Fever and Neutropenia in Pediatric Patients with Cancer

Fever a nd Neutropenia in Pediatric Patients with Ca ncer Garth Meckler, MD, MSHSa,b,c,*, Susan Lindemulder, MDd,e KEYWORDS  Neutropenia  Fever  Pediatric  Oncology  Management

OVERVIEW

The treatment for most pediatric malignancies is based on systemic, aggressive multimodality therapy including systemic antineoplastic and radiation therapy. Although this approach has led to impressive improvements in the cure rates for many pediatric malignancies, it has secondary effects on a variety of normal cells, including hair, skin, mucous membranes, and the hematopoietic elements of the bone marrow. The resulting bone marrow suppression produces intermittent periods of leukopenia (especially neutropenia), anemia, and thrombocytopenia of varying severity and duration. The risk of morbidity and mortality because of serious infection during periods of neutropenia is greatly increased. Although most pediatric oncology patients are managed by pediatric oncologists at large academic centers, they may live far from the tertiary care setting and present with fever to local community hospital emergency departments (EDs) for initial evaluation, management, and stabilization before transfer for further care. Therefore, it is important for all providers in an emergency medical setting, regardless of location, to be familiar with the concepts involved in the evaluation and management of febrile, neutropenic, pediatric cancer patients.

a

Department of Emergency Medicine, Oregon Health & Science University, CDW-EM, 3181 SW Samuel Jackson Park Road, Portland, OR 97239-3098, USA b Department of Pediatrics, Oregon Health & Science University, CDW-EM, 3181 SW Samuel Jackson Park Road, Portland, OR 97239-3098, USA c Section of Pediatric Emergency Medicine, Oregon Health & Science University, CDW-EM, 3181 SW Samuel Jackson Park Road, Portland, OR 97239-3098, USA d Department of Pediatrics, Oregon Health & Science University, CDRCP, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA e Division of Pediatric Hematology/Oncology, Oregon Health & Science University, CDRCP, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA * Corresponding author. Department of Emergency Medicine, Oregon Health & Science University, CDW-EM, 3181 SW Samuel Jackson Park Road, Portland OR 97239-3098. E-mail address: [email protected] (G. Meckler). Emerg Med Clin N Am 27 (2009) 525–544 doi:10.1016/j.emc.2009.04.007 0733-8627/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.

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DEFINITIONS

Though some variability exists in the definition of fever for the pediatric oncology patient, it is most often defined as a single oral or equivalent temperature of greater than 38.3 C (101 F) or two consecutive temperatures greater than 38.0 C (100 F) in a 12-hour period lasting at least 1 hour.1 Although rectal measurement most accurately reflects core body temperature, the theoretical risk of bacterial translocation during the procedure of inserting the thermometer into the anus (particularly in the child with mucositis) is a contraindication, and therefore oral or axillary measurements are recommended. Neutropenia is defined as an absolute neutrophil count (ANC) <500/mm3 or <1,000/mm3 with an expected decline.1 PATHOPHYSIOLOGY

To understand the impact of multimodality regimens on infection risk, one must understand the impact these therapies have on the body’s defenses, including innate and adaptive immunity and the physiologic response to infection. Nonspecific recognition of an invading pathogen falls in the innate immune system, which includes mucocutaneous barriers, phagocytic cells, natural killer cells, nonclonal T and B cells, and the response networks that regulate these cells. Adaptive immunity includes those aspects of the immune system that provide a pathogen-specific response including production of specific antibodies and T-lymphocyte cell-mediated immunity. The physiologic response to infection involves all of the major organs, but of particular importance in this setting are the cardiovascular, pulmonary, and endocrine systems, including stress hormones. INNATE IMMUNITY

The first line of defense against invasive disease is the mucocutaneous barrier, which includes specialized cells of the skin and respiratory, gastrointestinal (GI), and genitourinary tracts. For example, the GI tract contributes to innate immunity through acidproducing parietal cells, antimicrobial molecules, and bactericidal fatty acids secreted in the intestine, as well as secretory IgA, which protects mucosal surfaces.2,3 The respiratory tract includes ciliated and mucus-producing cells that trap and expel pathogens, and surfactant-producing cells that help to opsonize bacteria, viruses, and fungi.4–6 Pediatric cancers and their treatment compromise the innate immune system in a variety of ways. Breakdown of the mucocutaneous barrier by local tumor invasion, surgical removal of the primary or metastatic lesions, radiation therapy, graftversus-host disease (GVHD), and mucositis caused by cytotoxic chemotherapy agents (eg, methotrexate, high-dose cytosine arabinoside, and etoposide) allow invasion of pathogens. Furthermore, most pediatric oncology patients have indwelling surgical devices (central venous catheter, ventricular drain, chest tube, nasogastric tube, or urinary catheter) placed during therapy, which may further disrupt the mucocutaneous barrier. In addition to indwelling devices, frequent blood draws compromise the epidermal barrier and provide an additional opportunity to introduce pathogens directly into the bloodstream. Functional compromise by local radiation therapy to the lung can result in paralysis of the ciliated cells. Even supportive measures meant to protect the patient can inadvertently disrupt the physiology of the innate immune system. For example, antacids used to prevent gastritis associated with high dose steroids can compromise the physiologic barrier by decreasing or inactivating gastric acid secretion.

Fever and Neutropenia in Pediatric Patients

The next line of defense in the innate immune system includes phagocytic cells such as neutrophils, circulating monocytes, and tissue macrophages. These cells phagocytose and destroy pathogens through oxidative and nonoxidative mechanisms and help regulate the immune response through the release of cytokines. Chemotherapy has quantitative and qualitative effects on these cells. Cytotoxic agents decrease the number of circulating neutrophils and monocytes. Infectious risk increases directly with the following: (1) severity of neutropenia (ANC < 100 cells/mm3 imposes a greater risk than ANC < 500 cells/mm3), (2) rate of ANC decline (rapidly falling rate imposes a greater risk than chronic neutropenia or aplastic anemia), and (3) duration of neutropenia.7 In addition to quantitative changes associated with therapy, functional changes in the phagocytic cells occur as well. Neutrophils from patients with leukemia or lymphoma can have impaired chemoattractant responsiveness, bactericidal killing, and superoxide production.8–11 In addition, concomitant corticosteroid treatment reduces oxidative and nonoxidative killing mechanisms of host cells.12–14 The result of these quantitative and functional impairments of the phagocytic cells is an inability of the immune system to adequately respond to invading bacterial and fungal pathogens. ADAPTIVE IMMUNITY

