A Clinical guide to pediatric infectious disease

17

Fever and Neutropenia

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/m3, often seen in patients undergoing chemotherapy, is considered life threatening. The most recent guidelines suggest thatneutropenia 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.

ANC = white blood cell count × % (segmented neutrophils + band forms)

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.

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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/m3. 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/m3 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:

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Aspergillus Species

The classic fungal pathogen in the neutropenic oncology patient is Aspergillus 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.

 

FIG. 17-1. Progressive pneumonia in a child with fever and prolonged neutropenia caused by Aspergillus species infection.

 

FIG. 17-2. Computed tomography scan of patient with prolonged fever and neutropenia. Cerebral abscess grew Aspergillus species.

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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 débridement 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

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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 débridement, 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 débridement should be attempted if at all possible.

Trichosporon Species

Trichosporon asahii, formally referred to as Trichosporon 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 andAspergillus 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

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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.

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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.

Fungi and Mold Seen in Fever and Neutropenia

Organism

Comment

Candida species

Sensitive to fluconazole, with exception of C. krusei and C. glabrata

Aspergillus species

Resistant to fluconazole
Sensitive to amphotericin, itraconazole, voriconazole, caspofungin

Fusarium species

High incidence of in vitro amphotericin resistance
Voriconazole reported effective
Surgical débridement often needed

Scedosporium species

Intrinsic amphotericin resistance
Voriconazole reported affective
Surgical débridement often needed

Trichosporon species

High frequency of amphotericin resistance
Intrinsically resistant to caspofungin

Zygomycetes

   Mucor species

Resistant to itraconazole, voriconazole

   Rhizopus species

Amphotericin, sensitive surgical débridement often needed

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

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gram-positive organism frequently isolated is the α-hemolytic streptococcus (AHS). This includes a diverse group of streptococci, such asStreptococcus mitisStreptococcus 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.

TABLE 17.1. Antimicrobials Used in Pediatric Fever and Neutropenia

1. Initial treatment: gram-negative coverage

1. Tobramycin, 6–7.5 mg/kg/d divided q6–8h, in combination with ceftazidime (Fortaz), 50 mg/kg IV q8h

2. Cefepime (Maxipime), 50 mg/kg IV q8h

3. Imipenem/cilastatin (Primaxin), 15–25 mg/kg q6h

2. Persistent fever, neutropenia with negative blood cultures

1. Amphotericin B deoxycholate, 0.6 mg/kg/d

2. Lipid formulation amphotericin (Abelcet), 3–5 mg/kg/d

3. Liposomal formulation amphotericin (AmBisome), 3–5 mg/kg/d

4. Voriconazole (Vfend)—dose recommended for children older than 12 years: 6 mg/kg IV q12h for two doses, then 4 mg/kg q12h

5. Caspofungin (Cancidas). Pediatric dose not established. Adults receive 70 mg IV ×1, then 50 mg/d thereafter.

3. Consideration for initial vancomycin use (15–20 mg/kg IV q12h)

1. Hypotension

2. In-dwelling catheter

3. Severe mucositis

4. Acute myelogenous leukemia

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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/m3 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/m3. In these children, antibiotics may be stopped when the child is afebrile for about 1 week. A small number of studies have suggested

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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.

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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.

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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.