Fever

Overview
Etiology
Assessment
Interventions
Primary Interventions
        Infection-associated fever
        Paraneoplastic fever
        Drug-associated fever
        Neuroleptic malignant syndrome
        Blood product–associated fever
Nonspecific Interventions for Palliation of Fever

Normal human body temperature displays a circadian rhythm. Body temperature is lowest in the predawn hours, at 36.1°C (97°F) or lower, and rises to 37.4°C (99.3°F) or higher in the afternoon. Normal body temperature is maintained by thermoregulatory mechanisms that balance heat loss with heat production.[1-3]

Abnormal elevations of temperature result from either hyperthermia or pyrexia (fever). Hyperthermia results from failure of thermal control mechanisms. In fever, thermoregulatory mechanisms are intact, but the hypothalamic set-point is elevated above normal by exogenous or endogenous pyrogens. There are three phases to fever. In the initiation phase, cutaneous vasoconstriction promotes heat retention and shivering generates additional heat. When the new (elevated) set-point is reached, heat production balances heat loss and shivering stops. With lowering of the set-point to normal, cutaneous vasodilatation promotes heat loss to the environment in the form of sweating. These same mechanisms maintain normal core body temperature in afebrile individuals.[1-4]

Response to fever varies with age. In older people, inadequate thermoregulatory mechanisms may contribute to hyperthermia and result in arrhythmias, ischemia, mental status changes, or heart failure from increased metabolic demands. In children between the ages of 6 months and 6 years, febrile convulsions may occur.

In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.

The major causes of fever in cancer patients include infection, tumor (also known as paraneoplastic fever), drugs (allergic or hypersensitivity reactions), blood product transfusion, and graft-versus-host disease (GVHD).[2-8] Infection is a particularly important cause in the neutropenic host, given its high frequency (almost two-thirds of patients) and potentially fatal outcome. Whereas gram-negative infections predominated as the cause of neutropenic fever in cancer patients in the 1970s and early 1980s, gram-positive infections, mainly streptococci and coagulase staphylococci, have predominated since. The increased incidence of staphylococcal and streptococcal infections relates to the use of intravascular devices, severe mucositis due to high-dose chemotherapy, and prophylactic antibiotic therapy with fluoroquinolones. Although fluoroquinolone use has not decreased the morbidity or mortality of neutropenic fever, it has resulted in increased incidence of resistant gram-negative bacteremia.[9] Many consider paraneoplastic fever to be more common in primary tumors such as renal cell carcinomas and lymphomas, but available data suggest that it occurs in tumors of diverse primary sites.[2] Hypersensitivity reactions, pyrogen production, primary cytokine production and tumor necrosis with secondary cytokine production are among the postulated causes of tumor fever. Drug causes of fever include a variety of cytotoxic chemotherapy agents, biologic response modifiers, vancomycin, amphotericin, and multiple other medications. Tumor-associated fevers may be cyclic, occur at a specific time of the day, or be intermittent, alternating with afebrile periods lasting days or weeks.[3,4] Fever pattern does not differentiate drug-associated fever from other causes of fever, except when the temporal relationship is unambiguous. For many drugs, a highly variable lag time between the initiation of the offending agent and the onset of fever masks the causative relationship.[4,6,7,10]

Other etiologies of fever in the cancer patient include drug withdrawal (i.e., opioids, benzodiazepines), neuroleptic malignant syndrome (NMS), obstruction of a viscus (i.e., bladder, bowel, kidney), and tumor embolization. Comorbid medical conditions such as thrombosis, connective tissue disorders, and central nervous system bleeds or strokes may also produce fever.[4] The differential diagnosis of fever in the cancer patient is extensive, and differentiating infection from other causes may be difficult. From a palliative perspective, establishing a fever-specific diagnosis is important, as the specific diagnosis impacts management, comfort, and patient prognosis.

