What is Febrile Neutropenia?

Neutropenic fever occurs when a person’s temperature rises above 101 F (38.3 C) once, or above 100.4 F (38 C) for at least one hour, while having a low count of a specific type of white blood cells called neutrophils (under 1500 cells/microliter). When someone has severe neutropenia, their neutrophil count is below 500 per microliter. If it’s profound neutropenia, the count is less than 100 cells/microliter. A very low neutrophil count can put a person at higher risk of getting bacteria in their blood.

To figure out the count of neutrophils, you multiply the total number of white blood cells by the combined percentage of a couple types of cells (polymorphonuclear cells and band neutrophils), then divide by 100. So, the formula is:

ANC = WBC (cells/microL) x percent (PMNs + bands) / 100

There are several terms doctors use to talk about abnormal neutrophil counts:

When the neutrophil count is less than 200 cells/microL, it’s called agranulocytosis.
If someone has neutropenia for more than three months, it’s referred to as chronic neutropenia.
If a person has neutropenia without also having a low red blood cell count (anemia) or a low platelet count (thrombocytopenia), it’s known as isolated neutropenia.
A reduced number of several types of white blood cells – neutrophils, eosinophils, and basophils – is called granulocytopenia.

What Causes Febrile Neutropenia?

In many cases, the exact cause of an infection cannot be determined and it’s referred to as a fever of unknown origin (FUO). This term is used for cases where a person has a fever higher than 38.3 C, but no clear source of the infection can be found. Approximately 30% of these cases can be traced to a specific infection. Even though the exact cause might not be known, infections remain the main reason for health risks and fatalities in patients with cancer who also have a fever and low neutrophil count – a condition known as neutropenia.

Most of these infections are caused by bacteria, but they can also be due to viruses or fungi. Common bacteria causing these infections include types like Staphylococcus, Streptococcus, and Enterococcus. Drug-resistant bacteria, including Pseudomonas aeruginosa, Acinetobacter, Stenotrophomonas maltophilia, Escherichia coli, and Klebsiella species, have also been identified as common culprits.

There can be several reasons behind neutropenia:

* Inborn neutropenia: This is usually suspected in adults with a severe drop in neutrophil count (<500 cells/microL), who also show signs like early graying of hair, issues with pancreas function, or abnormalities of fingernails or skeleton.

* Medications: Apart from chemotherapy, several other medicines can also cause neutropenia. This includes types of antibiotics, malaria treatment drugs, anti-inflammatory drugs, antidepressants, thyroid hormones regulators, heart-related drugs, seizure control medicines, and even drugs containing gold salts.

* Nutritional deficiency: Severe lack of vitamin B12, folate, or copper can also drop neutrophil counts, leading to neutropenia.

Risk Factors and Frequency for Febrile Neutropenia

Agranulocytosis, a drop in the number of white blood cells, is a rare condition with approximately 1.0 to 3.4 cases per million people per year. People with HIV, acute leukemias, and myelodysplastic syndromes are often found to have agranulocytosis. Another type of condition known as drug-induced neutropenia also occurs in about one in a million people each year.

About half of people with agranulocytosis who develop a fever will also develop an infection. Of these, 20% with a severe drop in white blood cells will develop bacteremia, a serious condition where bacteria gets into the bloodstream.

The majority of these infections are caused by a type of bacteria known as Gram-positive bacteria. Often, people get these infections from long-term central venous catheters, which are tubes placed in a large vein to give medications or nutrients. Although Gram-negative bacteria also cause a considerable number of infections, the rate is slightly less – about 60 to 40.

The most common Gram-positive bacteria behind these infections include Staphylococcus aureus, especially the ones resistant to certain drugs (methicillin), enterococci (especially those strains resistant to vancomycin), and certain types of streptococci.

Signs and Symptoms of Febrile Neutropenia

Understanding a patient’s history is crucial, especially when they’re dealing with an illness, undergoing chemotherapy, or taking medications. Awareness of past instances of infections, particularly those involving bacteria-resistant organisms, as well as any allergies, can help guide the treatment plan. It’s sometimes difficult to identify an infection, as pain and sensitivity might be the only symptoms.

