Neutropenic Fever – Causes, Symptoms, Treatment

Neutropenic Fever is when there is a single oral temperature of greater than or equal to 101 F, or a temperature greater than or equal to 100.4 F for at least an hour, with an absolute neutrophilic count (ANC) of less than 1500 cells/microliter.[rx] In severe neutropenia, the ANC is less than 500 per microliter or ANC that is expected to decrease below 500 cells/microL in the next 2 hours. In profound neutropenia, the ANC is less than 100 cells/microliter. To calculate ANC, multiply the total white blood cell (WBC) count by the percentage of polymorphonuclear cells (PMNs) and band neutrophils.[rx]

Febrile Neutropenia is the development of fever, often with other signs of infection, in a patient with neutropenia, an abnormally low number of neutrophil granulocytes (a type of white blood cell) in the blood. The term neutropenic sepsis is also applied, although it tends to be reserved for patients who are less well. In 50% of cases, an infection is detectable; bacteremia (bacteria in the bloodstream) is present in approximately 20% of all patients with this condition.^[rx]

Pathophysiology

Neutropenic fever is the most common and serious complication associated with hematopoietic cancers or with patients receiving chemotherapeutic regimens for cancer. Neutropenic fever occurs when a neutropenic patient encounters an infectious pathogen. In this immunocompromised state, patients lose or have weakened immunity to fend off infections. The host barriers, such as the mucosal lining of the GI tract or sinuses, may be damaged, leading the host, open to invasion from an infectious pathogen.[rx About 1% of patients undergoing chemotherapy and radiation experience this complication.[rx]

Causes of Neutropenic Fever

Febrile neutropenia can develop in any form of neutropenia, but is most generally recognized as a complication of chemotherapy when it is myelosuppressive (suppresses the bone marrow from producing blood cells)

In the majority of cases, the infectious etiology is unable to be determined and gets marked as a fever of unknown origin (FUO). The definition of FUO is neutropenic cases with a fever greater than 38.3 C, without any clinically or microbiologically defined infection.[rx][rx] Documented infections only comprise approximately 30% of cases. However, infections are the primary cause of morbidity and mortality in patients with cancer who present with fever and neutropenia.[rx] The majority of infections are bacterial, but viral or fungal etiology is possible.[rx] Common bacterial pathogens include gram-positive bacteria infections such as Staphylococcus, Streptococcus, and Enterococcus species.[rx] Drug-resistant organisms, including Pseudomonas aeruginosa, Acinetobacter species, Stenotrophomonas maltophilia, Escherichia coli, and Klebsiella species, have also been identified as infectious agents.

Symptoms of Neutropenic Fever

For people with neutropenia, even a minor infection can quickly become serious. Talk with your health care team right away if you have any of these signs of infection:

• A fever, which is a temperature of 100.5°F (38°C) or higher
• Chills or sweating
• Sore throat, sores in the mouth, or a toothache
• Abdominal pain
• Pain near the anus
• Pain or burning when urinating, or urinating often
• Diarrhea or sores around the anus
• A cough or shortness of breath
• Any redness, swelling, or pain (especially around a cut, wound, or catheter)
• Unusual vaginal discharge or itching
• pneumonia
• sinus infections
• otitis media, or an ear infection
• gingivitis, or gum inflammation
• omphalitis, or navel infection
• skin abscesses

Diagnosis of Neutropenic Fever

History and Physical

A detailed history of the patients presenting illness, chemotherapy treatment, medication use, previous history of infections, especially with bacterial resistant organisms, and the presence of allergies, should be noted to guide your therapy.[rx] Signs of infection may require assessment; Pain and tenderness may be the only indicators of infection. Significant risk factors for the development of febrile neutropenia include older age, comorbidities, the specific type of cancer, and the type and number of myelosuppressive chemotherapy agents in use.[rx]

Evaluation

Lab tests should be ordered; complete blood count to determine the patient’s neutropenic level; blood, urinalysis, and throat cultures are needed to determine the source of infection. Two sets of blood cultures should be obtained from a peripheral vein and any venous catheters as well as specimens for testing from any sites of infection, before the immediate administration of empirical broad-spectrum antimicrobial therapy. Urinary tract infections should be suspected in asymptomatic patients with a history of such infections.[rx] If diarrhea is present, a sample may be checked. If the patients have any respiratory symptoms, a chest x-ray is necessary.

Two widely used assessment tools, The Multinational Association for Supportive Care in Cancer (MASCC) and The Clinical Index of the Stable Febrile Neutropenia (CISNE), can be part of the patient interview. These tools can help to risk-stratify patients into high risk and low-risk neutropenic fever.

