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606 PART 5: Infectious Disorders

A more recent study wherein the investigators identified all potential from <1% to 7% and 73%, respectively. The addition of irinotecan to
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clinical foci of infections reported the GI tract as the focus of infection in carboplatin and paclitaxel increased the incidence of severe neutropenia
41% of patients with the oropharynx accounting for 70%, esophagus 3%, from 7% to 61% but did not enhance the odds of developing a febrile
clinical neutropenic enterocolitis 17%, and perirectal soft tissue infection neutropenic episode. The median incidence of febrile neutropenic
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10%. Other foci included the respiratory tract in 10%, urinary tract in episodes in patients with small cell lung cancer is reported as 35% for
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6%, and skin and soft tissue in 10%. Of the skin foci, indwelling central recipients of cyclophosphamide, doxorubicin, and etoposide (CAE)
venous catheter sites accounted for 59%, folliculitis for 6%, and cellulitis compared with 18% for recipients of a less myelosuppressive regimen
for 35%. Unexplained fevers accounted for only 10% of cases and containing cyclophosphamide, doxorubicin, and vincristine (CAV).
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microbiologically documented bloodstream infections in 23% of patients In addition to neutropenia, the propensity of a given regimen to induce
of which gram-negative bacteremia accounted for 37%, coagulase- mucosal damage resulting in mucositis correlates directly with the
negative staphylococcemia 19%, streptococcemia 27%, and other gram- incidence of febrile neutropenic episodes. The severity of mucositis is
positive microorganisms in 16%. These observations illustrate that directly related to the incidence of febrile events, the duration of hospi-
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with clinical diligence, clinical foci of infection may be identified in the talization, the costs of medical care, and treatment-related mortality. 99
majority of febrile neutropenic patients receiving cytotoxic therapy. Febrile neutropenic episodes occur in 70% to 90% of patients receiv-
ing cytotoxic therapy for acute leukemia and bone marrow trans-
plantation. 119,128,129 This difference is due to the more prolonged
APPROACH TO NEUTROPENIC FEVER cytotoxic therapy–induced myelosuppression and greater intestinal
Fever is the hallmark of infection for most patients with prolonged epithelial damage in these patients. 93
severe neutropenia; the definition of fever due to suspected infection Prolonged neutropenia may be punctuated by one or more febrile
in a neutropenic patient has varied greatly. 25-27,97,106-117 The International episodes, and a single febrile neutropenic episode may represent more
Antimicrobial Therapy Cooperative Group (IATCG) of the European than one infectious process. For example, febrile neutropenia associ-
Organization for Research and Treatment of Cancer (EORTC), 27,112,113 the ated with a viridans group streptococcal bacteremia may not defervesce
Intercontinental Antimicrobial Therapy Study Group, and others promptly despite appropriate antibacterial therapy and documentation
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have used an oral temperature of >38°C (100.8°F) sustained over a of a microbiologic cure on the basis of subsequent sterile blood cultures.
12-hour period or a single oral temperature of >38.5°C as the criterion This phenomenon of a persistent febrile state may occur in association
for infection-related fever. The recently published German guidelines with the concomitant administration of pyrogenic blood products, the
define an unexplained fever by a single oral temperature of ≥38.3°C presence of a coexisting infection such as a herpes simplex virus (HSV)
or ≥38.0°C lasting over an hour or measured twice within 12 hours. mucositis, or a possible fungal superinfection. It is frequently impossible
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The National Cancer Institute of Canada Clinical Trials Group also has to distinguish clinically the boundaries defining separate sequential
used a single oral temperature of >39°C together with chills or rigors infectious processes by the pattern of fever unless a clear pattern of
instead of a single temperature of >38.5°C. 26,119 In order to avoid the defervescence is seen between one infection and the next. This is partic-
administration of antimicrobial therapy for noninfectious causes of ularly frustrating when managing febrile neutropenic patients without a
fever, a stipulation that other causes of noninfectious fever should be clinical focus of infection or a defined pathogen.