There are several risk factors that could lead to the development of febrile neutropenia (a condition where the patient has a fever and a low number of a type of white blood cells). These risk factors include older age, the presence of other diseases, the specific type of cancer the patient has, and the type and quantity of cancer chemotherapy drugs that suppress bone marrow (myelosuppressive agents) being used.

Testing for Febrile Neutropenia

If doctors think you have a severe infection (neutropenia), they may use different tests to confirm it or to learn more details about the infection. First, they use a complete blood count test to gauge the severity of your neutropenia. After that, they might take samples of your blood, urine, and throat to find out the source of the infection. It’s crucial to run these tests before starting any broad-spectrum antimicrobial therapy, a type of treatment using a wide range of antibiotics, to ensure the therapy will effectively combat the infection.

If you’ve previously had urinary tract infections, the doctors might suspect this as the source, even if you aren’t currently showing symptoms. If you have diarrhea, a stool (fecal) sample may be tested. If you exhibit any respiratory symptoms, like a persistent cough, doctors may order a chest x-ray to check for infections in the lungs. They will also take samples from any obvious infection sites for further testing.

There are many different types of bacteria that could potentially be found in patients with neutropenia, some common ones being Staphylococcus aureus or Escherichia coli. Others are less common, such as Bacillus spp or Acinetobacter spp. Knowing exactly what type of bacteria is causing an infection can help your doctors choose the most effective treatment.

In some cases, additional tests might be necessary. If doctors suspect a fungal infection, they might run a Galactomannan test or 1,3-beta-D-glucan test, using either a blood sample or lung fluid sample. Procalcitonin, a substance that increases in the blood during a severe bacterial infection, might also be tested to see if you have sepsis. Finally, if Chest X-rays show unknown abnormalities, BAL (Bronchoalveolar Lavage) fluid culture might be done to confirm the type of infection.

Your doctor might follow up the tests by assessing your fever and other symptoms using specific tools such as the Multinational Association for Supportive Care in Cancer (MASCC), or the Clinical Index of the Stable Febrile Neutropenia (CISNE). These tools assign scores based on various factors and help the doctor understand the risk of serious complications. With this information, your doctor can make an informed decision on what should be the best course of action for your treatment.

For instance, the MASCC score considers your symptoms, whether you have conditions such as chronic obstructive pulmonary disease, the type of cancer you might have, your age, and more. The maximum score one can achieve on this index is 26. If your score is higher than 21, you’re considered as a low-risk patient. However, a score below 21 suggests you’re at a high risk.

Another tool, the CISNE index, evaluates your ability to undergo therapies for severe illnesses based on your everyday functionality (ECOG performance status). It also considers whether you have chronic diseases such as heart disease or lung disease, high stress-related blood sugar, the level of a type of white blood cells called monocytes, and the severity of inflamed and sore mouth or throat. Scores on the CISNE index can guide whether your treatment would be best managed at home or require hospitalization.

Treatment Options for Febrile Neutropenia

If a patient is at high risk, their treatment plan for neutropenic fever tends to be more thorough. Patients are considered high-risk if they have received a particular type of therapy likely to greatly reduce their number of white blood cells for more than seven days, have a CISNE score of 3 or more, have a low MASCC risk index score, have severe ongoing medical issues, have cancer that is not under control or is getting worse, show signs of liver or heart problems, have a reduced ability to filter waste products from their blood, or have used certain cancer treatments in the past two months.

Patients not at high risk can be managed at outpatient clinics. Doctor may prescribe a combination of fluoroquinolone and amoxicillin/clavulanate to help fight off infections. However, if the patient is still having a fever after two to three days of treatment, they will need to be admitted to a hospital.

High-risk patients must be carefully managed when they show signs of neutropenic fever; this includes being given antibiotic treatment intravenously within an hour after being seen and continuous monitoring for at least four hours before leaving the healthcare setting. The Infectious Disease Society of America (IDSA) suggests specific antibiotics, including cefepime, carbapenems, or piperacillin/tazobactam, to combat particular bacteria called pseudomonas. They do not recommend the initial use of another antibiotic, vancomycin unless it is suspected that the infection is due to an intravenous catheter, an infection of the skin or tissue, pneumonia or if the patient’s vital signs are unstable.

