Fever and Neutropenia
Fever and Neutropenia: Excerpt from Pediatric Infectious Disease
Epidemiology
Patients undergoing chemotherapy are at considerable risk for serious infection.
The primary cell line affected by aggressive chemotherapy is the neutrophil.
The absolute neutrophil count (ANC) is calculated by multiplying the total
number of white blood cells by the combined percentage of segmented neutrophils
and band forms.
A neutrophil count of less than 1,000/m3 is frequently associated with serious invasive infection. An absolute
neutrophil count of less than 100/m
3, often seen in patients undergoing chemotherapy, is considered life
threatening. The most recent guidelines suggest that
neutropenia be defined as an absolute neutrophil count of less than 500/m3, or less than 1,000/ m3 if there is the expectation that the counts will decrease to less than 500/m3.
Presentation
Fever in the neutropenic patient is usually defined as a single temperature
greater than 38.3
°C, (101.3°F) or a sustained temperature of 38°C (100.4°F) temperature for more than 1 hour.
Diagnosis
Due to the risk for life-threatening infection in the patient with fever and
neutropenia, current practice suggests that patients meeting the above
definitions be admitted to the hospital.
Cultures of the blood, urine, and if possible, induced sputum should be
obtained. Chest radiographs are also suggested, especially if respiratory
symptoms are present.
Management
The management of the patient with neutropenia and fever can be divided into
three major pathogen groups, discussed in the following sections.
Gram-negative Bacteria in Fever and Neutropenia
In the 1970s, oncology patients were admitted to intensive care centers with
fever and neutrophil counts of less than 500/m
3. It was found that a large number of these patients quickly died from
gram-negative sepsis. These gram-negative organisms included
Escherichia coli, Klebsiella species, and Enterobacter species. It was then that the first rule of management of fever and neutropenia
was made; the aggressive empiric treatment of gram negative organisms.
Management
To this day, there is no agreement on the optimal gram-negative coverage. Some
institutions use double therapy with two separate classes of antibiotics,
combining an aminoglycoside and a
β-lactam antibiotic such as ceftazidime. Other institutions use monotherapy with
a fourth-generation cephalosporin (such as cefepime) or very
broad-spectrum combination therapy consisting of imipenem and amikacin. No therapy has proved to be superior. Whatever the regimen used, it is important to
realize that gram-negative organisms are the bacteria that cause the patients
to expire quickly. A patient with fever and an absolute neutrophil count of
less than 1,000/m
3 is usually admitted with appropriate cultures taken and empirically started on
antibiotics effective against gram-negative bacteria.
Fungal Pathogens in Fever and Neutropenia
The second management principle of fever and neutropenia came about 10 years
later. Patients with fever and neutropenia were admitted to the hospital and
placed on antibiotics. A number of these patients continued to be febrile with
negative blood cultures. A large number of these individuals ultimately died;
at autopsy, they were found to have disseminated fungal infection. In the
1980s, results of several large clinical trials suggested that there were fewer
fungal infections in persistently febrile neutropenic patients who, after 7
days of fever with negative blood cultures, were given amphotericin B as
empiric antifungal therapy. Based on these studies and the autopsy evidence, a
patient with fever, neutropenia, and negative blood cultures should have
empiric antifungal treatment started after 3 to 7 days; we assume that these
patients have fungal infections. The following is a description of the fungal
pathogens encountered in the febrile neutropenic patient:
Aspergillus Species
The classic fungal pathogen in the neutropenic oncology patient isAspergillus species. A ubiquitous mold present throughout the environment, aspergillus
enters the host by way of the respiratory tract. In the setting of severe
qualitative or quantitative neutrophil deficiency, the fungus becomes invasive,
resulting in progressive respiratory disease and extrapulmonary dissemination.
The common sites of dissemination include the brain, skin, and bone (Figs. 17.1
and 17.2). Progressive sinus disease, pneumonia, and the appearance of new skin
or brain lesions should heighten suspicion for aspergillosis in the febrile,
neutropenic patient. High-resolution computed tomography (CT) of the chest can
be helpful in detecting small nodular lesions, which are common early in the
course of invasive aspergillosis.