Assessment of fever requires careful history taking, medication review, and a physical examination that includes all major body systems. Individuals with suspected infection, especially those with neutropenic fever, should undergo meticulous evaluation of the skin, all body orifices (i.e., mouth, ears, nose, throat, urethra, vagina, rectum), finger stick and venipuncture sites, biopsy sites, and skin folds (i.e., breasts, axilla, groin). Oral assessment includes evaluation of the teeth, gingiva, tongue, floor of the mouth, nasopharynx, and sinuses. The perirectal area is a common source of infection, especially in individuals with leukemia. Vascular access devices (VAD) and other artificial indwelling devices (i.e., percutaneous nephrostomy tubes, biliary drainage tubes, gastrostomy or jejunostomy tubes) are other commonly implicated sources of infection. Urine, sputum, and blood cultures (peripheral and from ports or lumens of VADs) and radiographic imaging with chest radiography as directed by these findings complete the initial evaluation. Individuals undergoing cytotoxic chemotherapy should be instructed to seek immediate medical attention if they develop fever when neutrophil counts are low or declining. Frequent reassessment, including physical examination, is especially important in the neutropenic host, as signs and symptoms of infection may be minimal. Evaluation for recurrent or progressive tumor can be performed at the same time as evaluation for potential infection and other causes of fever.[3]

The presence of fever is associated with the potential metabolic consequences of dehydration and increased metabolic demand. Effects may be especially pronounced in debilitated cancer patients and include uncomfortable constitutional symptoms such as fatigue, myalgias, diaphoresis, and chills. Potential interventions for fever management include primary interventions directed at the underlying cause, hydration with parenteral fluids or by hypodermoclysis, nutritional support, and nonspecific palliative measures. The specific interventions utilized are determined by the patient’s location in the disease trajectory and patient-determined goals of care. Some patients near the end of life may decide not to treat the underlying cause. For example, patients with advanced cancer may decline treatment of pneumonia or other infections but still seek nonspecific palliative measures and hydration to optimize quality of life. Alternatively, others may elect antibiotic therapy for the palliation of symptoms such as cough, fever, dyspnea, or abscess pain. (Refer to the Nonspecific Interventions for Palliation of Fever section of this summary for more information.)

Effective antibiotic treatment results in palliation of fever-associated constitutional symptoms, as well as palliation of site-specific symptoms such as cough secondary to pneumonia or localized pain due to abscess formation. For febrile neutropenic patients (granulocyte count <500), immediate initiation of broad-spectrum antibiotic treatment is imperative, as the mortality rate is 70% for patients not receiving antibiotics within 48 hours. For the purposes of neutropenia, fever is defined as a single temperature elevation above 38.5°C or three elevations above 38°C in a 24-hour period.[4]

Since the cause of neutropenic fever is not documented in 50% to 70% of patients, antibiotic use is guided by knowledge of the treating institution’s antimicrobial spectrum and antibiotic resistance pattern, as well as the suspected cause. There is no consensus on the particular antibiotic or combination of antibiotics to be used, but empiric antibiotic therapy generally falls into one of four protocols:

1. Aminoglycoside plus antipseudomonal beta-lactam.
2. Combination of two beta-lactams.
3. Vancomycin plus aminoglycoside and antipseudomonal beta-lactam.
4. Monotherapy.

When multiple-lumen catheters are present, antibiotic therapy should be rotated through each lumen. Bacteriostatic antibiotics (i.e., tetracycline, erythromycin, chloramphenicol) are not beneficial in the absence of granulocytes, which, when given concomitantly, reduce the efficacy of the bactericidal antibiotics.[4,11]

Treatment regimens are further modified by the duration of fever and individual patient risk factors such as the presence of central lines or other artificial devices, history of steroid use, and history of injection drug use. Various investigators have developed models predicting risk groups of febrile neutropenia, with implications for management strategies. Therapeutic options under evaluation include early hospital discharge, home intravenous antibiotic therapy, and oral antibiotic regimens. A subset of these studies focus on the pediatric population. Because of rapid changes in the field, the reader is directed to specialized sources for specific management recommendations of febrile neutropenia.[12-14]