The adaptive immune system is composed of B and T cell populations responsible for regulating the humoral and cell-mediated host response. This arm of the immune system is also impaired quantitatively and qualitatively by malignancy and its treatment. Decreases in antibody producing B cells and plasma cells over the course of therapy result in defective immunoglobulin synthesis and hypogammaglobulinemia. This results in an increased susceptibility to infection with bacterial, fungal, and viral organisms. The encapsulated bacteria Streptococcus pneumoniae, Haemophilus influenzae type B, and Neisseria meningitidis are bacterial organisms that can cause overwhelming infection in patients with an impaired immunity. Some therapeutic regimens target T cells preferentially, impairing the cellular immune response and increasing the risk for fungal, viral, or intracellularly replicating bacterial infection. T-cell function is also impaired by corticosteroids, radiation, and by receiving T-celldepleted stem cell sources for bone marrow transplant. Some patients may have prolonged deficits in T-cell function.15,16 Other organ systems affected by cancer or its treatment further contribute to impaired host defenses. For example, splenectomy may be part of the treatment plan for some malignancies. The spleen functions to filter the blood, produce antibodies, remove damaged cells from circulation, and opsonize circulating organisms. Physical or functional asplenia increases the risk for fulminant sepsis because of encapsulated bacteria. Another example is neurologic impairment caused by treatment or disease, which can increase the risk for aspiration pneumonia. Mechanical obstruction of hollow organs by tumor, including bowel, bronchi, or ureters, can lead to colonization and postobstructive infection. Finally, nutritional deficiency is common among children undergoing chemotherapy and can adversely impact immune function in a multitude of ways. PHYSIOLOGIC COMPENSATION TO INFECTION

In addition to impacting the immune system directly and indirectly, malignancy and its treatment can impair the host’s physiologic response to overwhelming infection. Chemotherapy and radiation can injure the lung, leading to restrictive lung disease and impaired gas exchange, which can worsen hypoxia and respiratory failure in

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the setting of pneumonia. Cardiac dysfunction caused by agents such as doxorubicin can impair the ability of the heart to meet the increased output seen in sepsis and can contribute to decompensation and shock. Cranial irradiation may induce permanent pituitary dysfunction resulting in an inadequate stress hormone response to sepsis, further exacerbating physiologic decompensation. ETIOLOGY

The epidemiology of neutropenic infection varies with the geographic location of the treatment center.17–23 Only 10% to 30% of neutropenic fevers yield a microbiologic diagnosis.17–27 When a source is identified, 85% to 90% of the pathogens are either gram-positive or gram-negative bacteria. The most common causes of neutropenic fever in children are listed in Table 1. Although this section describes the microbiology of neutropenic fever, it should be emphasized that noninfectious causes of fever, including response to chemotherapeutic agents such as cytosine arabinoside, are diagnoses of exclusion. Gram-negative and anaerobic infections often originate from GI flora, whereas skin and respiratory flora contribute to gram-positive infections. Gram-positive organisms predominate and are often related to indwelling central catheters and mucositis from aggressive chemotherapy; however, gram-negative infections are nearly as common and must be considered in the ill-appearing patient. Antibiotic resistance, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus, are also important when considering empiric antibiotic coverage. Acute viral infections of concern in this population include respiratory and GI viruses

Table 1 Potential infectious etiologies in febrile neutropenic children Bacterial Gram-Positive

Gram-Negative

Viral

Fungal

Other

Staphylococcus spp

Escherichia coli

Herpes simplex

Candida spp

Pneumocystis jiroveci

Streptococcus spp

Pseudomonas aeruginosa

Varicella-zoster

Aspergillus spp

Protozoa

Enterococcus spp

Klebsiella spp,

Respiratory syncytial virus

Zygomycetes

Chemotherapyrelated fever

Corynebacterium Enterobacter spp spp

Influenza A and B

Fusarium spp

Bacillus spp

Parainfluenza

Scedosporium spp

Adenovirus

Cryptococcus neoformans

Clostridium spp

Anaerobes

Rotavirus Enterovirus Cytomegalovirus Epstein-Barr Human herpes virus 6 BK virus JC virus

Fever and Neutropenia in Pediatric Patients

often acquired from others in daycare or school settings or from siblings, in addition to nosocomial infection. Varicella, influenza, respiratory syncytial virus (RSV) and adenovirus carry high morbidity and mortality in neutropenic patients. Bone marrow transplant recipients are also at risk for acute infection or reactivation of latent infection with the herpes family viruses (cytomegalovirus, Epstein-Barr virus, herpes simplex virus [HSV]), and the polyomaviruses (John Cunningham or JC and BK).28,29 Given ubiquitous colonization with Pneumocystis jiroveci, this intracellular organism can become an opportunistic pathogen causing significant mortality. Most patients receiving immunosuppressive therapy are empirically placed on Pneumocystis prophylaxis for the duration of therapy.30–32 Fungal pathogens are a less common cause of clinical disease, but are more likely in patients with prolonged neutropenia (>10 days), relapsed disease, prolonged or high-dose steroids, and in the setting of chronic immunosuppression after bone marrow transplant.33 Protozoan infections are uncommon among children in the United States but must be considered in any immunocompromised host. RISK FACTORS

Several attempts have been made to stratify risk for serious infection and complications in the febrile neutropenic patient.34–40 A number of factors conferring high risk of infection have been identified. Aggressive surveillance and empiric treatment of these patients with broad-spectrum intravenous antibiotics has lead to a decrease in gram-negative sepsis-related mortality from 80% several decades ago to its current level of 1% to 3%.26,27 In addition to the ANC and duration of neutropenia, several factors seem to confer an increased risk for failure of first line empiric therapy, lifethreatening infection, or death. Some of these factors are nonspecific clinical signs universally recognized as harbingers of serious infection: (1) pneumonitis, (2) severe mucositis, (3) signs of compensated or decompensated shock, (4) dehydration, (5) hypotension, (6) respiratory distress or compromise, and (7) failure of a major organ system. Mucosal ulceration, vomiting, and diarrhea increase the risk of infection through disruption of the mucocutaneous barrier as previously described. Additional factors that confer higher risk of infection include relapsed leukemia because of circulating cancer cells that have impaired immune function and decreased bone marrow capacity to produce normal numbers of functional cells. Poorly controlled solid malignancies associated with alterations in cytokine, chemokine, and other protein production may impair regulation of immune response even in the face of normal neutrophil counts. Treatment with high-dose cytarabine is associated with increased susceptibility to infection and mortality from Streptococcus viridans and fungal infection because of prolonged neutropenia. Age less than 1 year has also been implicated as an independent risk factor, possibly the result of developmental immaturity of innate immunity, use of diapers, which leads to increased exposure of skin to urine and stool, and inability to communicate symptoms or localize pain to caregivers and medical staff. Additional laboratory markers associated with high risk of infection include C-reactive protein (CRP) greater than 90 mg/L, platelet count less than 50,000, and absolute monocyte count less than 100. Additional serum markers under investigation include a range of cytokines. Inpatient management of high-risk patients using broad-spectrum antibiotics has decreased overall mortality among pediatric cancer patients. However, this management scheme is associated with disruption of family life, prolonged hospital admissions, high medical costs, nosocomial complications, and increasing resistance to antibiotics. As a result, interest has recently turned toward identifying low-risk criteria

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that may allow for less aggressive management strategies in the outpatient setting. Comparison of low-risk models is difficult because of variable methodology and outcomes, but some of the proposed low-risk factors include a temperature less than 39 C, monocyte counts of 1000/mm3 or more, lack of medical comorbidity or radiographic evidence of pneumonia, outpatient status at time of febrile episode, anticipated short duration of neutropenia (<7 days), and malignancy other than acute myelogenous leukemia. Research into laboratory markers of risk (CRP, interleukin (IL)-6, IL-8, tumor necrosis factor-a, interferon-g, and others) and host genetic characteristics associated with infection risk are ongoing. A number of studies in Europe and South America have demonstrated the safe treatment of select low-risk populations with oral antibiotic therapy.25,38–46 Although preliminary data suggests that outpatient management of carefully selected patients may be safe and effective, these management strategies are not yet standard-of-care and should not be used outside of the setting of a clinical trial. ASSESSMENT AND EVALUATION