In recent years, a variety of newer molds have been implicated in severe disease
in the neutropenic host. These can present in a fashion similar to
aspergillosis, with fever in the setting of continuing neutropenia accompanied
by progressive pneumonia, skin lesions, or intracranial lesions. The correct
diagnosis of these molds must be confirmed by the isolation in culture because
these newer molds may have an initial histologic appearance similar to that of
aspergillosis but different antimicrobial sensitivities. These newer molds
include the following.
Fusarium Species
Disseminated disease is common in neutropenic patients, often appearing as
painful skin lesions. Unlike other molds, the incidence of positive blood
cultures is 50%. Sinusitis and pneumonia are also common. The appearance on
biopsy will be similar to that of aspergillus, highlighting the importance of
culture diagnosis.
Fusarium species have a high incidence of in vitro amphotericin resistance. Treatment is typically with the newer azole agents such
as voriconazole. Surgical d
ébridement of affected areas should be attempted whenever possible.
Zygomycetes
Zygomycetes includes infections with molds Mucor, Rhizopus, Rhizomucor, and Cunninghamella. They may be differentiated from aspergillosis by their septate hyphae
possessing right-angle branching, as opposed to the acute-angle branching seen
in aspergillus. Zygomycetes have a predilection for invasion of blood vessels
and subsequent dissemination. Rhinocerebral disease is the most common form
seen, in which the infection begins in the sinuses and rapidly extends to the
orbit and brain. Mucormycosis is typically associated with tissue necrosis and
black discoloration; these provide major clues to diagnosis.
Standard treatment for mucormycosis remains amphotericin B. Itraconazole,
fluconazole, and voriconazole do not appear useful in treatment of this
organism. Adjunctive surgical d
ébridement, with documentation of disease-free margins, is critical for
resolution.
Scedosporium Species
When in its sexual state,Scedosporium is also known as Pseudallescheria boydii. This organism is noteworthy for resistance to most conventional antifungal
agents, including an intrinsic amphotericin resistance.
Scedosporium apiospermum, with its acutely branching hyphae tissue, is similar to aspergillus, stressing
the importance of culture in the final identification of any pathogenic mold.
Recently, successful treatment has been reported with voriconazole. Surgical d
ébridement should be attempted if at all possible.
Trichosporon Species
Trichosporon asahii, formally referred to asTrichosporon beigelii, is increasingly found in neonatal infections and can also be seen in the
neutropenic host.
T. asahii is unusual in that it can be frequently isolated in blood culture. An additional
feature of this organism is its ability to cross-react with the capsular
polysaccharide of cryptococcus neoformans, resulting in a false-positive latex
agglutination test. These fungi have a high frequency of amphotericin
resistance and are intrinsically resistant to caspofungin. Therapy with
fluconazole has been reported to be successful in the neonatal population.
Diagnosis
Essential to the management of the febrile, neutropenic patient is the
establishment of the diagnosis of fungal infection. Certainly, not every
patient with fever and neutropenia has a fungal infection. Polymerase chain
reaction (PCR) testing against genetic sequences of
Candida and Aspergillus species has been used to detect evolving fungal infection in febrile neutropenic
hosts. Preliminary reports suggest that this is a sensitive method and in the
future may help define the patient population that can most benefit from
antifungal therapy. Galactomannan is a polysaccharide component of the fungal
wall that has recently been approved as a method for early detection of
invasive aspergillosis. An enzyme-linked immunoabsorbent assay (ELISA) has been
developed, and serial evaluations of this component in neutropenic hosts may be
useful in detecting evolving invasive aspergillosis. The test uses an optical
density index; a positive result in the United States is greater than or equal
to 0.5. It should be stressed that a single negative test does not rule out
evolving aspergillosis. Serial evaluations in conjunction with clinical,
radiographic, and culture examinations are always necessary.
