When exogenous pyrogens enter a host, an inflammatory response is initiated. Macrophages and phagocytic cells recognize an invader, and proinflammatory cytokinines are produced and released into the circulation, stimulating the production of prostaglandins. The cytokinines include interleukins 1B (IL-1B), 6 (IL-6), interferon, and tumor necrosis factor (TNF). In addition to producing prostaglandins, these cytokinin mediators are thought to stimulate central production of the inducible enzyme cyclooxygenase-2 (COX-2) (Dalal & Zhukovsky, 2006). Current research suggests that it is this prostaglandin production that activates the thermoregulatory aspects of the hypothalamus and begins the febrile response and fever. Another factor is that a person loses about 1% of the body’s immune function each year after age 30; therefore a person who is 80 years old has about 50% of his or her original immunity, which leads to lower regulation levels.

Infection is one of the most common causes of fever in patients with cancer, and it is associated with high rates of morbidity and mortality. Without rapid intervention and treatment (i.e., within 48 hours), the mortality rate among patients with cancer who have a fever caused by infection can be as high as 70%. The severity of infection is inversely proportional to the number of circulating neutrophils; therefore patients who are neutropenic are at a much higher risk for more frequent and severe infections than patients who are not immunocompromised. In patients with neutropenia (defined by an absolute neutrophil count [ANC] of less than 500 cells/mm³), fever should be considered an absolute emergency and intervention begun immediately. An additional factor in predicting outcomes is the nadir of the neutropenic causative agent and the nadir of the neutropenia itself. An antineoplastic agent with a short nadir leads to rapid depletion of neutrophils and puts the patient at much higher risk of infection, sepsis, and death. One area that requires continued research in oncology is the relationship between chemotherapeutic agent nadirs and patients’ risk for neutropenia. Certain chemotherapeutic regimens (Crawford et al., 2005) correlate with a higher risk of neutropenia (Table 16-1). Research seems to support the prophylactic use of colony-stimulating factors in these high-risk patients (Rolston, 2004).

Neutropenic patients are at the highest risk for infection (Baden & Rubin, 2002). The organisms that cause the infections are related to the geographic and site-specific origin of the infection. The most common sites of infection in patients with cancer are the pharynx, lower esophagus, lung, perineum, anus, eye, skin, periodontium, vascular catheter access sites, and tissue around the nails (Urabe, 2004). Some common organisms have been associated with specific sites (Table 16-2) (Hughes et al., 2002). The clinician should pay close attention to these sites and inspect and evaluate any redness, tenderness, drainage, or abnormal conditions. As mentioned, in oncology patients the body’s ability to mount an effective immune response may be significantly blunted, and subtle abnormalities may be the only signal of infection.

A significant proportion of the fever-causing infections in patients with cancer now are gram positive in nature. The main culprits are staphylococci (S. aureus and S. epidermidis), streptococci (e.g., S. pneumoniae, a common cause of pneumococcal pneumonia), enterococci, and strep A and B. These organisms must be treated; however, immediate initiation of a glycopeptide antimicrobial (vancomycin) is not necessarily required unless the patient’s symptoms are consistent with sepsis or an exact pathogen has been identified.

Gram-negative organisms are a less likely pathogen in patients with cancer. However, gram-negative bacilli and cocci are potentially the most deadly and therefore require immediate treatment to prevent sepsis and progression. Because gram-negative organisms can be isolated from multiple sites in a patient with cancer, the sites of origin (e.g., urinary tract, pulmonary and gastrointestinal tracts) must be evaluated extensively for potential infection-causing organisms. Gram-negative organisms (e.g., Escherichia coli and Klebsiella and Pseudomonas spp.) require immediate, broad-spectrum antimicrobial coverage because of the potentially rapid and overwhelming effects of sepsis in a patient with cancer. Even though gram-positive organisms are seen more often in these patients, progression of gram-negative infections is associated with a higher mortality rate (Klastersky, 2004).

Fever is a common associated illness with some cancers and may parallel the progression of the tumor or cancer. Paraneoplastic fevers are most often associated with Hodgkin’s lymphoma. However, several other types of cancer are coming to be associated with paraneoplastic fever. Cancers such as acute leukemia, lymphoma, renal cell carcinoma, bone sarcoma, adrenal carcinoma, and pheochromocytoma are associated with paraneoplastic fever. Cancers involving solid tumors (e.g., breast, lung, and colon cancers) are not normally associated with this type of fever (Dalal & Zhukovsky, 2006). The definitive treatment for paraneoplastic fever is treatment of the underlying malignancy. In the absence of effective antineoplastic therapy, treatment with nonsteroidal antiinflammatory drugs (NSAIDs) is the treatment of choice. A common choice of NSAID for this type of fever is naproxen (Naprosyn), and response to initiation of this therapy has been used to diagnose tumor-associated fevers. However, chronic use of NSAIDs may cause bleeding problems, therefore the patient needs continued follow-up and teaching regarding the signs and symptoms of undesired bleeding, such as black, tarry stools, excessive bruising, and worsening or abnormal fatigue. These symptoms should be reported to the caregiver immediately.

The diagnosis of medication-induced fever in an oncology patient is often a diagnosis of exclusion, except for specific medications (Box 16-1). These include biologic modifiers (interferon, TNF), bleomycin, and amphotericin B. These drugs routinely cause fevers, and the patient may need to be treated prophylactically before initiation of therapy. Premedication with NSAIDs, acetaminophen, or corticosteroids may lessen the fever. In most cases, a fever related to medication administration resolves once the drug therapy is stopped. Other medications that may cause fever are antibiotics, cardiac medications, antiseizure medications, cytotoxics, and growth factors. In a review study, antibiotic therapy accounted for approximately 31% of drug-related fevers (Dalal & Zhukovsky, 2006). However, patients with cancer are not exempt from cardiovascular disease, diabetes, seizures, and infection, therefore the medications used to treat these conditions should routinely be evaluated in cases of suspected medication-induced fever.

Patients with cancer often are treated with antineoplastic medications aimed at killing the rapidly multiplying cancer cells. Because these therapies may also deplete the patient’s blood counts, multiple transfusions of blood products may be required. Fever in response to transfusions is not uncommon in oncology patients. The febrile response is thought to be a result of antibody production by the body as a defense against antigens on the donors’ cells and the resulting inflammatory response. The more transfusions a patient receives, the greater the likelihood of a febrile reaction. Treatment of this type of fever includes premedication with acetaminophen and diphenhydramine. In addition, use of blood products that have been irradiated and depleted of leukocytes can minimize these reactions.