Fever of Unknown Origin in Neutropenic Cancer Patients: A Patient-Friendly Guide to the 2017 German AGIHO Guidelines

Table of Contents

• Why This Research Matters
• How the Guidelines Were Developed
• Key Definitions: Neutropenia and Fever
• How Doctors Grade Recommendations and Evidence
• Risk Stratification: Standard-Risk vs. High-Risk Patients
• The MASCC Score: Identifying Standard-Risk Patients
• Criteria for Outpatient Management
• What Causes Fever in Neutropenic Patients?
• Local Resistance Patterns and Fluoroquinolone Prophylaxis
• Baseline Tests Before Starting Chemotherapy
• Screening for Fungal Infections in Asymptomatic Patients
• Diagnostic Tests at the Moment Fever Begins
• What Specific Symptoms Tell Doctors
• Antimicrobial Treatment: First-Line Antibacterial Therapy
• Antibacterial Combination Therapy
• Clinical Implications for Patients
• Limitations of These Guidelines
• Recommendations for Patients and Caregivers
• Frequently Asked Questions
• Source Information

Why This Research Matters

Cancer patients who develop neutropenia (a dangerously low count of neutrophils, the white blood cells that fight bacterial and fungal infections) are at high risk of infectious complications. The level of risk depends on how low the neutrophil count drops and how long it stays low, as well as on additional factors such as suppressed immunity and damage to skin and mucosal barriers. The duration and lowest point (nadir) of neutropenia are directly correlated with the incidence of fever and infections.

These infections cause significant illness and death, and they may also force doctors to delay or reduce further chemotherapy. When a neutropenic patient develops fever of unknown origin (FUO, meaning fever without an immediately obvious source), prompt and effective, evidence-based treatment is mandatory.

Over the past decade, resistance among bacteria to widely used antibiotics, particularly beta-lactams (such as penicillins and cephalosporins) and fluoroquinolones (such as ciprofloxacin), has increased. At the same time, only a small number of newer antimicrobial drugs have become available. These include tigecycline, linezolid, moxifloxacin, cefozopran, telavancin, oritavancin, ceftazidime-avibactam, ceftolozan-tazobactam, and micafungin. However, data on using these newer agents empirically (without knowing the exact germ) in neutropenic patients are limited or do not exist.

New diagnostic tests and biomarkers (biological signs of infection or inflammation) also need careful evaluation. This guideline, which updates a 2003 version, focuses on risk-adapted diagnostic procedures and empirical antimicrobial treatment in neutropenic cancer patients with FUO. The goal is to tailor the approach according to each patient's likelihood of a complicated course of infection.

The AGIHO has published separate guidelines for related topics, including sepsis, prevention of bacterial and fungal infections, prevention of infections after allogeneic stem cell transplantation, invasive fungal infections, pulmonary infiltrates, abdominal complications, venous catheter infections, central nervous system infections, infections after autologous stem cell transplantation, and community respiratory viral infections.

How the Guidelines Were Developed

A group of hematologists, oncologists, and infectious disease specialists was formed within the AGIHO. The team performed a thorough literature search that included only full publications and excluded studies of allogeneic hematopoietic stem cell transplant (a stem cell transplant from a donor) recipients.

The experts created a set of core slides with statements and recommendations. These were discussed in face-to-face meetings, telephone conferences, and electronic correspondence. The final version was approved at an AGIHO plenary meeting on 10 February 2017, and the manuscript was reviewed by all co-authors. A detailed methodological report is available in the online supplementary material of the original article.

Key Definitions: Neutropenia and Fever

Neutropenia is defined as a neutrophil count (segments and bands) below 500/μl (microliter), or below 1000/μl with a predicted decline to below 500/μl within the next 2 days. There is no single cut-off value that clearly separates patients with and without increased risk of infections, but this definition matches most recommendations and risk stratifications used in clinical trials.

Fever in neutropenia is defined as one of the following:

• A temperature measured orally (in the mouth) of 38.3°C (101°F) or higher on one occasion, OR
• A temperature of 38.0°C (100.4°F) or higher lasting for at least 1 hour, OR
• A temperature of 38.0°C or higher measured twice within 12 hours, OR
• Any other method shown to be equivalent to these results

When no definite non-infectious cause is found, fever must be regarded as a sign of an infectious complication. Possible non-infectious causes include a febrile reaction to cytokines (immune-signaling proteins), cytotoxic drugs (chemotherapy agents such as cytarabine or bleomycin), or a transfusion of blood products.