After a specific pathogen is isolated, antibiotic therapy is modified to provide optimal therapeutic response with minimal toxicity. Broad-spectrum coverage must be maintained to prevent secondary bacterial and fungal infections. Antibiotic therapy is usually discontinued after 5 to 7 days provided that the patient’s granulocyte count exceeds 500 and the patient remains free of fever and infection. There is no consensus as to appropriate management in cases of persistent granulocytopenia when the patient is afebrile. Some advocate continued therapy, whereas others favor discontinuing antibiotics once the patient stabilizes. Empirical antifungal therapy is often added if a neutropenic patient remains febrile after 1 week of broad-spectrum antibiotics or has recurrent fever, since continued granulocytopenia is usually associated with the development of nonbacterial opportunistic infections, particularly those caused by Candida and Aspergillus. Prolonged therapy (>10–14 days) is indicated in the patient with a residual focus of bacterial or mycotic infection. Amphotericin B is usually the agent of choice. Alternative antifungal agents (5-fluorocytosine, miconazole, fluconazole, or itraconazole) are indicated when organisms develop resistance to amphotericin B.

Acyclovir is the drug of choice in the treatment of herpes simplex or varicella zoster viral infection. Ganciclovir has activity against cytomegalovirus. Both agents can be used prophylactically in the management of patients at high risk for these infections. Foscarnet is useful in the treatment of cytomegalovirus and acyclovir-resistant herpes simplex virus.

When available, the best management of tumor-associated fevers is treatment of the underlying neoplasm with definitive antineoplastic therapies. In the absence of effective antineoplastic therapy, nonsteroidal anti-inflammatory drugs (NSAIDs) are a mainstay of treatment. Naproxen may preferentially control paraneoplastic fever relative to other NSAIDs or acetaminophen. Response to naproxen has been considered diagnostic of tumor fever; however, efficacy of naproxen and other NSAIDs for infection-related fever is a common clinical observation. Release of tumor fever may respond to treatment with a structurally different NSAID.

The occurrence of fever is predictable for some drugs, such as biologic response modifiers, amphotericin B, and bleomycin. For many other drugs, drug fever is a diagnosis of exclusion. Drug-associated fever responds to cessation of the offending agent, when possible. Fever and related symptoms with biologic response modifier administration is type-, route-, dose-, and schedule-dependent. These factors may sometimes be altered for fever control without sacrificing efficacy. Fever may also be attenuated by the use of acetaminophen, nonsteroidal anti-inflammatory, and steroid premedication. The same may be true for fever associated with some cytotoxic agents and antimicrobials (i.e., amphotericin).[6,7,10] It is common clinical practice to administer meperidine to attenuate severe chills associated with a febrile reaction, although empirical data confirming its efficacy are not available.

Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal syndrome that may develop during treatment with neuroleptic drugs for conditions such as psychotic disorders, delirium, nausea, and vomiting. It is marked by fever, rigidity, confusion, and autonomic instability, as well as by elevations in white blood cell count, creatinine phosphokinase, and urine myoglobin. NMS should be considered in the differential diagnosis of the delirious patient receiving neuroleptic agents who develops rigidity and whose condition does not improve on neuroleptics (e.g., haloperidol). Treatment of NMS includes discontinuation of neuroleptic agents, supportive measures, and occasionally, administration of bromocriptine or dantrolene. (Refer to the PDQ summary on Cognitive Disorders and Delirium for more information.)

Suspected febrile reactions can be minimized by the use of leukocyte-depleted or irradiated blood products, when clinically appropriate. Common clinical practice includes premedication with acetaminophen and diphenhydramine.[8]

Along with treatment of the underlying cause, comfort measures are helpful in alleviating the distress that accompanies fever, chills, and sweats. During febrile episodes, increasing a patient’s fluid intake, removing excess clothing and linens, and tepid water bathing/sponging may provide relief. Results of a pediatric randomized placebo-controlled trial of sponging with ice water, isopropyl alcohol, or tepid water, with or without acetaminophen, demonstrated that all combinations enhanced fever control. Comfort was greatest in children receiving a placebo or sponging, followed by those who received acetaminophen combined with tepid-water sponging. Sponging with either ice water or isopropyl alcohol, with or without acetaminophen, resulted in the greatest discomfort.[15] During periods of chills, replacing wet blankets with warm, dry blankets, keeping patients out of drafts, and adjusting ambient room temperature may also improve patient comfort.

