Hospital Medicine

Neutropenic Fever

Neutropenic Fever

I. Problem/Condition.

Neutropenia is defined as absolute neutrophil count (ANC) < 500 cells/microL, or ANC <1000 cells/microL with a predicted decrease to <500 cell/microL. The term "profound" neutropenia is referred to an ANC ≤ 100 cells/microL.

ANC = White blood cell (WBC) count ((segs/100) + (bands/100))

Fever in a neutropenic patient is defined as a sustained temperature > 38°C (100.4°F) for an hour or a single temperature >38.3°C (101°F).

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

Acquired Neutropenia:

  • Acute and chronic leukemia

  • Infection (bacterial, viral, parasitic, Rickettsial)

  • Post chemotherapy

  • Transplant recipients

  • Collagen Vascular Disease (SLE, Felty's syndrome)

  • Drug induced (sulfasalazine, clozapine, thionamides)

  • Complement activation (ARDS, hemodialysis, filtration leukophresis)

  • Hypersplenism

  • Transfusion reaction

  • Nutritional deficiency (alcoholism, Vit B12 or folate deficiency)

  • Hypoplasia (aplastic anemia, Fanconi anemia)

  • Autoimmune (large granular lymphocyte syndrome)

  • Isoimmune neutropenia

  • Pure white blood cell aplasia

  • Chronic idiopathic neutropenia

Congenital Neutropenia (partial list)

  • Cyclic neutropenia

  • Severe infantile agranulocytosis

  • Chediak-Higashi syndrome

  • Myeloperoxidase deficiency

  • Reticular dysgenesis

B. Describe a diagnostic approach/method to the patient with this problem.

Is your patient a high-risk patient?

Be aware that occasionally a neutropenic patient may not present with fever. In these patients (most commonly elderly and patients receiving steroids) other symptoms such as hypotension, hypothermia, new unexplained organ dysfunction, or clinical deterioration/mental status changes are the primary signs of infection.

It is imperative to recognize high-risk patients when evaluating febrile neutropenic patients. This initial Risk Assessment directs the diagnostic approaches, the venue of treatment (inpatient versus outpatient), the choice of empiric antibiotic therapies, and the route of administration.

High-risk patients are recognized by clinical factors or MASCC (Multinational Association for Supportive Care in Cancer) scoring system. These patients should be admitted to the hospital for further management and empiric IV antibiotic therapy.

High-risk patients selected based on clinical factors have the following comorbidities such as:

  • New neurological changes

  • New pulmonary findings (pulmonary infiltrates, hypoxemia, respiratory failure) and underlying COPD

  • Hemodynamic instability including uncontrolled bleeding with severe thrombocytopenia

  • GI symptoms (abdominal pain, nausea/vomiting, diarrhea, oral and GI mucositis interfering with swallowing or causing severe diarrhea, hepatic insufficiency; transaminitis of more than 5 fold above the upper limit of normal)

  • Renal insufficiency (Cr Cl <30 mL/min)

  • Poor functional status - inadequate outpatient fluid intake or pain control

  • Profound neutropenia (ANC ≤ 100 cells/microL) that is anticipated to last for more than 7 days

  • Neutropenia as part of the conditioning regimen for allogeneic hematopoietic cell transplant

  • Neutropenia as a result of induction therapy for AML

Low-risk neutropenia, on the other hand, are patients with anticipated neutropenia lasting 7 or less days and no comorbidities. These patients, if selected carefully in an appropriate medical care setting, can be treated with oral empiric therapies as outpatients.