Doctors must also remember that fever can be hidden by antipyretic drugs (fever-reducing medicines) used for pain or cancer treatment. These include prednisone (a corticosteroid), non-steroidal anti-inflammatory drugs (NSAIDs such as ibuprofen), and metamizole (dipyrone).

How Doctors Grade Recommendations and Evidence

The guidelines use a grading system adapted from the European Society for Clinical Microbiology and Infectious Diseases (ESCMID). This system tells clinicians how strongly a recommendation is supported and how good the underlying evidence is.

Strength of recommendation:

• Grade A: Strongly supports a recommendation for use
• Grade B: Moderately supports a recommendation for use
• Grade C: Marginally supports a recommendation for use
• Grade D: Supports a recommendation against use

Quality of evidence:

• Level I: Evidence from at least 1 properly designed randomized, controlled trial
• Level IIa: Evidence from at least 1 well-designed clinical trial without randomization; from cohort or case-controlled analytic studies (preferably from more than 1 center); from multiple time series; or from dramatic results of uncontrolled experiences
• Level III: Evidence from opinions of respected authorities, based on clinical experience, descriptive case studies, or reports of expert committees

An added index letter is used in some recommendations. The letter "r" means a meta-analysis or systematic review of randomized controlled trials; "t" means transferred evidence from different patient cohorts or similar immune-status situations; "h" means the comparator group is a historical control; and "u" means an uncontrolled trial. For example, a recommendation labeled "BIIr" is a moderately strong recommendation supported by evidence from meta-analyses of randomized trials.

Risk Stratification: Standard-Risk vs. High-Risk Patients

The incidence of infections in cancer patients is directly related to the lowest point (nadir) and duration of neutropenia. However, predicting the exact course in an individual patient is difficult. Clinical trials on treating fever in patients with short periods of neutropenia (below 5 or 7 days) are limited, and some patients with neutropenia lasting more than 5 days have been enrolled in studies involving oral therapy and outpatient care.

After reviewing the literature, the expert panel agreed on stratifying patients into two risk groups:

• Standard risk: expected duration of neutropenia of up to 7 days
• High risk: expected duration of neutropenia of at least 8 days

All patients with neutropenia lasting 8 or more days are considered high-risk patients with respect to a complicated course of a febrile episode. However, patients assigned to the standard-risk group may have individual characteristics that justify classifying them as high-risk as well. These individual factors can be identified using the Multinational Association of Supportive Care in Cancer (MASCC) criteria, which have been repeatedly validated.

The MASCC Score: Identifying Standard-Risk Patients

Standard-risk patients with a MASCC score of 21 or higher make up a group with a high likelihood of a non-complicated course of infection. The maximum theoretical score is 26 points. Here is how the score is calculated:

The points for the "burden of febrile neutropenia" variable are not cumulative, which is why the maximum theoretical score is 26.

If a patient meets all individual criteria listed below, primary outpatient management (home treatment) of neutropenic fever is possible. The strength of this recommendation is BIIr — a moderate recommendation supported by evidence from randomized trials.

Criteria for Outpatient Management

Not every patient can be treated at home. The guidelines list specific criteria that must all be met before primary outpatient management is considered. These fall into three categories:

General medical criteria:

• No signs of central nervous system (CNS, brain or spinal cord) infection, severe pneumonia, or venous catheter infection
• No signs of sepsis (a life-threatening whole-body reaction to infection) or shock
• None of the following: associated organ failure, pronounced abdominal pain (with or without diarrhea), dehydration, recurrent vomiting, need for intravenous supportive therapy, or need for permanent or close monitoring (for example, due to metabolic decompensation or hypercalcemia)
• No new electrocardiogram (ECG, heart tracing) abnormalities requiring treatment
• No new severe organ impairment

Oral antibiotic criteria:

• No fluoroquinolone prophylaxis (preventive antibiotic treatment) or therapy within the last 7 days
• Oral medication is feasible
• Good compliance with oral medication is expected

Outpatient management criteria:

• Medical care is ensured (different options available)
• The patient does not live alone; the patient or a helper has a telephone; the patient can reach a clinic skilled in treating neutropenic patients within 1 hour
• The patient is conscious, knows the risks, and understands them

What Causes Fever in Neutropenic Patients?

At the onset of fever, antibiotic therapy must be started immediately. Because microbiological tests take time, the initial treatment is empirical (chosen based on the most likely germs) in patients who do not show a suspected clinical focus of infection. In about half of patients with febrile neutropenia (roughly 1 in 2), the antibiotic therapy remains empirical, because no relevant pathogen or focus of infection can be identified during the following days.