Ideally, a member of the primary oncology team will notify staff at the emergency facility that a febrile, potentially neutropenic, pediatric oncology patient needs emergent evaluation. This provides an opportunity to record information about the patient’s age, diagnosis, and recent therapy, in addition to pertinent past medical history, especially related to infection. This conversation also provides an opportunity to discuss specific plans for assessment and management. Important considerations in the history, physical examination, and evaluation of the febrile oncology patient are further reviewed later in this article. History

The history should include a thorough review of symptoms and exposures to try to identify a potential source of infection. It is important to remember that a neutropenic patient has a decreased response to inflammation, so clues regarding a potential source of infection may be subtle. Routine questions on history should include the height and duration of fever, associated chills or shaking, orthostatic symptoms, myalgias, and associated symptoms such as headache, cough, rhinorrhea, shortness of breath, chest pain, ear pain, sore throat, abdominal pain, vomiting, diarrhea, pain with urination, and skin lesions. Potential exposures at home or at school should be sought. Oral intake and urine and stool output should be ascertained. Symptoms of particular importance in this population include pain with stools that could indicate perirectal cellulitis or abscess, symptoms of mucositis (extent and location, degree of pain and interventions, active sloughing of mucosa), signs of infection (redness, swelling, or tenderness) around a central venous line or other hardware, and changes in surgical wounds that often demonstrate delayed healing because of chemotherapy and may provide a portal for infection. A careful review of medications with attention to recent chemotherapeutic agents, (inpatient, intravenous [IV], oral, intrathecal) prophylactic antibiotics and colony-stimulating factors should be documented. Patients and their families should be questioned carefully about adherence to prophylaxis regimens. For example, were any doses accidentally forgotten, does the child routinely spit out the medications and is it redosed, does the child vomit regularly after medication administration, is it possible that a teenager could ‘‘cheek’’ or throw away the medicine? It is also important to check that medication dosage is appropriate for the child’s weight, which may change with therapy (eg, weight gain associated with steroid therapy). Finally, a review

Fever and Neutropenia in Pediatric Patients

of past febrile episodes, surveillance culture results, and immunization status including influenza vaccination should be sought. Vital Signs

All patients should have a full set of vital signs recorded and frequently reassessed during their ED visit. Temperature, respiratory rate, heart rate, blood pressure, pulse oximetry, and weight are essential to record for all oncologic patients with fever and suspected neutropenia. Abnormal vital signs may be the only sign of impending lifethreatening infection in the otherwise well-appearing child. Tachypnea or mild hypoxia may represent pneumonitis or an evolving consolidation. Tachycardia out of proportion to fever, crying, anxiety, or pain should be considered compensated shock, particularly when persistent. Weight recorded in the ED can be compared with a recent clinic weight to aid in assessing the degree of dehydration from poor oral intake or fluid losses from vomiting or diarrhea. Physical Examination

Every patient evaluated for fever and neutropenia requires a thorough examination to attempt to identify a source of infection. This requires full exposure of the skin and all patients should be placed in a gown, despite the temptation to spare the child or family another invasive examination with an unfamiliar provider. A ‘‘look, listen, feel’’ approach as taught in basic life support is often helpful to establish a quick assessment of illness severity—visual assessment of the patient’s color, muscle tone, degree of activity, respiratory pattern, and mental status (note interactions with caregivers, environment, and examiner); listening for grunting, stridor, or wheezing; and feeling for skin temperature, pulses, and capillary refill. This rapid assessment will help classify the patient in respiratory distress or failure and define whether the patient’s presentation is compensated or decompensated. The practitioner may then turn to a systematic head-to-toe examination. The headears–eyes-nose-throat (HEENT) examination should specifically note the presence and extent of mucositis (few discrete ulcers vs extensive involvement with sloughing) and the moisture of the mucous membranes. The mouth, nose, sinuses, and palate should also be carefully examined; white plaques may indicate yeast infection such as Candida and black plaques may indicate fungal infection such as Aspergillus or Mucor. The lungs should be carefully auscultated for signs of consolidation, though tachypnea may be the only sign of respiratory infection in the severely neutropenic child. The chest wall and central venous catheter site should be inspected for erythema, warmth, tenderness, or fluctuance. The abdomen should be examined carefully for tenderness that might indicate pancreatitis (especially following recent asparaginase chemotherapy), liver enlargement, gallbladder inflammation, or diffuse right lower quadrant pain potentially signaling typhlitis. As noted earlier, pulses and capillary refill should be assessed, remembering that warm shock presents with bounding pulses and brisk capillary refill, whereas cold shock is associated with cool, mottled extremities and sluggish capillary refill. Any surgical site, including catheters, ventriculoperitoneal shunts, biopsy sites, resection sites, and orthopedic incisions should be examined for signs of superficial or deep infection. In addition, the perirectal area should be visually inspected for erythema and the perianal area palpated for evidence of abscess. Digital rectal examination is contraindicated as it may result in further translocation of bacteria. Primary varicella and zoster infections deserve special mention with regard to physical examination in the neutropenic population. The rash associated with these diseases is often altered in children undergoing therapy and may initially appear as

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papules in small numbers rather than the expected multiple vesicular lesions. Occasionally zoster reactivation will present only as pain and hypoesthesia without rash (zoster sine herpete). These patients should be considered extremely infectious as they are much more likely to have disseminated disease and should be placed in airborne and contact isolation until the diagnosis is ruled out or the disease resolves completely. Laboratory Tests

The initial laboratory evaluation of the febrile pediatric oncology patient should include a complete blood count with manual differential to determine whether the patient is neutropenic, and blood cultures should be performed on samples from all central venous catheters. Peripheral blood cultures are no longer indicated because they have been proven to provide limited additional information when the central blood culture is of adequate volume. Additional laboratory studies are not routinely useful and should be directed by the clinical picture (Table 2). In some institutions, radiographs of the chest (CXR) are routinely included in the initial evaluation of all febrile neutropenic patients, regardless of symptomatology. Evidence suggests that a CXR may not be as useful as a screening test. The incidence of pneumonia on CXR in febrile neutropenic patients has been found to be 3% to 6%,

Table 2 Additional laboratory tests for consideration in the initial evaluation Test

Indications

Complete metabolic panel

Concern for metabolic abnormality due to nephrotoxic drugs Excessive fluid losses (vomiting, diarrhea) TPN–dependence History of liver dysfunction

Lipase

Examination findings consistent with pancreatitis Recent therapy with asparaginase

Urinanalysis and urine culture

Urinary frequency, urgency, dysuria

Nasal wash for rapid viral evaluation

Exposure to influenza A, B Exposure to RSV Consistent clinical picture

Chest radiograph (2 views)

Hypoxia Unexplained tachypnea Concerning symptoms Physical examination findings (rales, wheeze)

Throat culture and rapid Streptococcus test

Pain and exudate on examination Exposure to group A Streptococcus Clinical picture consistent with group A Streptococcus

Abdominal imaging (radiograph, ultrasound, CT scans)

Focal tenderness on examination Concern for typhlitis Concern for surgical abdomen

Skin swabs for viral or bacterial culture

Vesicular lesions consistent with VZV and HSV Erythema or exudate at the site of hardware or surgical incision

Abbreviations: TPN, total parenteral nutrition; VZV, varicella zoster virus.