MASCC Risk Index Score is an alternative method to the above clinical criteria in recognizing high-risk patients. Patients with MASCC score of less than 21 are considered High-risk:

  • Age < 60 years old (2)

  • Outpatient status (3)

  • No hypotension (SBP <90 mmHg) (5)

  • No COPD (4)

  • No dehydration requiring parenteral fluids (3)

  • Solid tumor or hematological malignancy with no previous fungal infection (4)

  • Burden of illness (febrile neutropenia) - No or mild symptoms (5), Moderate symptoms (3), Severe symptoms (0)

1. Historical information important in the diagnosis of this problem.

Duration of fever

Past infections

Exposures

Outpatient antibiotic therapies

Confirm allergies (especially to antimicrobial agents)

2. Physical Examination maneuvers that are likely to be useful in the diagnosing the cause of this problem.

These patients deserve a thorough physical exam with particular attention to localized symptoms or signs of infection and/or subtle signs of inflammation (due to absence of neutrophils). An important part of the exam is to examine the skin and mucous membrane for signs of erythema, rash, ulcers, mucositis, cellulitis, furuncles, herpetic eruptions, paronychia, dental or peritonsillar abscesses, pilonidal disease. Remember to inspect the perianal area but avoid digital rectal exam or rectal temperature.

Neutropenic patients with IV catheters and recent line sites should be examined for subtle infection signs such as: slight tenderness, erythema, exudate, fluctuance. These signs may represent a "tunnel" infection. Think about infected clot when there is difficulty drawing blood or infusion via a catheter in these patients. Rigors or chills associated with infusion through the IV catheter may represent IV line related infection.

Repeat the Review of Systems and Physical Exam daily. Symptoms and signs of infection become more evident as the neutrophil counts start to recover.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Laboratory tests

CBC with differential, blood chemistry, urine analysis, pan culture (blood, urine +/- respiratory), sputum gram stain, liver function tests, lactate level, other specimens (stool exams including clostridium difficile antigen assay and stool cultures, skin), as clinically appropriate are among the initial lab evaluation in febrile neutropenic patients. Considering the etiology of neutropenia and symptoms, viral studies including CMV, EBV, HSV should be included as well.

Perform lumbar puncture in patients with new severe headache and/or mental status changes (consider non contrast head computed tomography (CT) to rule out intracranial bleed prior, if clinically indicated). Some patients may need platelet transfusion before performing a safe lumbar puncture.

Keep in mind lack of cerebrospinal fluid pleocytosis, pyuria, or PMN on patients' fluid exams does not exclude the possibility of infection.

On a case to case basis, fungal markers can be helpful in making a diagnosis and starting the proper treatment. Beta-D-glucan is a non-specific test for several invasive fungal infections including candidiasis and aspergillosis, while galactomannan antigen is specific to aspergillosis infection.

When drawing specimen for blood culture, draw at least two sets of blood cultures from two separate venupuncture sites. In patients with a central line, draw a set of blood cultures from each lumen and from a peripheral vein site simultaneously. If patient has continuous fevers or rigors continue to draw two sets of blood cultures for the first 2 days following the empiric antibiotic therapy and one set a day thereafter, unless your institution's guidelines specify otherwise. If central line cultures are positive, discontinue the line and send peripheral cultures and repeat blood cultures every 24 hours until documenting that the infection has cleared.

Blood cultures can be drawn less frequently (every 72 hours) in patients with persistent fever who are clinically stable and have at least three sets of negative blood cultures. Every effort should be made to draw cultures before administration of antibiotics.

Neutropenic patients with pulmonary infiltrates that cannot produce sputum and/or continue to clinically worsen despite appropriate empiric antibiotic therapy may warrant more invasive approach such as bronchoscopy with bronchoalveolar lavage or VATS (video assisted thoracoscopic surgery) to obtain samples for diagnostic exams (Pulmonary/Thoracic Surgery Consult).

Radiographic Imaging

CXR is part of the initial work up in patients with neutropenic fever regardless of presence of pulmonary symptoms. CXR should be repeated in patients with worsening pulmonary symptoms. If there is high suspicion for pulmonary involvement in a patient with a normal CXR, high resolution chest CT can be the next step to diagnosis and assist with the direction and duration of therapy. Also helpful in evaluating invasive fungal infection.