Management
Traditionally, the gold standard antifungal agent has been amphotericin B. The
traditional form of amphotericin B is amphotericin B deoxycholate. The dose
given is 0.6 to 1.0 mg/kg per day. Although progressive dosing over several
days has been tried in the past, many clinicians believe this is no longer
necessary and delays the administration of an appropriate dose. There are now
three lipid-associated formulations of amphotericin B: amphotericin B lipid
complex (Abelcet), amphotericin B colloidal dispersion (Amphotec), and
liposomal amphotericin B (AmBisome). There is still no definitive evidence that
these newer formulations are actually better antifungal agents. There is some
evidence that these newer agents may decrease the metabolic or renal
complications seen with amphotericin B deoxycholate. Some clinicians use the
lipid-associated amphotericin preparations as front-line agents in patients
with a higher risk for nephrotoxicity or renal failure (i.e., additional
concurrent nephrotoxic drugs, history of underlying renal disease). If these
are to be used, it is important that the practitioner realize that the dosing
is different. The dosing of the lipid and liposomal formulations is 3 to 5
mg/kg per day.
Newer Antifungal Agents
A common question is the role of newer antifungal agents in the management of
neutropenic fever in the oncology unit. Fluconazole (Diflucan) is readily
available and is often well tolerated; the major disadvantage is that it lacks
activity against
Aspergillus species, a major pathogen in this patient population. Some investigators have
attempted to define the use of a particular antifungal based on the duration of
neutropenia. Yeasts, usually
Candida species, are common early in the course of neutropenia. Molds, such as Aspergillus species, usually are seen in the second week of a low neutrophil count. The use
of fluconazole for treatment of fever and neutropenia should be discouraged in
patients who have been on long-term fungal prophylaxis because these patients
are known to have an increased risk for infection with fluconazole-resistant
isolates (such as
Candida krusei and Candida glabrata). In addition, fluconazole should not be used if a patient has progressive
sinus or pulmonary disease consistent with an
Aspergillus species infection.
Several additional agents have been developed to treat disseminated fungus in
the immunocompromised host. Intravenous itraconazole is an azole that has
activity against
Aspergillus species. Response rates are similar to other agents; concerns about potential
drug interactions at the cytochrome P450 level can limit use. Recently, the
U.S. Food and Drug Administration (FDA) has licensed caspofungin (Cancidas),
which belongs to a new class of drugs called echinocandins. This drug is
indicated for patients with invasive aspergillosis that is nonresponsive to
amphotericin. Early studies report a salvage rate of 40%. Caspofungin is also
effective for candidemia and invasive candidiasis and has FDA approval for
these indications. Voriconazole (Vfend) has recently been approved and offers
the advantage of good
Aspergillus species coverage, good cerebrospinal fluid penetration, and coverage against
some of the newer molds affecting cancer patients. Studies comparing
voriconazole versus amphotericin B have found it a suitable alternative for
empiric antifungal treatment in patients with fever and neutropenia. In the
future, these drugs, either alone or in combination, may represent a major
advantage in antifungal therapy in the neutropenic patient.
Gram-positive Pathogens in Fever and Neutropenia
In the 1990s, a new chapter was added to the management of fever and
neutropenia. The emergence of infections with gram-positive organisms was seen
in oncology centers across the country. Currently, up to 60% of the bacteria
isolated from blood cultures of febrile children with cancer are now
gram-positive organisms. A gram-positive organism frequently isolated is the
α-hemolytic streptococcus (AHS). This includes a diverse group of streptococci,
such as
Streptococcus mitis, Streptococcus sanguis, and Streptococcus milleri. When isolated from blood culture, these bacteria are often identified as α-hemolytic or viridans streptococci rather than a specific species designation.
These organisms are part of the normal oral flora and are also part of the
flora of the gastrointestinal tract. They are thought to enter the bloodstream
and become invasive following the breakdown of oral and gastrointestinal mucosa
that accompanies chemotherapy. There are several risk factors associated with
viridans streptococcal bacteremia in febrile neutropenic patients; these
include oral mucositis, acute myelogenous leukemia, and high-dose cytosine
arabinoside therapy.
It is also appreciated that viridans streptococcal bacteremia in patients with
profound neutropenia can be associated with a variety of severe
life-threatening complications. A syndrome similar to toxic shock syndrome
characterized by hypotension, rash, and the development of acute respiratory
distress syndrome (ARDS) has been seen in up to one fourth of neutropenic
patients with AHS bacteremia. Progression to severe hypotension and respiratory
failure can occur despite rapid clearance of bacteria from the bloodstream. The
mechanism of this
severe syndrome is not understood, although it may involve production of toxins.
