Neutropenic Fever · What Is It, Causes, Symptoms, Diagnosis, Risk Assessment, Treatment, Prevention, and More

Neutropenic fever, also known as febrile neutropenia, refers to the presence of fever in someone with neutropenia. Neutropenia refers to a decrease in the number of neutrophils in the blood. Neutrophils are an important type of white blood cells of the innate immune system that act as a first-line defense against infections.

The Infectious Diseases Society of America defines neutropenia as an absolute neutrophil count (ANC) of less than 1500 cells/mm³. The risk of infection and neutropenic fever increases dramatically with severe neutropenia, which is defined as an ANC below 500 cells/mm3, or an expected decrease to less than 500 cells/mm³ during the next 48 hours. A fever is defined as either a single oral temperature greater or equal to 101° Fahrenheit (38.3° Celsius) or a sustained temperature greater or equal to 100.4° Fahrenheit (38.0° Celsius) or higher for an hour or longer.

Neutropenic fever can be dangerous and is considered a medical emergency. A marked decrease in the absolute neutrophil count compromises the immune system’s ability to fight against opportunistic infections, with a high risk of progression to severe sepsis and major complications, including organ failure and death. Therefore, in the absence of an alternative explanation, neutropenic fever is assumed to be caused by an infection and is promptly treated with empiric broad-spectrum antibiotics. Health outcomes of neutropenic fever depend on the severity and duration of the neutropenia, along with additional factors. Fever and neutropenia that last for less than seven days are associated with a more positive prognosis. Conversely, higher risk of infection-related morbidity and mortality is seen in individuals with persistent neutropenia that lasts for more than seven days, or the presence of profound neutropenia with a neutrophil count lower than 100 cells/mm³.

Neutropenic fever is caused by conditions that decrease neutrophil production or increase neutrophil destruction. Most cases are caused by cytotoxic chemotherapy given as cancer treatment. Radiation therapy (especially total body irradiation, or therapy targeted at the bone marrow) as well as hematopoietic stem cell transplantation (HSCT) may also lead to neutropenic fever. Other causes include hematologic malignancies; severe active infections such as sepsis, hepatitis, or tuberculosis; bone marrow failure disorders like aplastic anemia or myelofibrosis; autoimmune or rheumatic diseases like systemic lupus erythematosus and rheumatoid arthritis; and rare, serious, unpredicted drug reactions.

Chemotherapy is one of the most common causes of neutropenic fever, as many chemotherapy medications that destroy tumor cells can also affect the normal production of blood cells (i.e., hematopoiesis), resulting in bone marrow suppression.

To prevent the neutrophil count from decreasing further, chemotherapy dosage may need to be reduced or delayed, which, in turn, can adversely affect the prognosis.

In the presence of neutropenia, the usual signs and symptoms of infection may be reduced or absent, and often, fever is the only reliable symptom. Other concurrent signs and symptoms can include abdominal pain, mucositis of the gastrointestinal tract, and perirectal pain.

Some individuals may develop complications such as severe sepsis or septic shock. These may manifest as extreme pain, chills, increased heart rate and respiratory rate, hypotension, shortness of breath, altered mental status, and decreased urination.

Diagnosis of neutropenic fever involves rapid evaluation of medical history to identify potential causes, possible sites of infection, and likely pathogens. The history usually covers recent antibiotic therapy, surgery, invasive procedures, prior infections, and potential exposures through visitors, pets, plants, or contaminated foods. Clinicians would also inquire about the duration of fever and assess the presence of additional symptoms through questioning and physical examination. Any potential portal of entry for pathogens including the skin, mucous membranes, gastrointestinal tract, urinary tract, and any IV catheters or line sites, is carefully examined.

Laboratory tests and cultures help determine the causative pathogens. Laboratory tests include a complete blood cell count, including differential white cell count to determine the severity of neutropenia, as well as urinalysis. Cultures may involve blood culture sets and specimens from other potential sites of infection, such as stool, sputum, or nasal swab.  

Finally, individuals with neutropenic fever should be examined with chest X-rays and, depending on the clinical presentation, additional imaging studies such as a CT scan. 

Individuals diagnosed with neutropenic fever should be evaluated to determine their risk of developing medical complications, such as severe sepsis or septic shock.

The Multinational Association of Supportive Care in Cancer (MASCC) Risk Index is a clinical tool used to stratify the risk of poor outcomes in patients with chemotherapy-induced neutropenia. It incorporates factors such as burden of illness, patient status, age, and type of cancer. A MASCC score of 21 points or higher indicates a low risk for poor outcome, whereas a score of 20 or lower indicates a high risk for morbidity and mortality.