Head/sinuses and abdomen/pelvic CT should be considered with the presence of appropriate symptoms and signs.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Associated Pathogens

Bacterial Pathogens:

Bloodstream pathogens mostly consists of gram positive organisms, while non-bloodstream (respiratory, urinary, biliary, skin) pathogens mostly consists of gram negative organisms.

Common gram positive organisms: Coag-negative Staph, Staph aureus, Enterococcus spp., Strep pneumoniae, Strep pyogenes, Viridans strep. Less common gram positive cultured organisms in neutropenic patients: Bacillus spp., Listeria monocytogenes, Stomatococcus sp., Corynebacterium jeikeium.

Common gram negative organisms: E coli, Klebsiella spp., Enterobacter spp., Pseudomonas aeuroginosa, Citrobacter spp., Acinetobacter spp., Stenotrophomonas maltophila. Less common gram negative organisims: Proteus spp., Haemophilus spp., Serratia spp., Neisseria meningitidis, Capnocytophaga canimorsus, Legionella spp., Moraxella spp.

Infrequent Anaerobes: Bacteroids, Clostridium, and Fusobacter.

Viral Pathogens:

If you see skin eruptions, think Herpes viruses. Herpes simplex (HSV-1 and HSV-2) can also cause meningitis, encephalitis, myelitis, hepatitis, esophagitis, pneumonia, and erythema multiforme. Herpes zoster usually has an atypical pattern of involving multiple dermatomes. Varicella zoster can also cause pneumonia. Infection with other Herpes viruses (CMV, EBV, HHV-6) are seen via reactivation or seroconversion or transfusion of the virus (through blood products). Other viruses to consider: Enterovirus, RSV, Influenza and para influenza.

Fungal Pathogens:

Fungal infections can be present early or even prior to initial chemotherapy. However in general, patients with severe and longer periods of neutropenia, longer periods of chemotherapies, and prolonged antibiotic use have higher risk of fungal infections. Common fungal infections include Candidiasis, Aspergillus, Cryptococcus spp., Pneumocystis jiroveci followed by less common but as life-threatening mucormycosis, and fusarium spp.

Think of endemic fungal infections (blastomycosis, coccidioidomycosis, histoplasmosis) in neutropenic patients in appropriate setting who are chronic steroid users.

Note that other rare pathogens such as Mycobacteria, Toxoplasma, Malaria, Nocardia, Babesia, Strongyloides, have been isolated from neutropenic patients with cancer.

D. Over-utilized or "wasted" diagnostic tests associated with the evaluation of this problem.

Blood cultures should be drawn every 24 hours and do not need to be repeated the same day for a fever. Fungal blood cultures are rarely necessary during the first 24-48 hours as common fungal infections such as candida will grow in conventional blood culture media.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem Neutropenic Fever.

Neutropenic fever is considered a medical emergency. All patients need immediate assessment for localized symptoms and signs of infection, sepsis, and septic shock. Based on this assessment patients are categorized to High and Low risk groups (see above).

High-risk patients need to be admitted for inpatient IV antimicrobial therapy. Patients with lactate of ≥ 4 or systolic BP ≤ 90mmHg despite adequate IVF resuscitation should be admitted to ICU for EGDT.

Empiric antibiotic treatment should ideally begin within one hour of fever with the aim to cover the most likely and most virulent pathogens causing serious or life-threatening infection. Antibiotic therapy is guided by patient's history and physical exam, recent infections and antibiotic use, allergies, culture data, institution's antibiogram/antibiotic resistance patterns. Treat with bactericidal antibiotics and administer them through alternate ports of central venous catheter. Cover broadly for gram negative bacteria. Note that vancomycin is NOT recommended as part of the initial antibiotic treatment strategy, unless certain clinical features are present (see below).