If the initial treatment doesn’t work, the doctors may broaden the treatment to include different types of antibiotics to combat possible resistant microbes. After about a week of using antibiotics to treat the infection, if the fever isn’t relieved, doctors may suspect a fungal infection and recommend antifungal therapy.

Antibiotics are normally continued until the count of certain white blood cells (called ANC) is normal or the infection is cleared. If the patient still has low white blood cell count after the course of treatment, they usually continue taking antibiotics until their bone marrow recovers.

To prevent infection in patients with neutropenia (low white blood cell count), physicians often advise the use of antibiotics such as fluoroquinolones, an oral antifungal medicine, and other specific types of medications depending on the patient’s individual situation. Yearly influenza vaccination is also recommended for all patients receiving chemotherapy.

Patients who have a 20% or higher risk of developing a fever due to low white blood cell count may receive drugs called colony-stimulating factors as potential treatment. The National Comprehensive Cancer Network (NCCN) guidelines recommend that patients at high risk of neutropenic fever can benefit from granulocyte-colony stimulating factors (G-CSFs), which are used to stimulate the bone marrow to produce more white blood cells.

There are several conditions that can cause an increase in body temperature, including:

Transfusion reaction, which means the body is having a negative response to a blood transfusion
Allergic reactions to medications or toxicities, meaning harmful effects from drugs
Fever related to a tumor
Thrombophlebitis, which is inflammation of a vein caused by a blood clot
Resorption of blood from a large hematoma, which is the body reabsorbing blood from a large bruise
Viral infections
Invasive fungal infections

What to expect with Febrile Neutropenia

There are various factors that researchers use to predict how a disease might progress, and there’s ongoing debate over which of these factors are most reliable. These indicators include blood test results, preventative measures taken, and details specific to each patient. The results, however, have been inconsistent.

The MASCC risk-index score, a scoring system intended to determine patients at lower risk, showed an interesting trend. A lower MASCC score was linked with a worse outcome for patients with febrile neutropenia, an infection that can occur in people receiving chemotherapy. Particularly low scores (less than 15) were associated with a high rate of complications.

Procalcitonin is a substance produced by the body that can rise in response to bacterial infection. Patients with severe sepsis and septic shock often had procalcitonin levels greater than 2.0 ng/ml. This means that high levels of procalcitonin may indicate a higher likelihood of a negative outcome.

Possible Complications When Diagnosed with Febrile Neutropenia

Most individuals who have chemotherapy-induced febrile neutropenia, a condition where chemotherapy leads to a low level of white blood cells and fever, typically recover quickly without any serious complications. Yet, this side effect remains life-threatening and is related to the treatment. This might require a decrease in the dose of chemotherapy or delays in the continuity of it, which might adversely affect the results of the treatment. In severe cases, it can lead to shock and death.

Common Outcomes:

Quick recovery without serious complications
Potential life-threatening toxicity related to the treatment
Need for reduction in the chemotherapy dosage
Delays in the continuity of chemotherapy treatment
Negatively affected treatment results
Shock
Potential death

Preventing Febrile Neutropenia

Those undergoing chemotherapy should be informed about the possibility of developing a condition called febrile neutropenia, a side effect that is associated with fever and lower than normal number of white blood cells. They should also be educated about the signs and symptoms to watch out for. If they do develop this condition, it’s important to avoid contact with people who have respiratory infections and also stay away from crowded places. When their number of specific white blood cells, also known as Absolute Neutrophil Count (ANC), drops below 1000 per microliter of blood, they should wear a facemask when they are in public areas. They are advised to take their temperature every day, particularly if they start to experience symptoms such as sudden shivering, sweating, or a feeling of having a fever.

Frequently asked questions

Febrile neutropenia occurs when a person's temperature rises above 101 F (38.3 C) once, or above 100.4 F (38 C) for at least one hour, while having a low count of neutrophils (under 1500 cells/microliter).