Symptomatic relief of persistent or intermittent fevers can be aided by the use of NSAIDs (e.g., naproxen) or acetaminophen.[15] Aspirin may also be effective in reducing fever but should be used with caution in patients with Hodgkin lymphoma and cancer patients at risk for thrombocytopenia. Because of the associated risk of Reye syndrome, aspirin is not recommended in patients with fever.[4]

References

1. Boulant JA: Thermoregulation. In: Machowiak PA, ed.: Fever: Basic Mechanisms and Management. New York, NY: Raven Press, 1991, pp 1-22. 
   
   
2. Dinarello CA, Bunn PA Jr: Fever. Semin Oncol 24 (3): 288-98, 1997.  [PUBMED Abstract]
   
   
3. Young LS: Fever and septicemia. In: Rubin RH, Young LS, eds.: Clinical Approach to Infection in the Compromised Host. 2nd ed. New York, NY: Plenum Medical, 1988, pp 75-114. 
   
   
4. Cleary JF: Fever and sweats: including the immunocompromised hosts. In: Berger A, Portenoy RK, Weissman DE, eds.: Principles and Practice of Supportive Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 1998, pp 119-131. 
   
   
5. Knockaert DC, Vanneste LJ, Vanneste SB, et al.: Fever of unknown origin in the 1980s. An update of the diagnostic spectrum. Arch Intern Med 152 (1): 51-5, 1992.  [PUBMED Abstract]
   
   
6. Mackowiak PA, LeMaistre CF: Drug fever: a critical appraisal of conventional concepts. An analysis of 51 episodes in two Dallas hospitals and 97 episodes reported in the English literature. Ann Intern Med 106 (5): 728-33, 1987.  [PUBMED Abstract]
   
   
7. Mackowiak PA: Drug fever. In: Machowiak PA, ed.: Fever: Basic Mechanisms and Management. New York, NY: Raven Press, 1991, pp 255-265. 
   
   
8. Huh YO, Lichtiger B: Transfusion reactions in patients with cancer. Am J Clin Pathol 87 (2): 253-7, 1987.  [PUBMED Abstract]
   
   
9. Marchetti O, Calandra T: Infections in neutropenic cancer patients. Lancet 359 (9308): 723-5, 2002.  [PUBMED Abstract]
   
   
10. Quesada JR, Talpaz M, Rios A, et al.: Clinical toxicity of interferons in cancer patients: a review. J Clin Oncol 4 (2): 234-43, 1986.  [PUBMED Abstract]
    
    
11. Pizzo PA: Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 328 (18): 1323-32, 1993.  [PUBMED Abstract]
    
    
12. Karthaus M, Carratalà J, Jürgens H, et al.: New strategies in the treatment of infectious complications in haematology and oncology: is there a role for out-patient antibiotic treatment of febrile neutropenia? Chemotherapy 44 (6): 427-35, 1998 Nov-Dec.  [PUBMED Abstract]
    
    
13. 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 18 (16): 3038-51, 2000.  [PUBMED Abstract]
    
    
14. Talcott JA, Siegel RD, Finberg R, et al.: Risk assessment in cancer patients with fever and neutropenia: a prospective, two-center validation of a prediction rule. J Clin Oncol 10 (2): 316-22, 1992.  [PUBMED Abstract]
    
    
15. Steele RW, Tanaka PT, Lara RP, et al.: Evaluation of sponging and of oral antipyretic therapy to reduce fever. J Pediatr 77 (5): 824-9, 1970.  [PUBMED Abstract]