Continuing Education Activity

Neutropenic fever is defined as a single oral temperature greater than or equal to 101 F (38.3 C) or a temperature greater than or equal to 100.4 F (38 C) for at least an hour, with an absolute neutrophilic count (ANC) of less than 1500 cells/microliter. In most cases, the infectious etiology cannot be determined and gets marked as a fever of unknown origin (FUO). In severe neutropenia, the absolute neutrophil count (ANC) is less than 500 per microliter. Febrile neutropenia is the most common serious and common complication of cancer therapy. This activity reviews the management and highlights the tools needed by an interprofessional team to evaluate patients with febrile neutropenia properly.

Objectives:

• Review the etiology of febrile neutropenia.
• Identify indexes used to assess patients with febrile neutropenia.
• Describe the workup for patients with febrile neutropenia.
• Explain the importance of communication and urgency amongst the interprofessional team to improve the outcome in patients with febrile neutropenia.

Introduction

Neutropenic fever is when there is a single oral temperature greater than or equal to 101 F (38.3 C) or a temperature greater than or equal to 100.4 F (38 C) for at least an hour, with an absolute neutrophilic count (ANC) of less than 1500 cells/microliter.[1] In severe neutropenia, the ANC is less than 500 per microliter. In profound neutropenia, the ANC is less than 100 cells/microliter.[2] The risk of bacteremia increases with profound neutropenia. To calculate ANC, multiply the total white blood cell (WBC) count by the percentage of polymorphonuclear cells (PMNs) and band neutrophils.[3]

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

Following hematological terms are commonly employed to classify abnormal neutrophil counts:

• ANC <200 cells/microL: agranulocytosis
• Neutropenia for > three months: chronic neutropenia
• Neutropenia without associated anemia and/or thrombocytopenia: isolated neutropenia
• Reduced number of neutrophils, eosinophils, and basophils: granulocytopenia

Etiology

In most cases, the infectious etiology cannot 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. 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.[4] 

Most infections are bacterial, but viral or fungal etiology is possible. Common bacterial pathogens include gram-positive bacteria infections such as Staphylococcus, Streptococcus, and Enterococcus species. Drug-resistant organisms, including Pseudomonas aeruginosa, Acinetobacter species, Stenotrophomonas maltophilia, Escherichia coli, and Klebsiella species, have also been identified as infectious agents.

Other causes of neutropenia can be described as follows:

• Congenital neutropenia: It is suspected in adults with severe neutropenia (<500 cells/microL) along with a history of somatic findings (e.g., premature graying of the hair, pancreatic dysfunction, abnormalities of fingernails or skeleton).
• Drugs: Besides chemotherapeutic agents, the following list includes common drugs that may contribute to neutropenia.
  • Antibiotics
    • Macrolides
    • Vancomycin
    • Chloramphenicol
    • Trimethoprim-sulfamethoxazole
    • Sulfonamides
  • Antimalarials
    • Hydroxychloroquine
    • Amodiaquine
    • Quinine
  • Anti-inflammatory drugs
    • Nonsteroidal anti-inflammatory drugs
    • Penicillamine
    • Leflunomide
    • Methotrexate
    • Gold salts
    • Sulfasalazine
  • Psychotropic drugs
    • Tricyclic and tetracyclic antidepressants
    • Clozapine
    • Phenothiazines
  • Antithyroid drugs (thionamides)
    • Propylthiouracil
    • Methimazole
    • Carbimazole
  • Cardiovascular drugs
    • ACE inhibitors (enalapril, captopril)
    • Antiarrhythmic agents (tocainide, procainamide, flecainide)
    • Propranolol
    • Digoxin
    • Dipyridamole
  • Antiseizure medications
    • Ethosuximide
    • Carbamazepine
    • Phenytoin
• Nutritional deficiency: 
  • Severe vitamin B12, folate, or copper deficiency can also result in neutropenia.

Epidemiology

The specific frequency of agranulocytosis is unknown; It is estimated to be 1.0 to 3.4 cases per million people annually. Neutropenia was particularly associated with HIV infection, acute leukemias, and myelodysplastic syndromes. Drug-induced neutropenia has an incidence of one case per million persons per year. About 50% of patients with febrile neutropenia will develop an infection, of which 20% with profound neutropenia will observe bacteremia.

Gram-positive bacteria have now become the most common pathogens causing febrile neutropenia.[5] A lot of these infections are contributed by long-term indwelling central venous catheters.[6] Although there is a slight trend toward Gram-negative bacteria, the ratio of gram-positive to gram-negative bacteria as the cause of bacteremia in patients with cancer is approximately 60 to 40.[7] Among gram-positive bacteria, Staphylococcus aureus (particularly methicillin-resistant strains), enterococci (particularly vancomycin-resistant strains), and some viridans streptococci can cause serious infections.[5]

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. Patients lose or have weakened immunity to fend off infections in this immunocompromised state. 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.[8] About 1% of patients undergoing chemotherapy and radiation experience this complication.[9]

History and Physical

A detailed history of the patient presenting illness, chemotherapy treatment, medication use, previous history of infections, especially with bacterial-resistant organisms, and allergies, should be noted to guide your therapy.[9] 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.

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.[9] If diarrhea is present, a sample may be checked. If the patients have any respiratory symptoms, a chest x-ray is necessary.

