Febrile Neutropenia

Febrile neutropenia is a serious medical emergency that occurs when a person with very low white blood cell counts develops a fever, most commonly as a complication of cancer treatment. Without enough infection-fighting cells, even a minor infection can quickly become life-threatening, requiring immediate medical attention.

Table of contents

• What Is Febrile Neutropenia?
• Causes and Risk Factors
• Signs and Symptoms
• How It Is Diagnosed
• Treatment Approaches
• Prevention Strategies
• Outlook and Complications

What Is Febrile Neutropenia?

Febrile neutropenia is when a person has both a fever and an abnormally low number of neutrophils (a type of white blood cell that fights infections) in their blood^[1]. This condition is considered an oncological emergency, meaning it requires urgent medical care^[2].

The condition is defined by specific measurements. A fever is present when there is a single oral temperature reading of 101°F (38.3°C) or higher, or a temperature of 100.4°F (38°C) or higher that lasts for at least one hour^[1][2]. Neutropenia means having an absolute neutrophil count (ANC) of 500 cells per microliter or less, or an ANC of 1,000 cells per microliter or less that is expected to drop below 500 cells per microliter within the next 48 hours^[2].

Neutrophils are crucial for your body’s defense system. They destroy germs that cause infections, including viruses and bacteria^[3]. When neutrophil levels are too low, your body cannot fight infections effectively. The risk of serious bloodstream infections increases as neutrophil counts drop lower, with the greatest danger occurring when counts fall below 100 cells per microliter, a condition called profound neutropenia^[1].

Causes and Risk Factors

Febrile neutropenia is most commonly a complication of cancer therapy. It is the most common serious and life-threatening complication of cancer treatment^[1][2]. Research shows that approximately 50% of people receiving chemotherapy will develop neutropenia^[3], and about 1% of patients receiving chemotherapy develop febrile neutropenia^[7]. Each year in the United States, about 60,000 people with cancer are hospitalized due to neutropenia^[5].

Chemotherapy is the primary cause because these cancer-fighting drugs harm or destroy neutrophils and the bone marrow that produces them. Neutropenia typically develops 7 to 12 days after chemotherapy treatment^[4][7]. Radiation therapy can also damage the bone marrow and reduce neutrophil production^[3].

In most cases, doctors cannot identify the specific source of infection, and it gets marked as a fever of unknown origin. Only about 30% of febrile neutropenia cases have a documented infection^[1][4]. When infections are identified, most are bacterial. Common bacterial causes include gram-positive bacteria such as Staphylococcus, Streptococcus, and Enterococcus species^[1]. Drug-resistant organisms like Pseudomonas aeruginosa, Acinetobacter species, Stenotrophomonas maltophilia, Escherichia coli, and Klebsiella species have also been identified^[1]. Viral or fungal infections are also possible^[1].

Several factors increase the risk of developing febrile neutropenia during chemotherapy treatment^[5]:

• Being 65 years of age or older
• Having other chronic diseases such as diabetes and heart disease
• Being underweight or having poor nutrition
• Difficulty doing basic physical activities like walking
• Prior exposure to chemotherapy or radiation
• Persistent low white blood cell count
• Long-term weakened immune system due to infection, disease, or immune-suppressing medications
• Lung, kidney, or liver disease
• Recent surgery and/or open wounds
• Recent infection

Patients at high risk for medical complications include those with anticipated severe neutropenia lasting 7 days or longer, those undergoing bone marrow transplant, or those with significant other medical conditions^[2].

Signs and Symptoms

Because neutropenia weakens the body’s ability to mount an inflammatory response (the body’s reaction to injury or infection), many typical signs of infection may be absent^[2][4]. Fever may be the only sign of an underlying infection in people with febrile neutropenia^[4][16]. This is why it is critical to monitor temperature regularly and seek immediate medical attention when fever develops.

Common symptoms of neutropenia and infection include^[5]:

• Fever
• Chills
• Mouth sores
• Cough
• Difficulty breathing
• Abdominal or rectal pain

The fever itself is released by the body’s own chemical messengers (endogenous cytokines) from epithelial cells, which can cause fever during neutropenia even without a clear infection^[4]. Because barriers and protective linings in the body, including those in the gastrointestinal tract and sinuses, can be damaged by chemotherapy and radiation, germs can invade more easily^[4].

Due to the decreased ability to fight infections, patients with febrile neutropenia related to deep-seated infections often fail to demonstrate typical warning signs like warmth and swelling^[2].

How It Is Diagnosed

Diagnosing febrile neutropenia involves measuring both temperature and neutrophil count. The absolute neutrophil count (ANC) is calculated by multiplying the total white blood cell count by the percentage of neutrophils (including both mature neutrophils and immature forms called band neutrophils)^[1].

When a fever develops, patients undergo a complete infection workup to identify potential sources. This typically includes^[7]:

• Chest X-ray
• Blood cultures (samples taken from veins to test for bacteria)
• Urine studies
• Examination of any central venous lines or catheters
• Skin examination
• Additional tests based on specific symptoms

Doctors examine the most commonly infected sites, including areas of previous procedures or catheters, as well as the skin, mouth and throat, gastrointestinal tract, lungs, genitourinary region, and respiratory system^[7]. If there are signs of respiratory infection, chest radiography is performed^[7].