Fever and Neutropenia in Pediatric Patients

with almost all cases being associated with clinical signs and symptoms.47–50 Because there is no national consensus, the decision regarding when to obtain a CXR on febrile neutropenic pediatric patients should be based on institutional standards.

MANAGEMENT

All management should be performed in telephone consultation with the primary pediatric oncology team when possible. The care of critically ill patients should include early contact with an intensivist and arrangements for prompt transfer to definitive care after initial resuscitation and attempted stabilization. The general ED management of the neutropenic patient is depicted in Fig. 1. The goal for all oncology patients should be rapid triage, medical evaluation, and identification of neutropenic fever, leading to early administration of empiric antibiotics (discussed separately in a later section), careful observation and reassessment of vital signs, and transfer to the appropriate ward or intensive care unit. All pediatric oncology patients presenting to

Fig. 1. General approach to the febrile pediatric oncology patient. CBC, complete blood count; PICU, pediatric intensive care unit.

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the ED with fever should initially be placed on monitors. Management of the airway, breathing, and circulation should be the first priority. Definitions of sepsis, severe sepsis, and decompensated shock are listed in Table 3.9 The detailed management of sepsis is beyond the scope of this chapter; however, a number of excellent reviews of sepsis, including the importance of early goal-directed therapy have been recently published.51–55

EMPIRIC BROAD-SPECTRUM ANTIBIOTICS

Specific antibiotic choices should be guided by local microbiology, susceptibilities, and individual patient risk factors and therefore will vary by institution. The general principle guiding empiric treatment, however, remains the selection of antimicrobial agents with a broad spectrum of activity against gram-negative and gram-positive organisms likely to cause disease in this patient population. Early protocols used combination therapy, typically a b-lactam antibiotic (third or fourth generation cephalosporin) plus an aminoglycoside.56–59 More recently, monotherapy using broad-spectrum b-lactam antibiotics with antipseudomonal activity have been shown to be as effective as combination therapy. Common monotherapy choices include cephalosporins (ceftazidime, cefepime) or carbapenems (imipenem, meropenem).60–70 Individual choices must take into account institutional patterns of antibiotic resistance that vary widely.1 Although broad-spectrum monotherapy may suffice for most stable neutropenic patients, additional coverage should be considered for specific conditions or risk factors. Patients who have received high-dose cytarabine, for example, are at increased risk for alpha hemolytic Streptococcus infection, which is associated with significant resistance to antibiotics.71 Vancomycin should be added to the traditional

Table 3 Sepsis and related terminology Systemic inflammatory response syndrome (SIRS)

T > 38.5 or <36.0 C Tachycardia > 2 SD for age or bradycardia if < 1 y RR > 2 SD for age WBC above or below age norms (not related to chemotherapy)

Sepsis

SIRS in presence of proven or suspected infection

Severe sepsis

Sepsis 1 cardiovascular dysfunction (see next row), respiratory distress syndrome, or R2 organ dysfunctions (neurologic, renal, hepatic, hematologic)

Septic shock

Sepsis 1 cardiovascular dysfunction (hypotension, vasopressor dependence, acidosis, elevated lactate, oliguria, delayed capillary refill, core to peripheral temperature gap > 3 C)

Abbreviations: RR, relative risk; SD, standard deviation; SIRS, systemic inflammatory response syndrome; T, temperature; WBC, white blood cell. Data from Goldstein B, Giroir B, Randolph A. International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005;6(1):2–8.

Fever and Neutropenia in Pediatric Patients

broad-spectrum therapy of these patients. Vancomycin should also be considered for patients with signs of central venous catheter infection including surrounding cellulitis or tenderness and for patients with a known history or exposure to MRSA. When there is clinical suspicion of typhlitis or an intra-abdominal catastrophe, empiric coverage should be broadened to include better anaerobic activity—triple therapy with metronidazole, a third or fourth generation cephalosporin, and vancomycin is commonly used in this setting.

ANTIVIRALS

As discussed earlier, viral infections are common in pediatric oncology patients and are associated with significant morbidity and mortality in this population. The availability of rapid detection for many viruses (including influenza, RSV, and adenovirus) can lead to the early diagnosis and should be considered when symptoms are suggestive of viral disease. Although empiric use of antiviral agents is not standard-of-care in the ED, a number of antiviral drugs are available, and the select use of these medications should be considered in consultation with an oncologist and infectious disease specialist. Treatment for influenza, RSV, and adenovirus are briefly discussed later. Despite the recommendations of the Centers for Disease Control and Prevention (CDC) for annual influenza vaccination in healthy children older than 6 months and evidence that trivalent vaccine may be effective in cancer patients, vaccination rates for influenza remain low.72 Furthermore, there may be reduced immunogenicity of vaccination in children undergoing treatment for hematologic malignancy. When symptoms and local epidemiology suggest clinical infection with influenza, rapid antigen testing can confirm infection. Two classes of drugs with activity against influenza are available and approved for use in children. The adamantanes (amantadine and rimantadine) target the M2 ion channel protein found only on influenza A and are approved for children older than 12 months. Though relatively safe, recent widespread resistance to this class of drugs limits their efficacy, particularly among H3N2 strains, and their use should only be considered after consultation with infectious disease experts. Two neuraminidase inhibitors are available for use in children—oseltamivir is available in liquid preparation and has been approved for use in children older than 12 months , and zanamivir, administered as an inhalation powder, is approved for use in children older than 7 years. Both drugs are active against influenza A and B, although oseltamivir has a relatively decreased efficacy against influenza B. Both drugs have been shown to decrease the duration of fever and symptoms in otherwise healthy children and may decrease progression to lower-tract disease in adult bone marrow transplant patients.73–77 Data from widespread use of these drugs in Japan have led to recent concerns regarding the emerging resistance to oseltamivir and serious side effects. A total of 71 deaths have been reported in Japan between 2001 and 2007, including 18 sudden deaths in children younger than 10 years and five deaths related to neuropsychiatric disturbances in teenagers. The mechanism of sudden death is not fully understood but is believed to be related to the central suppressive effects of the drug leading to centrally mediated cardiopulmonary arrest.78–80 This has prompted the Food and Drug Administration to issue a black box warning regarding potential behavioral effects, particularly in adolescents. Zanamivir inhalation may precipitate bronchospasm in children with underlying reactive airway disease, and caution should be exercised in this population. Both drugs are effective for prophylaxis in cases of known exposure to influenza in the high-risk, unvaccinated oncology patient. Because of the potential adverse effects associated