Think about adding antibiotic coverage for anaerobes if treating sinusitis, periodontal abscess, necrotizing mucositis, intra-abdominal and pelvic infection, neutropenic enterocolitis (typhlitis), anaerobic bacteremia.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

Use your clinical judgement at all times. The following are the initial steps/order set sample not to be missed in caring for a febrile neutropenic patient (steps after a Complete physical exam):

  • Admit high-risk patients to the hospital - if meets EGDT criteria, admit to ICU.

  • Confirm patient's allergies on the chart.

  • Neutropenic precautions - Neutropenic diet.

  • Respiratory precautions in certain cases (e.g., possibility of pulmonary involvement with Varicella zoster).

  • Make sure patient has adequate/appropriate IV access.

  • No aspirin containing products or NSAIDs.

  • No rectal exam or suppositories or IM injections or ABG.

  • Make sure all the labs are drawn and imaging taken in ER/clinic: Pan culture, CBC with differential, Chem-7, Liver panel, Lactate (even if the patient is not hypotensive), urinalysis. If GI symptoms: lipase, amylase, magnesium, stool exams. Initial CXR (preferably PA and lateral).

  • If available obtain previous results for HSV IgG and CMV IgG. If not order the labs as clinically indicated.

  • While waiting for HSV IgG or if HSV IgG positive start Acyclovir 400mg PO TID as clinically indicated.

  • If CMV IgG negative and pt < 55 yo, all blood products to be CMV negative.

  • Continuous fever spikes > 101°F repeat pan cultures including two sets of blood cultures (see the details in section B-3), and CXR/high resolution CT scan - patient must already be on empiric antibiotic treatment (discussed in details below).

  • If platelet counts < 15k, order one unit of single donor platelet on hold. Transfuse if platelet < 10k, symptoms and signs of bleeding, patient needs procedures (central line placement, LP).

  • Type and cross 2 units of blood and transfuse as needed. Some patients need to be premedicated before the transfusion with oral acetaminophen (650 mg - 1000 mg) and intravenous diphenhydramine (25 mg) (typically given within half an hour before starting the transfusion). Depending on patient's comorbidities, if you are worried about fluid over load and patient's blood pressure allows, consider administering Lasix IV inbetween your transfusions. Patients on dialysis have to be treated under Nephrologist supervision.

  • All blood products to be irradiated and filtered (Leukopoor).

  • Magic mouthwash 5-10mL TID as needed.

  • Symptomatic treatments for nausea/vomiting and constipation as needed.

  • Adjust the dose and monitor the levels of certain antibiotics or ask your pharmacy to follow up. Adjust dose for renal function in pip/tazo, tobramycin, aztreonam, vancomycin, cefepime. Adjust the dose based on weight in vancomycin and tobramycin.

  • Fluconazole 200 mg PO daily, as clinically indicated.

Early empiric antibiotic therapy is essential to management and survival of neutropenic patients with fever.

The approach for initial antibiotic therapy in high-risk patients:

Monotherapy

Initiate with an anti-pseudomonal beta-lactam agent:

  • Piperacillin/tazobactam 4.5g IV q6h - Or

  • Cefepime 2g IV q8h - Or

  • Meropenem 1g IV q8h - Or

  • Imipenem 500 mg IV q6h

Note that ceftazidime is not the best choice for monotherapy as it has limited coverage for gram positive bacteria and the concern for increased resistance among gram negative bacteria.

Combination Therapy

Consider in patients with complicated clinical presentation such as: mental status changes, hypotension, focal findings (cellulitis, pneumonia), suspicion or history of resistance to antibiotic therapy, and ICU admission. Initiate with beta-lactam agent and aminoglycoside OR beta-lactam agent and ciprofloxacin:

  • Piperacillin/tazobactam 4.5g IV q6h ± Tobramycin IV Or Amikacin IV ± Vancomycin IV (see below)

  • Cefepime 2g IV q8h ± Tobramycin IV Or Amikacin IV ± Vancomycin IV (see below)

Special considerations:

