1. See also Chapter 61.

2. Fever in a neutropenic patient is a single oral temperature of ≥38.3°C (101°F) or a temperature of ≥38.0°C (100.4°F) for ≥1 hour.

3. Neutropenia is an absolute neutrophil count (ANC) of <500 cells/µL or an ANC between 500 and 1,000 cells/µL that is falling.

4. Severe neutropenia is an ANC of ≤100 cells/µL.

5. Risk of serious infection increases with severity of neutropenia and as the duration of neutropenia exceeds 7 days.

1. Low-risk patients (may be managed in an ambulatory setting initially).

a. Expected duration of neutropenia of ≤7 days and no significant comorbidities.

b. Relatively lower risk of complications from chemotherapy-induced neutropenia.

c. Exclusion criteria: hypotension, pneumonia, dehydration, bleeding, diabetes, leukemia, neurologic changes, history of fungal infection in the prior 6 months.

2. High-risk patients (should be hospitalized for initial management).

a. Patients with significant neutropenia (ANC ≤100 cells/µL) or anticipated duration of neutropenia of >7 days or significant medical comorbidities (i.e., age > 60, cancer not in remission, hypotension, altered mental status, evidence of pneumonia) or recent use of alemtuzumab.

b. Higher risk of complications due to neutropenia.

c. Hematopoietic cell transplant (HCT) recipients (particularly allogeneic or cord blood stem cell transplant [SCT]) and those receiving chemotherapy for acute leukemia are generally considered high risk for prolonged neutropenia and are managed in the inpatient setting.

1. An infectious etiology is found in only 20% to 30% of patients with neutropenic fever.

a. Bacteremia is found in approximately 10% to 25% of patients with neutropenic fever.

b. Eighty percent of organisms isolated are from the patient’s own flora.

2. Gram-negative organisms, such as Pseudomonas aeruginosa, have historically been the most significant cause of infections in this population.

a. Gram-positive organisms have become more prevalent recently, due in part to use of antimicrobial prophylaxis with fluoroquinolones at the onset of neutropenia.

b. Resistant gram-positive organisms (i.e., methicillin-resistant Staphylococcus aureus [MRSA], vancomycin-resistant enterococci [VRE]) are increasingly isolated.

c. Gram-negative organisms continue to cause substantial morbidity and mortality and must be covered with empiric antimicrobial therapy.

A. See also Section I.C Epidemiology and Section III Pathophysiology.

B. The risk/timing of infection due to specific pathogens depends upon the duration of neutropenia.

C. Common sites of infection in neutropenic patients with fever include the lungs (25%), oropharynx (25%), skin including central venous catheter (CVC) sites (15%), perineum (5%), gastrointestinal (GI) and genitourinary sites (5%), and sinuses (5%).

A. Underlying malignancies, and their associated deficiencies of neutrophils, T lymphocytes, and B lymphocytes, increase the risk of infections from fungal, intracellular, and encapsulated organisms, respectively.

1. Decreased antibody production, or impaired antibody-dependent cell-mediated cytotoxicity (ADCC), can be seen in multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and patients who have undergone splenectomy (see below, section on The Asplenic Patient). These patients have increased risk for infection due to encapsulated organisms, including Streptococcus pneumonia, Haemophilus influenzae, Neisseria meningitides, Capnocytophaga canimorsus, and Babesia spp.

2. Defects in cellular immunity can be seen in patients with lymphoma and those receiving high-dose steroids in chemotherapeutic regimens (see below). These patients have increased risk for infection due to intracellular pathogens such as Listeria monocytogenes, Salmonella spp., Cryptococcus neoformans, Mycobacterium tuberculosis, and Pneumocystis jirovecii.

B. Cancer chemotherapy is cytotoxic to bone marrow and to the GI tract.

1. Chemotherapy-induced mucositis breaks down the normal host barrier to invasive infections and causes seeding of the bloodstream with bacterial and fungal organisms.

2. Chemotherapy causes neutropenia of varying severity and duration and places patients at increased risk for potentially serious infections.

3. Chemotherapy also impairs the normal function of neutrophils.

C. Indwelling CVCs increase risk of bacteremia due to skin flora.

D. Prolonged neutropenia, acute leukemia, broad-spectrum antibiotics, corticosteroids, and total parenteral nutrition predispose patients to invasive fungal infections.

1. Fever may be the only sign of a serious underlying infection, as the typical signs of inflammation are often absent in neutropenic patients.

2. Consider sepsis in a patient with hypotension, confusion, hypoxemia, and tachypnea.

The approach to management of a patient with fever and neutropenia is to assume that infection is present and to cover the patient with broad antimicrobial therapy until fever and neutropenia both resolve (see Section V Treatment).

1. Noninfectious etiologies should be considered in the appropriate setting.

C. History: A thorough history must be obtained daily. Note the presence of any new complaints, including a detailed review of the following systems:

1. Neurologic: mental status changes or confusion, increased somnolence.

2. Ophthalmologic: tearing of the eyes, blurred vision, loss of vision, diplopia.

3. ENT: sinus pain, rhinorrhea.

4. Respiratory: cough, shortness of breath, new chest pain/discomfort.

5. GI: abdominal distension or pain, diarrhea, rectal pain or bleeding.

6. Skin: new lesions of any kind.

1. A thorough physical examination must be performed initially and repeated daily, with special attention to the oropharynx, sinuses, optic fundi, perirectal region, lungs, skin, recent surgical wounds, and vascular catheter sites.

2. Signs of inflammation may be diminished in neutropenic patients.

a. Fever may be absent or only slightly above baseline temperature.

b. Erythema and induration may be minimal or absent in neutropenic patients.

c. Abscess formation requires normal neutrophil function.