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with antiviral therapy, careful consideration of risks and benefits should be made before use of these antiviral agents. Infection with RSV can also result in serious disease in the pediatric oncology patient, particularly after T-cell-depleted bone marrow transplant. As with influenza, rapid testing for RSV is now available, and treatment options for severe disease include the antiviral agent ribavarin and human monoclonal antibody to RSV, palivizumab.81–85 A recent Cochrane review of ribavirin found from 12 clinical trials, all in infants younger than 6 months and in which confidence intervals from pooled data were wide, that ribavirin may decrease mortality, respiratory deterioration, and length of hospital stay.86 Controlled trials in older and immunocompromised children are lacking, and the use of this medication and palivizumab should be made in consultation with infectious disease experts. Adenoviral infection is associated with high mortality rates in bone marrow transplant recipients. No specific treatment strategies have been tested in controlled trials, though antiviral therapy with cidofovir, ribavirin, and vidarabine have been reported with variable efficacy.87–90 ANTIFUNGALS

Empiric antifungal therapy is rarely indicated in the ED unless there is specific evidence of fungal infection on the initial evaluation. Risk factors for invasive fungal disease include prolonged neutropenia (>10 days), relapsed leukemic disease or prolonged neutropenic fever despite antibiotic therapy (>5 days). Until recently, the treatment of fungal disease was associated with significant morbidity. Amphotericin B, the primary option for antifungal treatment in the past, was well known for adverse side effects including fever, chills, rigors, nausea, vomiting, and nephrotoxicity. Newer liposomal preparations of amphotericin (AmBisome, Abelcet, and Amphotec) are associated with fewer side effects. These newer antifungals can be used as initial empiric therapy or treatment for proven mycoses in patients receiving concomitant nephrotoxic agents, those with previous renal impairment, or in patients with an anticipated lengthy course likely to be limited by nephrotoxicity.91–95 Additional antifungal classes have recently shown promise for treating fungal disease with differing side-effect profiles. The azole class of antifungals include topical preparations (clotrimazole, miconazole, and ketoconazole) and parental formulations (itraconazole, fluconazole, voriconazole, and posaconazole). The azole group has activity against yeast and the newest approved agent, voriconazole, is considered the drug of choice for treatment of invasive aspergillosis.96–99 Significant drug interactions and hepatotoxicity are the main limitation of the azoles. Ketoconazole is no longer used in this population because of its high risk of hepatotoxicity. The echinocandin class of antifungals includes caspofungin, micafungin, and anidulafungin, which have activity against azole-resistant Candida species and Aspergillus. The echinocandins are attractive agents in this population because they are well-tolerated and have fewer drug interactions.100–103 ADDITIONAL MANAGEMENT CONSIDERATIONS Colony-Stimulating Factor

Many children will be receiving a colony-stimulating factor, such as granulocyte colony-stimulating factor, as part of the therapeutic regimen. Recent guidelines recommend that a colony-stimulating factor be given if the chemotherapy regimen is anticipated to result in rates of febrile neutropenia greater than or equal to 20%.104,105 In a meta-analysis, colony-stimulating factors were shown to reduce the

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rate of febrile neutropenia, decrease the length of hospitalization for febrile neutropenia, reduce the documented infection rate, and reduce amphotericin use; however, they have not been shown to reduce overall infection-related mortality. If a patient is not already on colony-stimulating factors, there is no information that the addition of these medications is of benefit, and they should not be initiated in the ED.106

Transfusions

Transfusions of either packed red blood cells (PRBCs) or platelets may need to be initiated in the ED as clinically indicated by critical values or evidence of bleeding. It is important to remember that all transfusions need to be irradiated and leukodepleted to avoid sensitization. If the evaluating facility cannot provide these blood products, transfusion should be delayed in the otherwise stable patient. Guidelines for PRBCs and platelet transfusion vary between centers, but general recommendations regarding indication, dose, and expected response for platelet transfusions are provided in the following paragraphs.107 The guidelines for transfusion of PRBCs depend on the clinical scenario in which the patient presents to the ED. In a stable, asymptomatic child presenting with fever and neutropenia, in whom recovery is expected soon, transfusion is not indicated until hemoglobin levels decrease to less than 7 g/dL. Patients presenting with alterations of normal vital signs such as tachycardia, tachypnea or hypotension that are otherwise stable should be transfused for hemoglobin levels less than 8 g/dL. Clinical scenarios that require transfusion at higher hemoglobin levels between 8 and 10 g/dL include oxygen requirement because of pulmonary or cardiac morbidity, thrombocytopenia with history of prior significant hemorrhage, procedure that is anticipated to be associated with blood loss, and fatigue. Fatigue may negatively impact the quality of life and is typically seen in adolescent patients who require a higher resting hemoglobin when compared with younger patients. The expected response to PRBC transfusion is approximately 2 g/dL for each 10 mL/kg transfused. The transfusion amount should be calculated based on the goal hemoglobin and should be administered by giving each 10 mL/kg over 4 hours. Guidelines for transfusion of platelets, much like PRBCs, vary with the clinical scenario in the ED. General considerations are summarized in Table 4. When dosing platelets, one random donor equivalent unit per 10 kg should raise the platelet count between 50 and 100/ mm3 and can be infused over 30 to 60 minutes. Before the initiation of any transfusion, the practitioner should consult previous medical records and

Table 4 General guidelines for platelet transfusion Clinical Context

Suggested Platelet Level (cells/mm3)

Asymptomatic patient

>10

Minor bleeding (epistaxis, mucosal bleeding)

>20

Major bleeding (hemoptysis, GI or CNS bleed, hemorrhagic cystitis)

>100

CNS tumor

>50

Diagnostic LP

>10–20

Surgical procedure

>50–100

Abbreviations: CNS, central nervous system; LP, lumbar puncture.

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ask the patient’s caregiver if there is any history of a transfusion reaction requiring premedication before infusion of the blood product. Pituitary Dysfunction

Some patients may develop pituitary dysfunction as a result of neurosurgery or cranial radiation. Most of these patients are routinely monitored for pituitary dysfunction or are aware of their condition and the primary oncology team should provide advanced notification of this special consideration at the time of the initial referral. All patients with panhypopituitary dysfunction should receive prompt stress-dose hydrocortisone to avoid further complications. Though dosing based on body surface area can be discussed with an endocrinologist, a safe rule-of-thumb is to administer 25 mg IV/intramuscular for patients in the first 2 years of life, 50 mg for toddlers and school aged children, and 100 mg for adolescents. Stress-dose steroids can be life-saving, have few side effects, will not interfere with the oncology treatment regimen, and should be administered without delay. Adrenal insufficiency should also be considered in patients receiving prolonged steroid therapy (some phases of acute lymphoblastic leukemia treatment, GVHD prophylaxis, treatment after bone marrow transplantation, or to control edema related to radiation effects). Observation Period

In the bacteremic patient, administration of antibiotics may precipitate decompensation or sepsis syndrome through lysis of bacteria and release of bacterial cell wall products, such as lipopolysaccharides. In addition, allergic reactions or idiopathic reactions to transfused blood products may compromise patient stability. Because of these risks, it is important to observe and monitor these patients for a period of time during and after antibiotic administration or transfusion, with reassessment of vital signs before transfer from the ED to the hospital ward. Unstable patients should be resuscitated and transferred as soon as possible to an intensive care unit.