Clinical judgment and validated risk assessment tools help determine which patients are at highest risk for complications. The Multinational Association for Supportive Care in Cancer (MASCC) scoring system can help identify patients who may be candidates for outpatient treatment versus those who need hospitalization^[2][10].

If fever persists for more than 24 hours, the infection workup may be repeated and may continue every 24 hours until the fever resolves and neutrophil counts improve^[16].

Treatment Approaches

Febrile neutropenia requires urgent treatment. Prompt administration of antibiotics is critical to reduce the risk of death^[2][4]. Patients with febrile neutropenia should receive initial doses of antibiotics within 1 hour of arriving at a medical facility and be monitored for at least 4 hours before discharge if outpatient treatment is considered^[10].

Because the source of infection often cannot be identified, treatment begins with empirical antibiotic therapy—meaning broad-spectrum antibiotics that work against many types of bacteria are started immediately without waiting to identify the specific germ^[1][4].

For low-risk patients who may be treated as outpatients, oral antibiotic regimens are recommended. A common combination is a fluoroquinolone antibiotic plus amoxicillin-clavulanate, or clindamycin if the patient has a penicillin allergy^[10]. However, these regimens should not be used if the patient was already taking fluoroquinolone antibiotics as prevention before the fever developed^[10].

High-risk patients require hospital admission for intravenous antibiotics and close monitoring^[4][9]. The average hospital stay for febrile neutropenia is approximately 10 days^[5]. First-line treatment typically uses a single antibiotic with activity against Pseudomonas bacteria. Options include piperacillin-tazobactam, cefepime, meropenem, or imipenem-cilastatin^[9]. In complicated cases, such as when a patient has low blood pressure or pneumonia, or when drug-resistant bacteria are suspected, combination therapy with two antibiotics may be used^[9].

If a specific source of infection is found, more targeted antibiotics are given^[7]. Medications such as acetaminophen are used to lower the fever^[16]. Antibiotics are continued until the patient no longer has fevers and neutrophil counts have recovered^[4][16].

Patients who do not improve after 2 to 3 days of initial antibiotic treatment should be re-evaluated and considered as candidates for continued inpatient treatment with adjusted therapy^[10].

Prevention Strategies

Preventing febrile neutropenia focuses on both medical interventions and careful hygiene practices. Medications called colony-stimulating factors (CSFs) or growth factors can stimulate the production of neutrophils and reduce the risk of febrile neutropenia^[5]. Examples include filgrastim and pegfilgrastim. These medications may shorten the duration of neutropenia, lowering the risk for infection^[5].

Prophylactic antibiotics (antibiotics given before infection develops) at the onset of neutropenia can decrease fever and bloodstream infection events in high-risk patients^[2]. However, the use of preventive antibiotics requires careful consideration of benefits and risks, including close monitoring for antibiotic resistance and adverse effects^[2].

Cancer care teams may also choose to delay cancer treatment to give the body time to produce more white blood cells^[5].

While neutropenic, patients should take several precautions to reduce infection risk^[11][15]:

• Take temperature several times daily and keep a written record
• Wash hands frequently with soap and water, especially before eating and after using the toilet
• Use a soft toothbrush and avoid flossing teeth
• If female, use sanitary pads instead of tampons and do not douche
• Avoid using rectal thermometers or suppositories
• Avoid tasks that expose you to germs, such as disposing of pet waste
• Avoid crowds and anyone who might have an infection or illness such as a cold or flu
• Avoid people who have recently received certain vaccinations
• Take steps to prevent cuts, burns, and sunburns
• In severe neutropenia, avoid fresh fruits, vegetables, and flowers if advised by your doctor

Patients should eat a healthy, balanced diet with plenty of fiber to help prevent constipation^[15]. In some cases, patients may be advised to follow a special neutropenic diet that avoids foods that might harbor bacteria, such as unwashed fruit or undercooked meat^[19].

Outlook and Complications

Infections are the primary cause of illness and death in cancer patients who present with fever and neutropenia^[1]. The consequences of febrile neutropenia can include dose reductions in cancer treatment, treatment delays, and substantial impact on both illness severity and death rates^[4].

Without treatment, severe neutropenia can be life-threatening^[3]. An infection can quickly progress to sepsis (a life-threatening response to infection) because patients with neutropenia are unable to fight infection effectively^[16].

The outlook depends on how quickly treatment begins and how well the patient responds to antibiotics. Once neutrophil counts recover and fever resolves for 24 hours without antibiotics, patients may be able to return home^[16]. If a specific source of infection is identified, patients need to complete the full course of antibiotic treatment^[16].

It is essential for patients to understand when to seek immediate medical help. Patients should call emergency services or go to the emergency department immediately if they experience^[15]:

• Severe shortness of breath
• Loss of consciousness

Patients should contact their doctor or seek immediate medical care if they have^[15]:

• Fever or chills, or sweating
• Signs of infection such as increased pain, swelling, warmth, or redness of the skin
• Red streaks leading from a wound
• Pus draining from a wound

When going to the emergency department with a fever, patients should present their Fever Advisory Card and inform staff that they have cancer, are receiving chemotherapy, and when they were last treated^[18]. However, even with this card, patients should understand their care is a priority but they may still need to wait while other patients with more urgent concerns are treated^[18].