1. Vancomycin or other agents for gram positive coverage is NOT part of the initial/standard therapy for the risk of increasing toxicities without improving outcomes and promoting resistance among Enterococci and Staph aureus. However, consider adding vancomycin IV (dose adjusted based on weight and renal function) in the following febrile neutropenic patients:

  • Suspected IV line related/exit site/tunnel infection

  • Evidence of cellulitis, wound/soft tissue infection, disseminated papulles or other cutaneous lesions

  • Severe hypotension/sepsis

  • Positive blood culture for gram positive organism (pending sensitivities)

  • History of prior infection with resistant gram positives (MRSA, penicillin-resistant Strep)

  • Grade III/IV mucositis, especially if ceftazidime is used as empiric therapy and patient has been on fluoroquinolone prophylaxis which is concerning for increased risk of viridans strep infection

In patients who cannot tolerate vancomycin, linezolid (600 mg IV q12h) or daptomycin are alternative treatment options. Be aware that Linezolid may cause myelosuppression usually after two or more weeks of therapy. In clinical trials, this drug has been given for 10 to 28 days. Additionally, daptomycin will not be effective for pulmonary infections as surfactant causes its inactivation.

2. Add Metronidazole 500 mg IV q8h for if intra-abdominal source of infection is suspected, particularly if initial antibiotic of choice was cefepime. Note that this is unnecessary for empiric therapies with a carbapenem or piperacillin/tazobactam.

3. Most patients who have documented allergy to penicillin can tolerate cephalosporines (3-5% cross reactivity). In patients with severe PCN type I-immediate hypersensitivity (e.g., hives and bronchospams) avoid beta-lactams and carbapenems. In these patients the alternative treatments include:

  • Aztreonam 2g IV q8h + Vancomycin IV ± Amikacin IV Or Tobramycin IV - OR

  • Ciprofloxacin 400 mg IV q8h Or Levofloxacin 750 mg IV q24h + Clindamycin 1.2-2.7g/day divided into 2-4 doses (Max dose 4.8g per day)

Empiric Antifungal Therapy

Start antifungal therapy after 4-7 days of empiric antibiotic therapy on high-risk patients who have persistent or recurrent fever, are expected to have a total duration of neutropenia > 7 days, and there is no source of infection. Start these agents earlier in the course of treating a clinically unstable patient or a patient with suspected fungal infection (send for appropriate lab tests if available). Consider the most likely fungal infections, toxicities of treatments, and the cost when starting the treatment. Fungal infections could be difficult to diagnose and delaying therapy until certain clinical diagnosis is associated with high mortality.

Patients not on any prophylaxis antifungal treatment are mostly at risk for Candida spp. infections while patients receiving fluconazole prophylaxis are mostly at risk for infection with fluconazole resistant Candida spp. or invasive fungal infections (aspergillus, mucormycosis).

Patients with oral, esophageal candidiasis and colitis are at increased risk for candidemia. Suspect aspergillus in patients with prolonged neutropenia, history of respiratory tract colonization with aspergillus, cutaneous, pulmonary, or CNS symptoms of aspergillus.

Amphotericin B is used as a broad spectrum agent but has been associated with severe nephrotoxicity. Liposomal amphotericin B is as effective as and less toxic than amphotericin B but more expensive. The dose can be variable based on patient's organ involvement, clinical status, and the type of fungal infection being treated. Dose at 0.5-0.6 mg/kg/day to treat suspected candidial infection and 1-1.5 mg/kg/day to treat aspergillus. If systemic or CNS aspergillosis is suspected, treat with combination of voriconazole + caspofungin ± high dose amphotericine B.

Caspofungin is a good choice and based on the efficacy, susceptibility, and safety data can be the first line treatment for empiric therapy. But if you have documented or suspected aspergillosis invasive infection (e.g., pulmonary nodules, sinus lesions, patients on fluconazole prophylaxis) alternative therapy such as liposomal amphotericin B or voriconazole should be started.