SUMMARY

The approach to the treatment of the febrile neutropenic pediatric patient has evolved considerably as high- and low-risk criteria have been defined and broad-spectrum antibiotics developed. Although individual evaluation and management strategies should be based on local epidemiology, microbial resistance patterns, and institutional practice standards, the general approach to these patients is the same. Critically ill or septic neutropenic patients should undergo resuscitation according to advanced life support guidelines, cultures should be obtained, and broad-spectrum antibiotics should be administered. Stable patients with a recognizable source of infection should have appropriate cultures obtained and source-specific antibiotics administered. Children with fever, neutropenia, and no obvious source of infection are typically managed as inpatients with broad-spectrum monotherapy antibiotics, pending results of blood cultures. In some institutions, stable patients with no obvious source of infection and an ANC that is expected to recover quickly may be managed as outpatients following administration of a long-acting broad-spectrum parenteral antibiotic with close outpatient follow-up and surveillance of cultures. In all cases, the management of these patients will ideally be conducted with good communication between ED physicians and pediatric oncologists.

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REFERENCES

1. Hughes WT, Bodey GP, Bow EJ, et al. Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002;34:730–51. 2. Cerutti A, Rescigno M. The biology of intestinal immunoglobulin A responses. Immunity 2008;28(6):740–50. 3. Schenk M, Mueller C. The mucosal immune system at the gastrointestinal barrier. Best Pract Res Clin Gastroenterol 2008;22(3):391–409. 4. Pastva AM, Wright JR, Williams KL. Immunomodulatory roles of surfactant proteins A and D: implications in lung disease. Proc Am Thorac Soc 2007; 4(3):252–7. 5. Hussain S. Role of surfactant protein A in the innate host defense and autoimmunity. Autoimmunity 2004;37(2):125–30. 6. Sano H, Kuroki Y. The lung collectins, SP-A and SP-D, modulate pulmonary innate immunity. Mol Immunol 2005;42(3):279–87. 7. Bodey GP, Buckley M, Sathe YS, et al. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966;64(2):328–40. 8. Pickering LK, Anderson DC, Choi S, et al. Leukocyte function in children with malignancies. Cancer 1975;35(5):1365–71. 9. McCormack RT, Nelson RD, Bloomfield CD, et al. Neutrophil function in lymphoreticular malignancy. Cancer 1979;44(3):920–6. 10. Baehner RL, Neiburger RG, Johnson DE, et al. Transient bactericidal defect of peripheral blood phagocytes from children with acute lymphoblastic leukemia receiving craniospinal irradiation. N Engl J Med 1973;289(23):1209–13. 11. Hersh EV, Gutterman JU, Mavligit GM. Effect of haematological malignancies and their treatment on host defence factors. Clin Haematol 1976;5(2):425–48. 12. Roilides E, Uhlig K, Venzon D, et al. Prevention of corticosteroid-induced suppression of human polymorphonuclear leukocyte-induced damage of Aspergillus fumigatus hyphae by granulocyte colony-stimulating factor and gamma interferon. Infect Immun 1993;61(11):4870–7. 13. Berenguer J, Allende MC, Lee JW, et al. Pathogenesis of pulmonary aspergillosis. Granulocytopenia versus cyclosporine and methylprednisolone-induced immunosuppression. Am J Respir Crit Care Med 1995;152(3):1079–86. 14. Lionakis MS, Kontoyiannis DP. Glucocorticoids and invasive fungal infections. Lancet 2003;362(9398):1828–38. 15. Mackall CL, Fleisher TA, Brown MR, et al. Age, thymopoiesis, and CD41 T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 1995; 332(3):143–9. 16. Fisher RI, DeVita VT Jr, Bostick F, et al. Persistent immunologic abnormalities in long-term survivors of advanced Hodgkin’s disease. Ann Intern Med 1980;92(5): 595–9. 17. Bakhshi S, Padmanjali KS, Arya LS. Infections in childhood acute lymphoblastic leukemia: an analysis of 222 febrile neutropenic episodes. Pediatr Hematol Oncol 2008;25(5):385–92. 18. Stabell N, Nordal E, Stensvold E, et al. Febrile neutropenia in children with cancer: a retrospective Norwegian multicentre study of clinical and microbiological outcome. Scand J Infect Dis 2008;40(4):301–7. 19. Katsimpardi K, Papadakis V, Pangalis A, et al. Infections in a pediatric patient cohort with acute lymphoblastic leukemia during the entire course of treatment. Support Care Cancer 2006;14(3):277–84.

539

540

Meckler & Lindemulder

20. Lai HP, Hsueh PR, Chen YC, et al. Bacteremia in hematological and oncological children with febrile neutropenia: experience in a tertiary medical center in Taiwan. J Microbiol Immunol Infect 2003;36(3):197–202. 21. Mahmud S, Ghafoor T, Badsha S, et al. Bacterial infections in paediatric patients with chemotherapy induced neutropenia. J Pak Med Assoc 2004; 54(5):237–43. 22. Ariffin H, Navaratnam P, Lin HP. Surveillance study of bacteraemic episodes of febrile neutropenic children. Int J Clin Pract 2002;56(4):237–40. 23. Castagnola E, Fontana V, Caviglia I, et al. A prospective study on the epidemiology of febrile episodes during chemotherapy-induced neutropenia in children with cancer or after hemopoietic stem cell transplantation. Clin Infect Dis 2007; 45(10):1296–304. 24. Mendes AV, Sapolnik R, Mendonca N. New guidelines for the clinical management of febrile neutropenia and sepsis in pediatric oncology patients. J Pediatr (Rio J) 2007;83(2 Suppl):S54–63. 25. Kern WV. Risk assessment and treatment of low-risk patients with febrile neutropenia. Clin Infect Dis 2006;42(4):533–40. 26. Viscoli C, Castagnola E. Treatment of febrile neutropenia: what is new? Curr Opin Infect Dis 2002;15(4):377–82. 27. Orudjev E, Lange BJ. Evolving concepts of management of febrile neutropenia in children with cancer. Med Pediatr Oncol 2002;39(2):77–85. 28. Ramphal R, Grant RM, Dzolganovski B, et al. Herpes simplex virus in febrile neutropenic children undergoing chemotherapy for cancer: a prospective cohort study. Pediatr Infect Dis J 2007;26(8):700–4. 29. Uys R, Cotton MF, Wessels G, et al. Viral isolates during febrile neutropaenia in children with cancer. J Trop Pediatr 2000;46(1):21–4. 30. Hughes WT, Price RA, Kim HK, et al. Pneumocystis carinii pneumonitis in children with malignancies. J Pediatr 1973;82(3):404–15. 31. Hughes WT, Kuhn S, Chaudhary S, et al. Successful chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med 1997;297(26):1419–26. 32. Hughes WT, Rivera GK, Schell MJ, et al. Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med 1987;316(26): 1627–32. 33. Lai HP, Chen YC, Chang LY, et al. Invasive fungal infection in children with persistent febrile neutropenia. J Formos Med Assoc 2005;104(3):174–9. 34. Santolaya ME, Alvarez AM, Becker A, et al. Prospective, multicenter evaluation of risk factors associated with invasive bacterial infection in children with cancer, neutropenia, and fever. J Clin Oncol 2001;19(14):3415–21. 35. Santolaya ME, Alvarez AM, Aviles CL, et al. Prospective evaluation of a model of prediction of invasive bacterial infection risk among children with cancer, fever and neutropenia. Clin Infect Dis 2002;35:678–83. 36. Santolaya ME, Alvarez AM, Aviles CL, et al. Early hospital discharge followed by outpatient management versus continued hospitalization of children with cancer, fever and neutropenia at low risk for invasive bacterial infection. J Clin Oncol 2002;22(18):3784–9. 37. Baorto EP, Aquino VM, Mullen CA, et al. Clinical parameters associated with low bacteremia risk in 1100 pediatric oncology patients with fever and neutropenia. Cancer 2001;92(4):909–13. 38. Hartel C, Deuster M, Lehrnbecher T, et al. Current approaches for risk stratification of infectious complications in pediatric oncology [see comment]. Pediatr Blood Cancer 2007;49(6):767–73.