The MASCC was created the assess the risk of serious complications in patients with neutropenic fever. The MAASC index has a max score of 26. Patients with a score greater than 21 are considered low risk, and patients less than 21 are high risk.[rx]

MASCC Scoring Index

Characteristic/Score

• The burden of illness: no or mild symptoms/5
• The burden of illness: none or mild/5
• The burden of illness: moderate symptoms/3
• The burden of illness: severe symptoms/0
• No hypotension (systolic BP greater than 90 mmHg)/5
• No chronic obstructive pulmonary disease/4

Type of Cancer

• Solid tumor/4
• Lymphoma with previous fungal infection/4
• Hematologic with previous fungal infection/4
• No dehydration/4
• Outpatient status (at the onset of fever)/3
• Age less than 60 years/2

A more specific scale for classification of low-risk patients is the CISNE and may be more useful in the emergency department setting.[rx] One of the components of the scale is the Eastern Cooperative Oncology Group (ECOG) Performance Status, which helps determines the patient’s functional status as a surrogate for the patient’s ability to undergo therapies in serious illnesses.

The Clinical Index of Stable Febrile Neutropenia Score

Characteristics/Score

• ECOG performance status (greater than 2)/2
• Chronic obstructive pulmonary disease (COPD)/1
• Stree-induced hyperglycemia/2
• Chronic cardiovascular disease/1
• Monocytes less than 200 per mcL/1
• Grade greater than or equal to 2 mucositis/1
• Interpretation

CISNE/Recommendation

• 0-2/Consider outpatient management with oral antibiotics
• Greater than or equal to 3/inpatient management

Treatment of Neutropenic Fever

Guidelines issued in 2002 by the Infectious Diseases Society of America recommend the use of particular combinations of antibiotics in specific settings; mild low-risk cases may be treated with a combination of oral amoxicillin-clavulanic acid and ciprofloxacin, while more severe cases require cephalosporins with activity against Pseudomonas aeruginosa (e.g. cefepime), or carbapenems (imipenem or meropenem).^[rx] A subsequent meta-analysis published in 2006 found cefepime to be associated with more negative outcomes, and carbapenems (while causing a higher rate of pseudomembranous colitis) were the most straightforward in use.^[rx]

In 2010, updated guidelines were issued by the Infectious Diseases Society of America, recommending use of cefepime, carbapenems (meropenem and imipenem/cilastatin), or piperacillin/tazobactam for high-risk patients and amoxicillin-clavulanic acid and ciprofloxacin for low-risk patients. Patients who do not strictly fulfill the criteria of low-risk patients should be admitted to the hospital and treated as high-risk patients.

In low-risk patients, oral empiric therapy with a fluoroquinolone plus amoxicillin/clavulanate is recommended in the outpatient setting.[rx] Clindamycin can be used for those with penicillin allergy. If the patient remains febrile for 48 to 72 hours, the patient will require admission.[rx]

For high-risk patients presenting with neutropenic fever, an intravenous antibiotic therapy should be given within 1 hour after triage and be monitored more than 4 hours before discharge. The Infectious Disease Society of America (IDSA) recommends monotherapy with antipseudomonal beta-lactam agents such as cefepime, carbapenems, or piperacillin and tazobactam. [rx] Vancomycin is not recommended for initial therapy but should be considered if suspecting catheter-related infection, skin or soft tissue infections pneumonia, or hemodynamic instability.[rx] If patients do not respond to treatments, coverage should be expanded to include resistant species[rx][rx][rx][rx][rx]:

• Methicillin-resistant Staphylococcus aureus (MRSA): vancomycin, linezolid, and daptomycin
• Vancomycin-resistant enterococci (VRE) – linezolid and daptomycin
• Extended-spectrum beta-lactamase (ESBL) – producing organisms: carbapenems
• Klebsiella pneumoniae – carbapenems, polymyxin, colistin, or tigecycline

Recommendation for prevention of infection in neutropenic patients:

• Fluoroquinolones as prophylaxis for patients who are high risk
• Antifungal prophylaxis with an oral triazole with patients with profound neutropenia
• Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended treatment for patients receiving chemotherapy regimens associated with greater than 3.5% risk for pneumonia from Pneumocystis jirovecii
• Yearly influenza vaccination is recommended for all patients receiving chemotherapy
• Treatment with a nucleoside reverse transcription inhibitor is recommended for patients who are at high risk of hepatitis B virus reactivation
• Herpes simplex virus- seropositive patients undergoing allogeneic HSCT or leukemia induction therapy should receive prophylaxis

In the National Comprehensive Cancer Network (NCCN) guidelines, it is recommended that patients that are at a high risk of neutropenic fever can benefit from granulocyte-colony stimulating factors (G-CSFs).[15]