The selection of empirical antimicrobial agents is based on two things: (a) the results of prospective, randomized clinical studies, and (b) the microorganisms identified by analogy in patients with microbiologically documented infections. The most frequent and relevant pathogens are:

• Staphylococcus aureus
• Streptococcus species
• Enterococci
• Coagulase-negative staphylococci
• Gram-negative enterobacteria (intestinal bacteria)
• Pseudomonas aeruginosa

Coagulase-negative staphylococci are numerically the most frequent microbial isolates in many institutions. However, a single blood culture positive for these commensal skin pathogens (bacteria that normally live harmlessly on the skin) should be considered contamination if there is no corresponding clinical focus of infection. The same is true for other potential contaminants such as Corynebacterium, Bacillus cereus, Propionibacterium, and Micrococcus species.

Among fungal pathogens, Candida species and Aspergillus species are predominant. Aspergillus is typically associated with a prolonged duration of neutropenia in high-risk patients.

Local Resistance Patterns and Fluoroquinolone Prophylaxis

A recent history of antibiotic prophylaxis or therapy increases the risk of infections due to bacterial pathogens resistant to the antibiotic used. After ciprofloxacin prophylaxis, a relative predominance of infections caused by gram-positive cocci (round bacteria that stain positive in lab tests) compared with gram-negative bacteria has been observed.

Quinolone antibiotics (a class that includes ciprofloxacin) have been linked to several problems:

• An increased rate of colonization (germs living in or on the body without causing disease) by vancomycin-resistant enterococci (VRE, bacteria resistant to the antibiotic vancomycin)
• An increased rate of colonization by methicillin-resistant Staphylococcus aureus (MRSA)
• A higher prevalence of multidrug resistance among enterobacteria via extended-spectrum beta-lactamases (ESBL, enzymes that make bacteria resistant to many beta-lactam antibiotics)

Colonization by ESBL, VRE, or MRSA has been associated with an increased rate of bacteremia (bacteria in the bloodstream) caused by these same pathogens. As a result, the use of quinolones for interventional treatment in febrile neutropenic patients should be limited to microbiologically documented infections caused by microorganisms that are susceptible to these drugs in laboratory testing.

Local epidemiology must be taken into account when choosing empirical antimicrobial therapy. Microbiological findings from patients treated in a given hematology-oncology institution should be discussed on a regular basis, at least once a year, with infection-control and antimicrobial stewardship (antibiotic management) experts. Baseline screening of newly or re-admitted patients for multidrug-resistant pathogens should be considered: screening for MRSA is grade BIII, for VRE grade BIII, and for ESBL grade BIIt.

Baseline Tests Before Starting Chemotherapy

Before starting myelosuppressive chemotherapy (treatment that suppresses bone marrow function), patients must be thoroughly evaluated for relevant previous or prevalent infections that might become important during treatment-induced neutropenia. This recommendation is grade AIII, meaning it is strongly supported by expert opinion.

Clinical examination should pay special attention to the skin, mucosa (moist linings of the body), puncture sites, vascular catheter exit sites, paranasal sinuses, lungs, and the perianal (area around the anus) region. This too is a strong, expert-opinion recommendation (AIII).

In patients with a self-reported penicillin allergy, skin testing is recommended (BIIt). A negative result — which is expected in the vast majority of cases — helps avoid unnecessary first-line use of carbapenems, aztreonam, or vancomycin. Baseline laboratory tests include:

• Blood count
• Liver enzymes (ASAT/SGPT, ALAT/SGOT, gGT)
• Total bilirubin, alkaline phosphatase, and LDH (lactate dehydrogenase)
• Creatinine and blood urea nitrogen (kidney function tests)
• Coagulation tests (INR, aPTT, which measure blood clotting)
• C-reactive protein (CRP, a marker of inflammation)
• Urinalysis (urine test)

All of these recommendations are graded BIII. Except for urinalysis, it is recommended to repeat these tests regularly, for example twice a week, during long-lasting neutropenia (BIII).

Procalcitonin or cytokine levels (such as interleukin-6) are not recommended for routine baseline diagnostics (grade DIII, a recommendation against use). If neither computed tomography (CT) nor magnetic resonance imaging (MRI) of the chest and abdomen has been done for staging of the underlying disease, chest radiographs (X-rays, two views) and abdominal ultrasound may be considered as a baseline examination before the first chemotherapy (CIII). This helps check for pre-existing abnormalities and makes it easier to compare with later studies.

Particularly in high-risk patients, a thoracic CT scan before chemotherapy appears desirable to document the baseline status of the lungs. However, because there are no prospective studies, no formal recommendation can be made. In patients with a history of an invasive infection, appropriate imaging is recommended even when there are no clinical symptoms of recurrence (BIII).

