Historically, fever in neutropenic patients has been considered a
medical emergency that requires hospitalization and the parenteral
administration of broad-spectrum antibiotics until resolution of
symptoms.[1,2] Identification of patients who are at low risk for
serious sequelae (eg, sepsis, death) allows caregivers to consider
ambulatory treatment, including both outpatient oral antibiotic
treatment and at-home administration of intravenous antibiotics.
Consequently, even though definitive evidence supporting this
approach is still lacking, increasing numbers of low-risk patients
with fever and neutropenia are being placed in these settings.
Potential advantages of ambulatory treatment are self-evident: lower
costs, less exposure to nosocomial pathogens, and improved quality of
life. Such treatment, however, requires the accurate identification
of low-risk patients, an appropriate infrastructure for implementing
these options, and easy access to emergency treatment should the
patients condition deteriorate.
The purpose of this article is to review the components of evaluation
and treatment that make ambulatory antimicrobial therapy feasible and
successful in patients with fever and neutropenia, to review the
effective use of ambulatory care in such patients, and to compare the
advantages of ambulatory antimicrobial therapy with its potential
risks and drawbacks.
Over the last decade, research has made it possible to reliably
identify a subset of patients in whom serious complications of
infection are unlikely to occur. These low-risk patients might be
appropriate for outpatient therapy. Features that delineate high-risk
vs low-risk patients are not universally accepted, but several
characteristics have been suggested as indicators of relative risk.
These include status at the time of presentation (inpatient vs
outpatient), acute medical comorbidity, control of cancer, type of
underlying neoplasm, type of treatment, predicted duration of
neutropenia, and presentation of infections (eg, pneumonia).
In 1988, a decision rule for stratifying patients was published,
wherein the first substantial progress was made in clarifying which
features were most likely to stratify for low-risk patients.
Relevant features for this stratification were derived from a
retrospective analysis of 261 medical records obtained from 184
cancer patients with febrile neutropenia, among whom four risk groups
were identified based on outcome (infection-related morbidity and
mortality). Validity of this risk-assessment model was subsequently
demonstrated in a prospective study of 444 patients.
The first of the four defined risk groups included bone marrow
transplant recipients with hematologic malignancies and other
patients who developed fever and neutropenia during their
hospitalization. Patients in this group had the highest risk for
complications, including high morbidity and mortality. The second
high-risk group included outpatients with comorbid conditions, such
as hypotension, altered mental status, respiratory failure, bleeding,
dehydration, abdominal pain, and spinal cord compression; morbidity
and mortality were high in this group as well.
The third group included outpatients with uncontrolled cancer, but
without comorbidity; as in the previous two groups, serious
complications and mortality were seen. This group, as well, was
associated with serious complications and mortality. The fourth group
was composed of clinically stable outpatients without comorbidity,
most of whom had solid tumors and were receiving conventional
chemotherapy. These patientsapproximately 40% of those with
fever and neutropenia and 60% to 70% of outpatientsreported a
low rate of serious complications and no mortality.
Among the conclusions drawn from these studies were 1) a low-risk
subpopulation indeed could be identified, and 2) patients in this
study were at a low enough risk to study their management with a less
intensive regimen than the standard inpatient, parenteral treatment.
A pilot study by the same group tested this latter idea, as have
other investigators,[6-11] with the growing consensus that risk
assessment is possible and that outpatient treatment, either
completely or in the form of early discharge, is feasible.
Definition of Low-Risk Patients
Low-risk patients can be loosely defined as being clinically stable,
having controlled malignancies, and presenting with no significant
acute comorbidity. The term, significant, is, of course,
a clinical judgment, but here indicates any condition suggesting
clinical instability or requiring hospitalizationwith or
without neutropenia. Another significant predictor of risk in
these patients is the degree and duration of neutropenia. For
instance, a study from the National Cancer Institute (NCI) revealed
that 95% of patients with neutropenia lasting seven days or less
responded to the initial antibiotic therapy, whereas only 32% of
patients with greater than 15 days of neutropenia responded to
treatment. Furthermore, the overall risk of medical complications
was lower for patients whose neutropenia resolved in less than seven
Degree of neutropenia also contributes to risk, with increasing
severity correlating with increased frequency of infectious
complications. Because patients with solid tumors are more likely
to have short-duration neutropenia, these patients may, in general,
have a lower risk of complications than patients with hematologic
malignancies. Some patients with leukemia in remission who are
intensively treated patients may also have low-risk
presentations.[1,2,14] Although the duration and degree of
neutropenia may be difficult to anticipate, both may be influenced by
the intensity of the patients previous chemotherapy and the
patients estimated bone marrow reserve.
Although this type of underlying neoplasm is associated with risk, in
part because of the intensity of chemotherapy, not all patients with
hematologic malignancies belong in this high-risk category.
Talcotts original risk assessment scheme included patients with
acute leukemia in remission among low-risk patients. Several
studies have upheld the validity of this assessment, such as those
conducted by the Ambulatory and Supportive Care Oncology Research
Program (ASCORP) at the M. D. Anderson Cancer Center in Houston,
Texas, which included patients with controlled leukemia, as well as
those with solid tumors.[4,5,14] One such study showed that while
patients with solid tumors had a significantly better response rate
(91%), patients with hematologic malignancies still responded well to
therapy, at a rate of 60% (P = .002). Low-risk presentations,
while occurring more frequently in patients with solid tumors, do
occur among patients with aggressively treated hematologic malignancies.
When fatal infections occur during episodes of fever and neutropenia,
they usually occur in the terminal phase of disease and are due to
untreatable cancer, not inadequate supportive care. Therefore,
many patients with controlled hematologic malignancies may qualify as
low risk and may potentially become candidates for ambulatory
therapy. Some experts consider such patients to be at intermediate or
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