Application of granulocyte-colony stimulating factor (G-CSF) can improve neutrophil functions and numbers.[rx][rx] Prophylactic use of antibiotics and antifungals is reserved for some forms of alteration in neutrophil function such as chronic granulomatous disease CGD).[rx][rx] The utilization of antimicrobials is compulsory if recurrent infections exist. Interferon-gamma has been successfully used to improve the quality of life of the patient suffering from neutropenia. Allogenic bone marrow transplantation from an HLA-matched related donor can cure CGD but has a high mortality rate [rx], and gene therapy is also a therapeutic option for treating disorders with neutropenia. Furthermore, intravenous immunoglobulins can be another option in the management of these disorders.[rx]

Recombinant granulocyte-colony stimulating factor preparations, such as filgrastim^[rx] can be effective in people with congenital forms of neutropenia including severe congenital neutropenia and cyclic neutropenia;^[rx] the amount needed (dosage) to stabilize the neutrophil count varies considerably (depending on the individual’s condition).^[rx]

Guidelines for neutropenia regarding diet are currently being studied.^[rx]

Most cases of neonatal neutropenia are temporary. Antibiotic prophylaxis is not recommended because of the possibility of encouraging the development of multidrug-resistant bacterial strains.^[rx]

Neutropenia can be treated with hematopoietic growth factors, granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). These are cytokines (inflammation-inducing chemicals) that are present naturally in the body. These factors are used regularly in cancer treatment with adults and children. The factors promote neutrophil recovery following anticancer therapy.^[rx]

The administration of intravenous immunoglobulins (IVIGs) has had some success in treating neutropenias of alloimmune and autoimmune origins with a response rate of about 50%. Blood transfusions have not been effective.^[rx]

If neutropenia is caused by medication, your doctor might tell you to stop the medication. If the cause is an underlying disease, that condition must be treated (as in the case of a vitamin deficiency). Your doctor might prescribe corticosteroids if you have an autoimmune disorder.

Patients with neutropenia caused by cancer treatment can be given antifungal drugs. A Cochrane review ^[rx] found that lipid formulations of amphotericin B had fewer side effects than conventional amphotericin B, though it is not clear whether there are particular advantages over conventional amphotericin B if given under optimal circumstances. Another Cochrane review ^[rx] was not able to detect a difference in effect between amphotericin B and fluconazole because available trial data analyzed results in a way that disfavoured amphotericin B.

Complications

• Recurrent and fatal bacterial and fungal infections[rx]
• Bacteremia
• Septic shock
• Premature death
• Failure to thrive
• Protein-energy malnutrition
• Multiorgan failure

How can you prevent infections if you have neutropenia?

Preventing infections if you have or are liable to develop neutropenia is key. These suggestions should help:

• Wash your hands frequently with soap and water. Wash your hands before and after you eat, after you use the toilet, after touching pets or things outside of your house, and after you cough or sneeze.
• Keep and use an alcohol-based hand sanitizer with you when you leave the house.
• Make sure you get the flu shot as early as you can, if your doctor says you can do this.
• Stay away from crowds of people and people who are sick.
• Do not share eating utensils, cups, food or beverages with other people.
• Do not share towels, razors or toothbrushes with other people.
• Wash raw fruits and vegetables.
• Keep raw meats, fish and poultry away from other foods.
• Use hot water and soap to clean the kitchen surfaces before you start cooking.
• Cook foods completely to the proper temperature.
• Use gloves if you are gardening in the dirt or working in the yard.
• It is best to not pick up pet waste. If you have to do so, use gloves. Wash your hands when you are done.
• Use a soft toothbrush to brush your teeth at least two times per day.
• Take a shower each day. Use lotion so your skin does not dry out and crack.
• Eat a healthy diet.
• Tell your doctor if you might need dental work so he or she can prescribe antibiotics before the work is done, if necessary.
• Do not get body piercings or tattoos.
• Do not swim in lakes or ponds.
• Avoid becoming constipated if you can.

Lifestyle precautions for people with neutropenia include:

• cleaning hands regularly, especially after using the toilet
• avoiding crowds and people who are ill
• not sharing personal items including toothbrushes, drinking cups, cutlery, or food
• bathing or showering daily
• cooking meat and eggs thoroughly
• not buying food in damaged packages
• cleaning the fridge thoroughly and not overfilling – doing so can raise the temperature
• carefully washing any raw fruit or vegetables or avoiding completely
• avoiding direct contact with pet waste and washing hands after handling any animals
• wearing gloves when gardening
• using a soft toothbrush
• using an electric shaver rather than a razor
• cleaning any wounds with warm water and soap and using antiseptic to clean the site
• wearing shoes outdoors
• not squeezing spots or picking scabs
• keeping surfaces clean
• getting the flu shot as soon as it becomes available

References