Fever and Neutropenia in Pediatric Patients

39. Ammann RA, Hirt A, Lu¨thy AR, et al. Identification of children presenting with fever in chemotherapy-induced neutropenia at low risk for severe bacterial infection. Med Pediatr Oncol 2003;41(5):436–43. 40. Klaassen RJ, Goodman TR, Pham B, et al. ‘‘Low-risk’’ prediction rule for pediatric oncology patients presenting with fever and neutropenia. J Clin Oncol 2000; 18(5):1012–9. 41. Kern WV, Cometta A, DeBock R, et al. Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. N Engl J Med 1999;341(5):312–8. 42. Freifeld A, Marchigiani D, Walsh T, et al. A double-blind comparison of empirical oral and IV antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy. N Engl J Med 1999;341(5):305–11. 43. Petrilli AS, Dantas LS, Campos MC, et al. Oral ciprofloxacin versus intravenous ceftriaxone administered in an outpatient setting for fever and neutropenia in low-risk pediatric oncology patients: randomized prospective trial. Med Pediatr Oncol 2000;34:87–91. 44. Mullen CA, Petropoulos D, Roberts WM, et al. Outpatient treatment of fever and neutropenia for low-risk pediatric cancer patients. Cancer 1999;86(1):126–34. 45. Pagnanini H, Gomez S, Ruvinsky S, et al. Outpatient, sequential, parenteral-oral antibiotic therapy for lower risk febrile neutropenia in children with malignant disease: a single-center, randomized, controlled trial in Argentina. Cancer 2003;97(7):1775–80. 46. Aquino VM, Herrera L, Sandler ES, et al. Feasibility of oral ciprofloxacin for the outpatient management of febrile neutropenia in selected children with cancer. Cancer 2000;88(7):1710–4. 47. Korones DN, Hussong MR, Gullace MA. Routine chest radiography of children with cancer hospitalized for fever and neutropenia: is it really necessary? Cancer 1997;80(6):1160–4. 48. Feusner J, Cohen R, O’Leary M, et al. Use of routine chest radiography in the evaluation of fever in neutropenic pediatric oncology patients. J Clin Oncol 1988;6(11):1699–702. 49. Katz JA, Bash R, Rollins N, et al. The yield of routine chest radiography in children with cancer hospitalized for fever and neutropenia. Cancer 1991;68(5): 940–3. 50. Renoult E, Buteau C, Turgeon N, et al. Is routine chest radiography necessary for the initial evaluation of fever in neutropenic children with cancer? Pediatr Blood Cancer 2004;43:224–8. 51. Goldstein B, Giroir B, Randolph A, International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics [see comment]. Pediatr Crit Care Med 2005;6(1):2–8. 52. Watson RS, Carcillo JA. Scope and epidemiology of pediatric sepsis. Pediatr Crit Care Med 2005;6(3 Suppl):S3–5. 53. Burns JP. Septic shock in the pediatric patient: pathogenesis and novel treatments. Pediatr Emerg Care 2003;19(2):112–5. 54. Talan DA, Moran GJ, Abrahamian FM. Severe sepsis and septic shock in the ED. Infect Dis Clin North Am 2008;22(1):1–31. 55. Catenacci MH, King K. Severe sepsis and septic shock: improving outcomes in the ED. Emerg Med Clin North Am 2008;26(3):603–23. 56. Walsh TJ, Schimpff SC. Antibiotic combinations for the empiric treatment of the febrile neutropenic patient. Swiss Med J 1983;113:58–63.

541

542

Meckler & Lindemulder

57. Ariffin H, Arasu A, Mahfuzah M, et al. Single-day ceftriaxone plus amikacin versus thrice-daily ceftazidime plus amikacin as empirical treatment of febrile neutropenia in children with cancer. J Paediatr Child Health 2001;37(1):38–43. 58. Takeuchi M, Tanizawa A, Mayumi M. Piperacillin plus aztreonam for treatment of neutropenic fever. Pediatr Int 2003;45(3):307–10. 59. Hamidah A, Lim YS, Zulkifli SZ, et al. Cefepime plus amikacin as an initial empirical therapy for febrile neutropenia in paediatric cancer patients. Singapore Med J 2007;48(7):615–9. 60. Pizzo PA, Hathorn JW, Hiemenz JW, et al. A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia. N Engl J Med 1986;315(9):552–8. 61. DePauw B, Deresinski S, Feld R, et al. Ceftazidime compared with piperacillin and tobramycin for the empiric treatment of fever in neutropenic patients with cancer. Ann Intern Med 1994;120(10):834–44. 62. The EORTC International Antimicrobial Therapy Cooperative Group. Ceftazidime combined with a short or long course of amikacin for empirical therapy of gramnegative bacteremia in cancer patients with granulocytopenia. N Engl J Med 1987;317(27):1692–8. 63. Freifeld A, Walsh T, Marshall D, et al. Monotherapy for fever and neutropenia in cancer patients: a randomized comparison of ceftazidime versus imipenem. J Clin Oncol 1995;13(1):165–76. 64. Klastersky JA. Use of imipenem as empirical treatment of febrile neutropenia. Int J Antimicrob Agents 2003;21:393–402. 65. Duzova A, Kutluk T, Kanra G, et al. Monotherapy with meropenem versus combination therapy with piperacillin plus amikacin as empiric therapy for neutropenic fever in children with lymphoma and solid tumors. Turk J Pediatr 2001;43(2): 105–9. 66. Chuang YY, Hung IJ, Yang CP, et al. Cefepime versus ceftazidime as empiric monotherapy for fever and neutropenia in children with cancer. Pediatr Infect Dis J 2002;21(3):203–9. 67. Pancharoen C, Mekmullica J, Buranachonapa J, et al. Efficacy and safety of meropenem as an empirical treatment for febrile neutropenia in children with cancer. J Med Assoc Thai 2003;86(Suppl 2):S174–8. 68. Hung KC, Chiu HH, Tseng YC, et al. Monotherapy with meropenem versus combination therapy with ceftazidime plus amikacin as empirical therapy for neutropenic fever in children with malignancy. J Microbiol Immunol Infect 2003;36(4):254–9. 69. Muller J, Garami M, Constantin T, et al. Meropenem in the treatment of febrile neutropenic children. Pediatr Hematol Oncol 2005;22(4):277–84. 70. Ariffin H, Ai CL, Lee CL, et al. Cefepime monotherapy for treatment of febrile neutropenia in children. J Paediatr Child Health 2006;42(12): 781–4. 71. Bruckner LB, Korones DN, Karnauchow T, et al. High incidence of penicillin resistance among a-hemolytic streptococci isolated from the blood of children with cancer. J Pediatr 2002;140(1):20–6. 72. National Advisory Committee on, Immunization (NACI). Statement on influenza vaccination for the 2008-2009 season. An Advisory Committee Statement (ACS). Canada Communicable Disease Report 2008;34(ACS-3):1–46. 73. Suzuki E, Ichihara K. The course of fever following influenza virus infection in children treated with oseltamivir. J Med Virol 2008;80(6):1065–71.