Febrile Neutropenia occurs in about one in a million people each year.

The signs and symptoms of Febrile Neutropenia include: - Fever: Patients with febrile neutropenia typically have a fever, which is often the primary symptom. - Low white blood cell count: Neutropenia refers to a low number of a type of white blood cells called neutrophils. This can be detected through blood tests. - Weakness and fatigue: Patients may experience weakness and fatigue due to the low white blood cell count and the underlying illness. - Pain and sensitivity: In some cases, pain and sensitivity may be the only symptoms of febrile neutropenia, making it difficult to identify. - Increased risk of infections: Neutropenia weakens the immune system, making patients more susceptible to infections. These infections can manifest in various ways, such as respiratory infections, urinary tract infections, or skin infections. - Other symptoms: Depending on the underlying cause and individual patient factors, other symptoms such as chills, headache, sore throat, or gastrointestinal symptoms may also be present. It is important for patients with febrile neutropenia to seek medical attention promptly, as this condition can be serious and potentially life-threatening.

There are several risk factors that could lead to the development of febrile neutropenia, including older age, the presence of other diseases, the specific type of cancer the patient has, and the type and quantity of cancer chemotherapy drugs that suppress bone marrow (myelosuppressive agents) being used.

The doctor needs to rule out the following conditions when diagnosing Febrile Neutropenia: - Transfusion reaction - Allergic reactions to medications or toxicities - Fever related to a tumor - Thrombophlebitis - Resorption of blood from a large hematoma - Viral infections - Invasive fungal infections

To properly diagnose Febrile Neutropenia, doctors may order the following tests: 1. Complete blood count (CBC) test to gauge the severity of neutropenia. 2. Blood, urine, and throat samples to identify the source of the infection. 3. Stool (fecal) sample if diarrhea is present. 4. Chest x-ray to check for lung infections. 5. Samples from obvious infection sites for further testing. 6. Galactomannan test or 1,3-beta-D-glucan test for fungal infections. 7. Procalcitonin test to check for sepsis. 8. Bronchoalveolar Lavage (BAL) fluid culture if chest x-rays show unknown abnormalities. 9. Assessment of fever and other symptoms using tools like the Multinational Association for Supportive Care in Cancer (MASCC) or the Clinical Index of the Stable Febrile Neutropenia (CISNE). 10. Additional tests may be necessary depending on the specific case.

Febrile Neutropenia is treated differently depending on whether the patient is considered high-risk or not. For patients who are not high-risk, outpatient management is possible with a combination of fluoroquinolone and amoxicillin/clavulanate. However, if the fever persists after two to three days of treatment, hospital admission is necessary. High-risk patients require more thorough treatment, including intravenous antibiotic treatment within an hour of being seen and continuous monitoring for at least four hours. The Infectious Disease Society of America (IDSA) recommends specific antibiotics such as cefepime, carbapenems, or piperacillin/tazobactam to combat pseudomonas bacteria. If the initial treatment doesn't work, doctors may broaden the treatment to include different types of antibiotics. If the fever persists after a week of antibiotic treatment, a fungal infection may be suspected, and antifungal therapy may be recommended. Antibiotics are continued until the white blood cell count is normal or the infection is cleared. In some cases, colony-stimulating factors may be used to stimulate the bone marrow to produce more white blood cells.

The side effects when treating Febrile Neutropenia include: - Quick recovery without serious complications - Potential life-threatening toxicity related to the treatment - Need for reduction in the chemotherapy dosage - Delays in the continuity of chemotherapy treatment - Negatively affected treatment results - Shock - Potential death

The prognosis for Febrile Neutropenia can vary depending on several factors, including the individual patient and the specific circumstances of their condition. However, some indicators suggest a worse outcome for patients with febrile neutropenia, such as a lower MASCC risk-index score and high levels of procalcitonin. It is important for healthcare professionals to assess these factors and monitor the patient closely to determine the prognosis and provide appropriate treatment.

An oncologist or hematologist.

Chemotherapy Immunocompromised State Infectious Disease Malignancy Neutropenia