Candidemia may be treated with fluconazole (in patients not on prophylaxis treatment) or caspofungin (if sensitive) or amphotericin B.

Caspofungin infusion loading dose 70 mg on day 1 followed by maintenance dose of 50 mg per day.

Voriconazole infusion loading dose 6 mg/kg every 12h for 2 doses followed by maintenance dose of 3-4 mg/kg every 12h.

Continue these empiric therapies for at least until 7 days after the symptoms and signs of the infection and neutropenia resolves. If cultures are positive continue the treatment up to 14 days after last positive culture. Longer period of treatment for invasive aspergillosis is required (sometimes up to 6-12 weeks). ID Consult is recommended in most inpatients suspected or documented having fungal infection.

Empiric Antiviral Therapy

Not recommended unless there is clinical evidence of viral infection such as herpes simplex or varicella zoster. Treat with acyclovir or valacyclovir or famciclovir. CMV infection is rare in this population and seen more in post BMT patients. Treat them with ganciclovir or foscarnet.

When to remove the central venous catheter:

Remove the catheter in patients with port pocket infection, tunnel infection, positive blood cultures for Staph aureus/Pseudomonas aeruginosa/nontuberculous mycobacteria/ fungemia. Continue the treatment for at least 2 weeks after the catheter removal and last positive cultures. Infectious disease consultation is recommended for any staph aureus bacteremia.

Continue the treatment for 4-6 weeks, if these patients have complicated clinical status such as septic thrombosis, endocarditis, deep tissue infection, persistent fungemia or bacteremia over 72 hours after removing the catheter while being treated with antimicrobial agents.

Reassessment of Febrile Neutropenic Patients:

Reevaluate patients who remain febrile despite of empiric antibiotic therapy. The most important factors in determining duration of antibiotic therapy are ANC and patient's clinical status.

If defervescence occurs with negative cultures, continue the empiric therapy until ANC > 500 cells/microL and continues to rise. As a general rule, discontinue the empiric gram positive coverage if cultures remain negative after 48 hours.

Persistent Fever After 2-4 Days of Empiric Therapy:

First Scenario - High-risk patient with unexplained persistent fever, continue the same empiric therapy while assessing for infection sites.

Second Scenario - High-risk patient with documented infection, modify the therapy according to culture results and/or infection site. If the patient continues to respond, continue the antibiotics for 7-14 days or as appropriate for the documented infection and until ANC > 500 cells/microL and continues to rise.

Third Scenario - High-risk patient with documented infection, modify the therapy according to culture results and/or infection site. If the daily ROS and PE indicate that the patient is Not responding: re-image (CT or MRI) for new or worsening sites of infection, re-examine the sites of worsening infection for possible biopsy/culture, review antibiotics dosing/coverage, if clinically unstable patient broaden the antibiotic therapy, add empiric antifungal treatment. Consider ID Consult.

Persistent Fever After 4 Days (prolonged fever) of Empiric Therapy:

Suspect nonbacterial infection, emergence of a second infection, resistant organism, abscess, or drug fever. Next steps are to re-examine the patient, review all the culture results, and repeat imaging (CXR, CT of any organ suspected of infection). Add antibiotics such as vancomycin and/or aminoglycoside and antifungal regimen as indicated. Consider ID Consult.

If the patient is receiving chemotherapy and neutropenic recovery is anticipated, therapy including G-CSF (granulocyte colony stimulating factor) could be considered. Though they are generally not recommended in use of treatment of neutropenic fever, their use may reduce length of hospitalization. The effect on mortality and morbidity, however, is minimal. This decision should be made in conjunction with the patient’s oncologist.

IV. What's the evidence?

Freifeld, AG, Bow, EJ, Sepkowitz, KA. "Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america". Clin Infect Dis. vol. 52. 2011. pp. e56-e93.

Aapro, MS, Bohlius, J, Cameron, DA. "2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours". Eur J Cancer. vol. 47. 2011. pp. 8-32.

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