Screening for Fungal Infections in Asymptomatic Patients

For high-risk patients with an expected duration of profound neutropenia longer than 7 days, serial monitoring for Aspergillus galactomannan in serum has been recommended. Galactomannan is a molecule released by Aspergillus fungi that can be detected in the blood. Monitoring should be done at least twice weekly.

Monitoring patients with 1,3-beta-D-glucan (a component of fungal cell walls) in blood samples is discussed as an alternative, but it is rarely used because of higher costs. A sensitive, validated Aspergillus PCR (polymerase chain reaction, a test that detects fungal DNA) may also be helpful (CIII) for screening blood samples in specific high-risk populations.

However, the sensitivity of these tests is strongly reduced in patients taking systemic mold-active antifungals (drugs that treat mold infections). False-positive results can be caused by beta-lactam antibiotics, parenteral nutrition (intravenous feeding), severe intestinal mucositis (inflammation of the gut lining), or transfusion of blood products. Therefore, screening of afebrile (fever-free) and asymptomatic patients should be restricted to those NOT receiving systemic mold-active prophylaxis (BIIu). These non-culture-based procedures do not replace clinical, imaging, endoscopic, or other microbiological diagnostics (BIII).

Diagnostic Tests at the Moment Fever Begins

When a neutropenic patient first develops fever, diagnostic measures have three aims: (a) rule out non-infectious causes of fever, (b) identify a clinical focus and/or causative pathogens, and (c) assess the severity of the inflammatory response to identify early which patients need intensive care. These diagnostic steps must never delay the start of appropriate antibiotic therapy (AIIt). In a clinically unstable patient, possibly arriving in the emergency room, prompt antimicrobial therapy is required (AI), and immediate referral to an intensive care unit must be considered.

Frequently Asked Questions

What is neutropenia and why is it dangerous in cancer patients after chemotherapy?

Neutropenia is a dangerously low count of neutrophils, the white blood cells that fight bacterial and fungal infections. It is defined as a count below 500/μl or below 1000/μl with a predicted drop within 2 days. The lower and longer the neutropenia, the higher the risk of fever and serious infections, which can delay chemotherapy.

When must antibiotic treatment start for a neutropenic patient with fever?

Treatment must begin within 2 hours of fever onset. The guidelines emphasize that diagnostic tests must never delay starting appropriate antibiotic therapy. In a clinically unstable patient, prompt antimicrobial therapy is required, and immediate referral to an intensive care unit may be considered.

What is the difference between standard-risk and high-risk neutropenic patients?

Standard-risk patients have an expected duration of neutropenia of up to 7 days. High-risk patients have neutropenia expected to last at least 8 days. High-risk patients need broad-spectrum antibiotics covering bacteria like Pseudomonas aeruginosa, and possibly antifungal therapy against Aspergillus if neutropenia lasts more than 7 days.

What is the MASCC score and what does a score of 21 or higher mean?

The MASCC score helps identify standard-risk patients likely to have a non-complicated course of infection. A score of 21 or higher (maximum 26) indicates a high likelihood of a non-complicated course. Points are given for factors like no hypotension, no COPD, solid tumor, outpatient status, and age under 60.

Can neutropenic fever be treated at home?

Primary outpatient management is possible only if all criteria are met. These include no signs of serious infection or organ failure, no fluoroquinolone prophylaxis in the last 7 days, oral medication is feasible, good compliance expected, medical care ensured, the patient does not live alone, has a telephone, and can reach a skilled clinic within 1 hour.

What causes fever in neutropenic patients and how is treatment chosen?

In about half of patients, no specific germ or infection focus is identified, so antibiotic therapy remains empirical. Common pathogens include Staphylococcus aureus, Streptococcus species, enterococci, gram-negative enterobacteria, and Pseudomonas aeruginosa. Fungal pathogens like Candida and Aspergillus are also considered, especially with prolonged neutropenia. Local resistance patterns guide antibiotic choice.

Should I seek a second opinion on the recommended antibiotic treatment for fever during neutropenia after chemotherapy?

The guidelines divide patients into standard-risk and high-risk groups, and treatment differs accordingly: high-risk patients need broad-spectrum antibiotics covering Pseudomonas, and antifungal therapy may be added if neutropenia lasts more than 7 days. If your doctor's risk assessment or choice of antibiotics differs from these published recommendations, a second opinion could help confirm whether the treatment plan is appropriate. Additionally, if you have a penicillin allergy, skin testing is recommended to avoid unnecessary drugs. A second opinion can review your risk status and antibiotic plan. Diagnostic Detectives Network provides independent expert second opinions.