thrombophlebitis, or hematoma) is often added to the definition. The ■ DIAGNOSIS
excluded (eg, blood products, pyrogenic drugs such as amphotericin B,
Infectious Disease Society of America has suggested that a single oral The diagnosis of a febrile state in a neutropenic patient requires a complete
temperature of ≥38.3°C (101°F) in the absence of other obvious envi- but directed clinical history and physical examination designed to identify
ronmental causes would be a reasonably safe working definition for an potentially infected foci for which those patients are at special risk.
infection-related fever in neutropenic patients. 65,120 Important historical facts may be obtained from the patient, signifi-
The extent to which characteristics of the febrile episode predict a cant others, and the medical record. The degree of neutropenia and the
bacteremic event has been somewhat variable in different studies; how- day of the chemotherapy cycle are important. The latter is determined
ever, most agree that initial oral temperatures of >39°C (102.2°F), shak- relative to the first day of the last cycle of chemotherapy or, in the case
ing chills, shock, initial ANC of <0.1 × 10 /L, and initial platelet count of HSCT recipients, the day of the HSCT.
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of <10 × 10 /L are somewhat predictive of gram-negative bacteremia. To avoid omitting the consideration of other noninfectious causes
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Viscoli et al demonstrated an 8.4-fold increase in risk for bacteremic of fever in neutropenic patients, the clinical evaluation should include
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infection in neutropenic patients with initial temperatures of >39°C questions pertaining to the temporal association of the febrile episode
(102.2°F). The duration of fever prior to evaluation, however, does not to the administration of blood products, to a history of fever associated
appear to influence the risk of gram-negative bacteremia. 22 with the underlying disease, administration of chemotherapeutic agents
The risk of developing a febrile neutropenic episode during each or amphotericin B, presence of thrombophlebitis, and the possible
cycle of outpatient cancer chemotherapy for solid tissue malignancies association of the febrile episode with thromboembolic or hemorrhagic
or lymphoreticular malignancies is generally low. However, this risk events. For example, in a series of neutropenic patients undergoing
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increases with the number of cycles administered and with the dose- remission-induction therapy for acute leukemia, 36% of febrile epi-
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intensity of the regimen selected. In a study of patients with lymphoma sodes were due to noninfectious causes.
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from the MD Anderson Cancer Center over 30 years ago, the cumulative The physical signs of inflammation and infection are influenced by
incidence of febrile neutropenic episodes increased from 12% among the ANC. The incidence and magnitude of localizing findings such as
recipients of cyclophosphamide, vincristine, and prednisone (COP) to exudate, fluctuance, ulceration, or fissure formation are reduced in a
27% among patients receiving a regimen where doxorubicin (hydroxy- direct relationship to the ANC. Other localizing findings, such as
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daunorubicin) was substituted for the cyclophosphamide (HOP) and erythema and focal tenderness, appear to remain as useful and reliable
46% among recipients of cyclophosphamide, doxorubicin, vincristine, signs of infection regardless of the ANC.
and prednisone (CHOP). In recent studies, the incidence of infec- The body systems most often involved with infection in neutropenic
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tion among CHOP recipients has been lower, approximately 15% of all patients are those associated with integumental surfaces, that is, the
cycles. Similar to the study by Feld and Bodey, the addition of cyto- upper and lower respiratory tracts, the upper and lower GI tracts, and
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toxic agents to a chemotherapy regimen has the effect of increasing the the skin. 107,130,131 Table 68-2 lists the pertinent historical and physical
likelihood of myelosuppression. For example, the addition of paclitaxel clues to be sought in the evaluation of a febrile neutropenic patient.
or docetaxel to carboplatin for the treatment of gynecological malignan- Examination of the head and neck area should include the optic
cies increased the incidence of severe neutropenia (ANC <0.5 × 10 /L) fundi, the external auditory canals and tympanic membranes, the
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