Fever and Neutropenia in Pediatric Patients

74. Sugaya N, Tamura D, Yamazaki M, et al. Comparison of the clinical effectiveness of oseltamivir and zanamivir against influenza virus infection in children [see comment]. Clin Infect Dis 2008;47(3):339–45. 75. Kawai N, Ikematsu H, Iwaki N, et al. A comparison of the effectiveness of zanamivir and oseltamivir for the treatment of influenza A and B. J Infect 2008;56(1): 51–7. 76. Vu D, Peck AJ, Nichols WG, et al. Safety and tolerability of oseltamivir prophylaxis in hematopoietic stem cell transplant recipients: a retrospective casecontrol study. Clin Infect Dis 2007;45(2):187–93. 77. Barr CE, Schulman K, Iacuzio D, et al. Effect of oseltamivir on the risk of pneumonia and use of health care services in children with clinically diagnosed influenza. Curr Med Res Opin 2007;23(3):523–31. 78. Maxwell SR. Tamiflu and neuropsychiatric disturbance in adolescents [see comment]. BMJ 2007;334(7606):1232–3. 79. Hama R. Oseltamivir’s adverse reactions: fifty sudden deaths may be related to central suppression [comment]. BMJ 2007;335(7610):59. 80. Fuyuno I. Tamiflu side effects come under scrutiny. Nature 2007;446(7134): 358–9. 81. Simon A, Schildgen O, Panning M, et al. Respiratory syncytial virus infection in patients with cancer: still more questions than answers [comment]. Clin Infect Dis 2008;46(12):1933–4 [author reply 1934–5]. 82. El Saleeby CM, Somes GW, DeVincenzo JP, et al. Risk factors for severe respiratory syncytial virus disease in children with cancer: the importance of lymphopenia and young age. Pediatrics 2008;121(2):235–43. 83. Ventre K, Randolph AG. Ribavirin for respiratory syncytial virus infection of the lower respiratory tract in infants and young children. Cochrane Database Syst Rev 2007;(1):CD000181. 84. Chavez-Bueno S, Mejıas A, Merryman RA, et al. Intravenous palivizumab and ribavirin combination for respiratory syncytial virus disease in high-risk pediatric patients. Pediatr Infect Dis J 2007;26(12):1089–93. 85. Mendoza Sanchez MC, Ruiz-Contreras J, Vivanco JL, et al. Respiratory virus infections in children with cancer or HIV infection. J Pediatr Hematol Oncol 2006;28(3):154–9. 86. Ventre K, Randolph A. Ribavirin for respiratory syncytial virus infection of the lower respiratory tract in infants and young children. Cochrane Database Syst Rev 2004;(4):CD000181. 87. Sivaprakasam P, Carr TF, Coussons M, et al. Improved outcome from invasive adenovirus infection in pediatric patients after hemopoietic stem cell transplantation using intensive clinical surveillance and early intervention. J Pediatr Hematol Oncol 2007;29(2):81–5. 88. Christensen MS, Nielsen LP, Hasle H. Few but severe viral infections in children with cancer: a prospective RT-PCR and PCR-based 12-month study. Pediatr Blood Cancer 2005;45(7):945–51. 89. Gavin PJ, Katz BZ. Intravenous ribavirin treatment for severe adenovirus disease in immunocompromised children. Pediatrics 2002;110(1 Pt 1):e9. 90. Bordigoni P, Carret AS, Venard V, et al. Treatment of adenovirus infections in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis 2001;32(9):1290–7. 91. Groll A, Gea-Banacloche J, Glasmacher A, et al. Clinical pharmacology of antifungal agents. Infect Dis Clin North Am 2003;17:159–91.

543

544

Meckler & Lindemulder

92. Shoham S, Walsh TJ. Strategies for use of lipid formulations of amphotericin B. Curr Treat Options Infect Dis 2002;4:535–47. 93. Walth TJ, Seibel NL, Arndt C, et al. Amphotericin B lipid complex in pediatric patients with invasive fungal infections. Pediatr Infect Dis J 1999;18:702–8. 94. Wiley J, Seibel NL, Walsh TJ. Efficacy and safety of amphotericin B lipid complex in 548 children and adolescents with invasive fungal infections. Pediatr Infect Dis J 2005;24:167–74. 95. Wingard JR, White MH, Anaissie E, et al. A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. L Amph/ABLC Collaborative Study Group. Clin Infect Dis 2003;31:1155–63. 96. Lee JW, Seibel ML, Amantea MA, et al. Safety and pharmacokinetics of fluconazole in children with neoplastic diseases. J Pediatr 1992;120(6):987–93. 97. Walth TJ, Karlsson MO, Driscoll T, et al. Pharmacokinetics and safety of intravenous voriconazole in children after single and multiple dose administration. Antimicrob Agents Chemother 2004;48:2166–72. 98. Walsh TJ, Lutsar I, Driscoll T, et al. Voriconazole in the treatment of aspergillosis, scedosporiosis, and other invasive fungal infections in children. Pediatr Infect Dis J 2002;21:240–8. 99. Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002;346:225–34. 100. Franklin JA, McCormick J, Flynn P. Retrospective study of the safety of caspofungin in immunocompromised pediatric patients. Pediatr Infect Dis J 2003;22: 747–9. 101. Seibel NL, Schwartz C, Arrieta A, et al. Safety, tolerability, and pharmacokinetics of micafungin (FK463) in febrile neutropenic pediatric patients. Antimicrob Agents Chemother 2005;49:3317–24. 102. Benjamin DK, Driscoll T, Siebel NL, et al. Safety and pharmacokinetics of intravenous anidulafungin in children with neutropenia at high risk for invasive fungal infections. Antimicrob Agents Chemother 2006;50(2):632–8. 103. Gafter-Gvili A, Vidal L, Goldberg E, et al. Treatment of invasive candidal infections: systematic review and meta-analysis. Mayo Clin Proc 2008;83(9): 1011–21. 104. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24(19):3187–205. 105. Sung L, Nathan PC, Lange B, et al. Prophylactic granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor decrease febrile neutropenia after chemotherapy in children with cancer: a meta-analysis of randomized controlled trials. J Clin Oncol 2004;22(16):3350–6. 106. Oxkaynak MF, Krailo M, Chen Z, et al. Randomized comparison of antibiotics with and without granulocyte colony-stinulating factor in children with chemotherapy-induced febrile neutropenia: a report from the Children’s Oncology Group. Pediatr Blood Cancer 2005;45:274–80. 107. Wong ECC, Perez-Albuerne E, Moscow JA, et al. Transfusion management strategies: a survey of practicing pediatric hematology/oncology specialists. Pediatr Blood Cancer 2005;44:119–27.