3. Head and neck.

a. Conjunctival injection, tearing of one or both eyes, restricted mobility of extraocular eye movements, and eschar in nasopharynx may suggest invasive fungal infection involving the orbits and/or sinuses.

b. Vesicles in the ear canal may indicate the presence of a herpesvirus infection.

4. Skin.

a. Pain, tenderness, and/or drainage (if present) at CVC entry sites/tunnels suggests the presence of a catheter-associated infection.

b. Skin lesions such as nodules, necrotic ulcers, and vesicles may be a sign of systemic fungal, bacterial, and viral infections, respectively.

c. Necrotic skin ulcers are frequently a sign of serious systemic infection due to gram-negative bacteria (i.e., P. aeruginosa, a cause of ecthyma gangrenosum) or invasive molds (i.e., Fusarium spp. or Mucorales).

5. Lungs.

a. Wheezing (focal or diffuse), rales, or rhonchi may indicate infection due to nosocomial or community-acquired bacterial, fungal, and viral pathogens.

b. Noninfectious causes may mimic infectious causes.

6. Abdomen.

a. Abdominal pain and distension may be minimal or absent in neutropenic patients.

b. Diarrhea may be due to chemotherapeutic regimens or mucositis.

c. Prominent abdominal findings may suggest the presence of neutropenic enterocolitis, Clostridium difficile colitis, or abdominal sepsis. Unusual organisms such as P. aeruginosa and Clostridium perfringens or Clostridium septicum must be considered.

1. Initial diagnostic tests should include the following:

a. Complete blood count (CBC) with differential leukocyte count and platelet count.

b. Serum creatinine, electrolytes, hepatic transaminases, total bilirubin.

c. Ideally, cultures of peripheral blood (at least two sets) should be sent before antibiotics are started.

d. Urinalysis and urine culture should be sent; however, pyuria is usually absent.

e. Sputum culture in patients who are able to produce sputum.

f. Stool culture and C. difficile toxin assay in patients with diarrhea.

g. Swab, aspiration, or biopsy of suspicious skin or mucous membrane lesions for smears, cultures (bacterial, fungal, and viral), and pathologic examination.

2. Definitive diagnosis may require histologic examination and special culture techniques of specimens obtained by tissue biopsy, bronchoalveolar lavage (BAL), GI endoscopy, surgery, or other invasive procedures.

3. Fungal antigen testing.

a. Serum galactomannan assay.

i. Detects the presence of the Aspergillus galactomannan antigen, a component of the Aspergillus cell wall that is released during growth of fungal hyphae.

ii. A positive test is suggestive of invasive Aspergillus infection.

iii. Sensitivity is diminished in patients receiving prophylactic antifungal agents.

iv. Specificity is diminished (results may be falsely positive) in patients who are being treated with piperacillin-tazobactam and in various other settings (infection with Fusarium spp. and in patients with severe mucositis due to chemotherapy or graft-versus-host disease [GVHD] after HCT).

v. The test is perhaps most useful in terms of its negative predictive value.

b. Galactomannan testing of BAL fluid.

i. Increased sensitivity as compared with culture of BAL fluid.

ii. Higher cutoff threshold for a positive result (≥0.8) results in excellent sensitivity (86%) and specificity (91%).

iii. May be useful for rapidly establishing a diagnosis in a neutropenic patient with nodular infiltrates suspicious for invasive fungal infection.

c. Beta-D-glucan assay (1,3-beta-D-glucan).

i. Component of the cell wall of many fungal pathogens, including Candida spp., Aspergillus spp., Fusarium spp., Trichosporon spp., and P. jirovecii.

ii. Nonspecific test for invasive fungal infection.

(a) Sensitivity between 55% and 95% and specificity between 77% and 96%.

(b) With a cutoff value of 80pg/mL, the positive predictive value is approximately 87%; negative predictive value is approximately 97%.

iii. False-positive results may be seen in the setting of albumin infusion, use of intravenous immunoglobulin, and occasionally in the setting of hemodialysis.

1. Chest radiograph (CXR) or computed tomography (CT) scan: Chest CT has increased sensitivity compared with CXR for the detection of infiltrates in neutropenic patients.

a. Focal or multifocal infiltrates suggest bacterial or invasive fungal pneumonia.

b. Diffuse interstitial infiltrates are more characteristic of viruses, Pseudomonas jirovecii, or noninfectious processes.

c. Cavitary and nodular disease can be associated with bacteria (e.g., P. aeruginosa, Staphylococcus aureus, anaerobes), Nocardia species, mycobacteria, Legionella, endemic or invasive fungi, and noninfectious processes.

2. Abdominal imaging if indicated.

a. Intravenous contrast may be necessary to evaluate for intra-abdominal pathology.

b. Abscess formation may be absent in neutropenic, immunosuppressed patients.

1. Neutropenia confers a high risk for life-threatening infections.

2. All febrile neutropenic patients should be treated with intravenous broad-spectrum antibiotics promptly, after appropriate culture specimens are obtained.

a. Initiate empiric antibiotics as soon as possible after the patient’s presentation for care, without unnecessary delay; delay in administration of antibiotics contributes to increased morbidity and mortality. A reasonable goal for administration is no longer than 60 minutes after initial presentation for care.

b. Empiric therapy must not be delayed while diagnostic testing is obtained.

c. Empiric therapy must cover P. aeruginosa, as increased mortality is related to uncontrolled infection due to gram-negative organisms.

3. Recommended initial empiric antibiotic regimens for high-risk patients should take into consideration local antibiotic resistance patterns of P. aeruginosa but could include one of the following options:

a. Ceftazidime 2 g IV every 8 hours (if no localizing signs or symptoms).

b. Cefepime 2 g IV every 8 hours (if no localizing signs or symptoms).

c.

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