversial. A meta-analysis of 13 studies with 1518 patients found that patients with neutropenic fever who were treated with G-CSFs had shorter hospitalizations and neutrophil recovery times but only a marginally significant benefit in infection-related mortality and no significant benefit in overall mortality.¹² Because the effects of G-CSFs on mortality are not clear and because these agents are very expensive, a G-CSF should not be given routinely in the ED for neutropenic fever. Rather, until more convincing evidence exists, G-CSFs should be given only after discussion with the patient’s oncologist and considered only for patients who are at high risk for infectious complications or who have prognostic factors predictive of a poor outcome.^10,13

Follow-Up and Next Steps

Nearly all patients with neutropenic fever require admission. Outpatient management could be considered for carefully selected low-risk patients within a well-designed institutional protocol and in concert with the patient’s oncologist. Certain decision rules have attempted to determine which neutropenic patients are at low risk for complications and therefore could be eligible for outpatient treatment with oral antibiotics. The most commonly cited decision rule for assessing low-risk patients is the Multinational Association for Supportive Care in Cancer (MASCC) index score^6,8 (Table 201.1). In its initial validation study, the MASCC index score was found to have a positive predictive value of 91%, a specificity of 68%, and a sensitivity of 71%.¹⁴ The MASCC decision rule is likely best applied to select patients who can quickly undergo conversion to oral antibiotics as inpatients and, in the absence of early complications, be targeted for early hospital discharge. If the patient is discharged, an oral antibiotic regimen is prescribed; ideally, the patient is observed taking the first dose in the ED. The two most common regimens used are a quinolone alone (e.g., ciprofloxacin) or a quinolone plus amoxicillin-clavulanate.¹⁵

Table 201.1 Multinational Association for Supportive Care in Cancer Index Score for Identifying Low-Risk Patients at Neutropenic Fever

^* Burden of illness: 5 for no or mild, 3 for moderate, 0 for severe.

^† Outpatient status means onset of fever as an outpatient.

From Klastersky J, Paesmans M, Rubenstein EB, Boyer M. 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;18:3038-51.

Infectious Causes of Fever Unique to the Patient with Cancer