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
Overview
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.
Etiology
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
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]
Interventions
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 PDQ summary on Nutrition in Cancer Care for more information, as well as the Nonspecific Interventions for Palliation of Fever section below.)
Primary Interventions
Infection-associated fever
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:
- Aminoglycoside plus antipseudomonal
beta-lactam.
- Combination of two beta-lactams.
- Vancomycin plus
aminoglycoside and antipseudomonal beta-lactam.
- 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.
Paraneoplastic fever
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.
Drug-associated fever
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
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.)
Blood product–associated fever
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]
Nonspecific Interventions for Palliation of Fever
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
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Boulant JA: Thermoregulation. In: Machowiak PA, ed.: Fever: Basic Mechanisms and Management. New York, NY: Raven Press, 1991, pp 1-22.
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Dinarello CA, Bunn PA Jr: Fever. Semin Oncol 24 (3): 288-98, 1997.
[PUBMED Abstract]
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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.
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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.
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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.
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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.
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Mackowiak PA: Drug fever. In: Machowiak PA, ed.: Fever: Basic Mechanisms and Management. New York, NY: Raven Press, 1991, pp 255-265.
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Huh YO, Lichtiger B: Transfusion reactions in patients with cancer. Am J Clin Pathol 87 (2): 253-7, 1987.
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Marchetti O, Calandra T: Infections in neutropenic cancer patients. Lancet 359 (9308): 723-5, 2002.
[PUBMED Abstract]
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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.
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Pizzo PA: Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 328 (18): 1323-32, 1993.
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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.
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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.
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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.
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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]
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