Management
A major concern is that antibiotic resistance among AHS is increasing. Although
studies are limited, it is found that up to half of the isolates showed at
least intermediate resistance to penicillin, defined as a minimal inhibitory
concentration (MIC) of 0.25 to 2.0
µg/mL. In addition, centers have reported that more than 50% of AHS show at least
intermittent resistance to ceftazidime, defined as an MIC of more than 1.0
µg/mL.
The emergence of the gram-positive infections in patients with cancer has led to
a discussion whether vancomycin should be used as initial empiric therapy in
the management of fever and neutropenia. Early studies showed that the initial
use of vancomycin in patients with fever and neutropenia did not significantly
alter outcome. Recent studies have shown that, although this may be true for
gram-positive organisms taken as a whole, there is evidence that the early use
of vancomycin can produce a survival advantage in specific cases of AHS
infection. Patients who ultimately were diagnosed with AHS infection who
received empiric vancomycin had a significantly improved outcome over that of
patients whose vancomycin was delayed until final identification of the
infecting organism. It may be that vancomycin does become a part of initial
empiric treatment for fever and neutropenia in children, especially if specific
risk factors are present (Table 17.1). If empiric treatment is initiated with
vancomycin, it should be discontinued once culture specimens fail to reveal
gram-positive organisms.
Duration of Therapy in Fever and Neutropenia
A major issue in managing the oncology patient with fever is the duration of
therapy. There are several possibilities when managing this patient population,
usually determined by the recovery of the neutrophil count.
Patient Afebrile within the First 3 to 5 Days of Treatment, Etiology Found
If a responsible pathogen is isolated, the antibiotics can be changed to give
optimal treatment to the specific pathogen. Antibiotic treatment should be
continued for a minimum of 7 days; many specialists continue treatment for at
least 10 to 14 days if an isolate is recovered in blood culture. Often,
antibiotics are continued until there is evidence of bone marrow recovery
(i.e., neutrophil count
> 500/m3). In cases in which neutropenia is predicted to be prolonged, afebrile patients
may have antibiotics stopped and are closely observed.
Patient Afebrile, No Etiology Found
The management of these patients is difficult because no infectious disease
process has been documented. Patients who are afebrile and who have an absolute
neutrophil count of more than 500/m
3 may have their antibiotics discontinued. In persistently neutropenic children,
there has been an effort to divide patients into low-risk and high-risk
categories. Children are considered at low risk if they lack ongoing signs of
sepsis, chills, hypotension, severe mucositis, and have a neutrophil count of
more than 100/m
3. In these children, antibiotics may be stopped when the child is afebrile for
about 1 week. A small number of studies have suggested that the antibiotic can
be changed to oral cefixime and the child monitored closely. It should be noted
that these studies involving the use of oral antibiotics often took place with
the patients remaining as inpatients for close monitoring. Children who are
labeled at high risk (i.e., those with continued absolute neutropenia or
mucositis, or in whom follow-up cannot be guaranteed) are continued on
intravenous antibiotics until the resolution of neutropenia.
Continued Fever without Etiology
Patients who continue to have fever without obvious etiology present the most
difficult management dilemma. The most important management principal in these
patients is continued evaluation with physical examination, blood cultures, and
radiographic studies. Because systemic fungal infections can be associated with
negative blood cultures and may present with progressive intracranial, sinus,
or pulmonary disease, these areas should be closely monitored. Examination of
the oropharynx for viral lesions caused by either herpes simplex virus or
cytomegalovirus is important. Children with persistent fever and neutropenia
are often treated for 2 weeks, with a complete reevaluation at that time. In
certain situations, it has been suggested that if the patient remains
clinically stable with no evidence of progressive infectious disease,
antibiotics may be discontinued under close observation.
Specific Clinical Entities in Fever and Neutropenia
Hepatosplenic Candidiasis
Etiology
An important clinical entity in the patient with fever and neutropenia is
hepatosplenic candidiasis. Hepatosplenic candidiasis represents a disseminated
candidal infection, with the liver and spleen being the primary sites affected.