Initial evaluation and management of neutropenic fever are guided by clinical practice guidelines to ensure prompt antibiotic therapy and risk stratification. Assessment begins with an immediate evaluation, risk assessment for complications, and blood cultures to find the causative bacteria. Then, broad-spectrum empiric antibiotic therapy is initiated within one hour of presentation to reduce morbidity and mortality. Low-risk individuals are commonly given oral antibiotics, while high-risk individuals generally receive intravenous antibiotics.

Although Gram-positive infections are more common, infections with Gram-negative bacteria are associated with higher morbidity and mortality and are therefore preferentially targeted with antipseudomonal beta-lactam agents, such as piperacillin-tazobactam. Individuals with hypotension or septic shock often require empiric combination antibiotic therapy. In any case, when blood culture results become available, the antibiotic regimen is modified accordingly.

Clinical and laboratory response to therapy is assessed after 48 hours in individuals without documented infection and after completion of the antibiotics course in those with confirmed infection. Antibiotics are generally continued until the absolute neutrophilic count exceeds 500/mm3. Additionally, if the fever does not resolve within two days, individuals treated at home should be admitted to the hospital and re-evaluated.

When fever and neutropenia persist for more than 4–7 days despite empiric antibiotic therapy, a fungal infection can be suspected. Management options in these cases include initiating empiric antifungal therapy, as well as performing chest CT scan and serial galactomannan assay (diagnostic test for invasive aspergillosis) to aid in identifying potential fungal infections and guide further treatment.

The recommended treatment for non-infectious causes of neutropenic fever (e.g., drug reactions, underlying malignancies) is to address the underlying etiology, while maintaining empiric antibiotic therapy until infection is effectively excluded. Empiric broad-spectrum antibiotic treatment is still recommended in these cases, due to the risk of occult infections and the potential rapid deterioration in this population.

Low-risk individuals with neutropenic fever can be treated at home with empiric antibiotic therapy and mandatory close follow-up. Caregivers are advised to practice strict standard precautions (e.g., rigorous hand hygiene, adequate use of personal protective equipment, and careful handling of invasive devices), in order to reduce the risk of transmitting infections to the immunocompromised individual, while maintaining their own safety. Persistent fever or new signs or symptoms of infection may require admission to the hospital.

Preventing neutropenic fever begins by taking steps to limit exposure to opportunistic pathogens in susceptible individuals. Measures include daily baths, oral hygiene, routine inspection of the skin and other portals of entry, cleaning and cooking food well, and avoiding contact with pets, plants, and visitors with active infections. Additionally, with hospitalized patients, healthcare workers and caregivers are expected to practice standard precautions, including regular hand hygiene and utilizing personal protective equipment, as well as limiting skin breaks or injury by minimizing use of rectal thermometers, enemas, suppositories, digital rectal examinations, and invasive procedures.

Additional preventive measures may include the use of colony-stimulating factors(G-CSF) to boost neutrophil production in the bone marrow. According to the American Society of Clinical Oncology, these agents are used as primary or secondary prophylaxis in high-risk individuals or alongside antibiotics during active neutropenic fever. High-risk individuals undergoing procedures such as hematopoietic stem cell transplantation, leukemia induction therapy, or with high-grade graft-versus-host-disease (GVHD) may also receive prophylactic antibiotics, antifungals, or antivirals. Screening for herpes simplex virus (HSV), hepatitis, and influenza, in order to assess for active or latent infections, can help guide prophylactic antiviral therapy.

Neutropenic fever refers to an absolute neutrophil count (ANC) of 1500 cells/mm³ or less, accompanied by a temperature greater or equal to 101° Fahrenheit (38.3° Celsius). It is a medical emergency that requires prompt management, due to a high risk for rapid progression to severe sepsis and major complications. The most common causes of neutropenic fever are cancer treatments, such as cytotoxic chemotherapy and hematopoietic stem cell transplant, but other etiologies like unusual drug reactions and autoimmune disorders are also possible. Diagnosis of neutropenic fever involves medical history, clinical examination, laboratory tests and cultures, and chest X-ray. Treatment is initiated promptly with broad-spectrum empiric antibiotic therapy, while empiric antifungal therapy can be considered when fever and neutropenia persist for more than 4–7 days. Preventing neutropenic fever involves limiting exposure to pathogens through infection prevention and control (by individuals, caregivers and medical staff), as well as administering primary or secondary prophylactic therapy with colony-stimulating factors or other agents for high-risk individuals.