All species of candida have been reported to cause this condition. The major
risk factor is prolonged neutropenia. Of note, most affected patients become
symptomatic only after recovery of their neutrophil count.
Presentation
Patients present with persistent fever and abdominal distention and pain. Blood
cultures, as in the case of most fungal infections in this patient population,
remain negative. Patients often have elevated transaminase and alkaline
phosphatase levels.
Diagnosis
Diagnosis is by CT or magnetic resonance imaging of the abdomen, which shows
numerous hepatosplenic lesions. Biopsy of these lesions is positive in more
than 80% of cases.
Management
Treatment is prolonged antifungal therapy. Antifungal treatment should continue
until there is radiographic resolution of lesions.
Typhlitis
Etiology
Typhlitis is also known as neutropenic enterocolitis. Often localized to the cecum, it is associated with profound neutropenia in a
patient with underlying malignancy. Affected patients often have absolute
neutropenia, fever, abdominal pain, and distention. Gastrointestinal bleeding
is frequently seen. The pathogenesis of typhlitis remains unknown. Chemotherapy
is thought to damage the mucosa of the bowel and predispose it to bacterial
overgrowth injury. Bacterial overgrowth can lead to invasion of the mucosa and
even breakthrough bacteremia. A variety of pathogens have been cultured from
the blood in patients with typhlitis, including
Pseudomonas species, Staphylococcus aureus, enteric gram-negative organisms, anaerobes, and viridans streptococci. Fungal
pathogens are also thought to be involved in the pathogenesis of typhlitis;
common isolates include
Candida and Aspergillus species.
Presentation
Patients with typhlitis typically have a history of prolonged neutropenia.
Abdominal pain and distention are prominent symptoms.
Diagnosis
Definitive diagnosis requires biopsy of the bowel, which shows focal hemorrhage,
ulceration, and intramural edema. Because physicians are often reluctant to
perform bowel biopsy in a patient so critically ill, CT has been increasingly
used in patients with suspected typhlitis. Findings on CT include thickening of
the bowel and accumulation of peritoneal fluid.
Management
Management of typhlitis includes intensive supportive care, including parenteral
nutrition. It is traditional that broad-spectrum antimicrobial agents be given
to such patients, including antibiotics with efficacy against resistant
gram-negative organisms, AHS, and fungi. Surgical management is done in extreme
cases, although most surgeons believe that patients who require surgery for
typhlitis face a very grim prognosis. Resolution of underlying neutropenia is a
major factor in recovery.
Selected Readings
Elting LS, Rubenstein EB, Rolston K, et al. Outcome of bacteremia in patients
with cancer and neutropenia: observation from two decades of epidemiological
and clinical trials.
Clin Infect Dis 1997;25(2):247–259.
Hughes WT, Armstrong D, Bodey GP, et al. 2002 Guidelines for the use of
antimicrobial agents in neutropenic patients with cancer.
Clin Infect Dis 2002;34(6):730–751.
Katz JA, Wagner ML, Gresik MV, et al. Typhlitis: an 18 year experience and
post-mortem review.
Cancer 1990;65(4):1041–1047.
Kauffman CA. Fungal infections. Infect Med 2003;20:424–436.
Sallah S, Semelka RC, Wehbie R, et al. Hepatosplenic candidiasis in patients
with acute leukaemia.
Br J Haematol 1999;106(3):697–701.
Tunkel AR, Sepkowitz KA. Infections caused by viridans streptococci in patients
with neutropenia. Clin Infect Dis 2002;34(11):1524
–1529.
Walsh TJ, Pappas P, Winston D. et al. Voriconazole compared with liposomal
amphotericin B for empirical antifungal therapy in patients with neutropenia
and persistent Fever.
N Engl of Med 2002;346(4):225–234.
Pictures
Book Source Details
- Book Title: Pediatric Infectious Disease
- Author(s): Donald Janner MD
- Year of Publication: 2004
- Copyright Details: Pediatric Infectious Disease, Copyright © 2004 Lippincott Williams & Wilkins.
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More About This Book:
Title: Pediatric Infectious Disease
Authors: Donald Janner MD
Publisher: Lippincott Williams & Wilkins
Copyright: 2004
ISBN: 0-7817-5584-0
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