Table 1. Bacteria cultured in febrile neutropenia

Additional testing may be required in some instances:

• For example, Galactomannan may be performed on patient serum, or bronchoalveolar lavage samples may serve as a diagnostic biomarker of fungal infections.
• 1,3-beta-D-glucan (BDG) is a fungal-specific cell wall component and may serve as a diagnostic biomarker of fungal infections.
• Procalcitonin, though still under investigation, may have moderate diagnostic accuracy for the detection of bacteremia in patients with sepsis.[10]
• Patients with unknown chest infiltrate on imaging may benefit from the culture of BAL fluid.[2]

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 risk-stratify patients into high-risk and low-risk neutropenic fever.

The MASCC was created the assess the risk of severe 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 less than 21 are high risk.[11]

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 low-risk patients classification is the CISNE which may be more useful in the emergency department setting. 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 for severe 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 / Management

Management is guided by whether the patients are high-risk or low-risk. Patients with the following are considered as high risk:

• Receipt of cytotoxic therapy sufficiently myelosuppressive to result in anticipated severe neutropenia (ANC <500 cells/mcL) for >7 days
• CISNE score of ≥3
• MASCC risk index score <21
• Active uncontrolled comorbid medical problems
• Uncontrolled or progressive cancer
• Evidence of hepatic insufficiency (aminotransferase levels >5 times normal values) or renal insufficiency (creatinine clearance of <30 mL/minute)
• Use of alemtuzumab or CAR-T cell within the past two months

In the outpatient setting, oral empiric therapy with fluoroquinolone plus amoxicillin/clavulanate is recommended in low-risk patients. Ciprofloxacin 500-750 mg orally every 12 hours and amoxicillin/clavulanate 500 mg orally every 8 hours is a common empiric regime.

Clindamycin can be used for those with penicillin allergies. If the patient remains febrile for 48 to 72 hours, the patient will require admission.[12]

For high-risk patients presenting with neutropenic fever, intravenous antibiotic therapy should be given within 1 hour after triage and 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/tazobactam.[12] The usual recommended dosages are as follows:

• Cefepime or ceftazidime: 2 g IV every 8 hours or
• Piperacillin/tazobactam: 4.5 g IV every 6 to 8 hours or
• Antipseudomonal carbapenems:
  • Imipenem-cilastatin: 500 mg IV every 6 hours
  • Meropenem standard: 1 to 2 g IV every 8 hours

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.[13] If patients do not respond to treatments, coverage should be expanded to include resistant species:[12][1]

• 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

Empiric antifungal coverage is advised in high-risk patients with persistent fever after 4 to 7 days of broad-spectrum antibacterial regimen and suspicion of fungal infection.

Appropriate antibiotics may be continued until the ANC is ≥ 500 cells/mm or when the infection is cleared. If the patients remain neutropenic after the appropriate treatment course is completed and oral fluoroquinolone prophylaxis with the resolution of all signs and symptoms of documented infection is resumed until marrow recovery.

Recommendation for prevention of infection in neutropenic patients:[14]

• Fluoroquinolones as prophylaxis for patients who are at high risk[15]
• 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.[16]
• Yearly influenza vaccination is recommended for all patients receiving chemotherapy.
• Treatment with a nucleoside reverse transcription inhibitor is recommended for patients at high risk of hepatitis B virus reactivation.
• Herpes simplex virus- seropositive patients undergoing allogeneic HSCT or leukemia induction therapy should receive prophylaxis.
• Patients with a ≥ 20% risk of febrile neutropenia may benefit from using colony-stimulating factors.

The National Comprehensive Cancer Network (NCCN) guidelines recommend that patients at a high risk of neutropenic fever can benefit from granulocyte-colony stimulating factors (G-CSFs).[17]

Differential Diagnosis

• Transfusion reaction
• Medication allergies and toxicities
• Tumor-related fever
• Thrombophlebitis
• Resorption of blood from large hematoma[2]  
• Viral infections
• Invasive fungal infections

Prognosis

Researchers have several prognostic factors, and there is controversy surrounding prognostic factors. Hematological parameters, prophylactic measurements, and individual patient risk factors have yielded inconsistent results. The MASCC risk-index score, originally designed to identify low-risk patients, showed a lower MASCC score correlated with a poorer prognosis of febrile neutropenia. Very low levels (<15) demonstrated a high rate of complications. Patients with severe sepsis and septic shock commonly had procalcitonin concentrations greater than 2.0 ng/ml, which merits consideration for an increased likelihood of poor prognosis.[18]

Complications

Most patients with chemotherapy-induced febrile neutropenia recover rapidly without serious complications. However, it remains life-threatening, treatment-related toxicity and correlates with chemotherapy dose reductions and delays in continuing chemotherapy, potentially compromising treatment outcomes, leading to shock and death.

Deterrence and Patient Education

Chemotherapy patients should be counseled regarding the potential for developing febrile neutropenia, including education on the symptoms for which they must watch. If they develop neutropenia, they need to avoid exposure to persons with respiratory infections, as well as crowded places. If their ANC falls below 1000/microL, they should wear a facemask in public places. Taking their temperature daily is also recommended, especially if they develop symptoms such as chills, sweats, or feeling feverish.

Enhancing Healthcare Team Outcomes

Febrile neutropenia is an oncological emergency that requires a team of infectious disease specialists, emergency medicine, oncology, pharmacy, and specialty-trained nurses and pharmacists for proper management, working as a collaborative interprofessional team. [Level 5] The most important determining factor of patient outcomes is the timing of administrating IV antibiotics. Early admission of antibiotics has been shown to reduce mortality and the hospital length of these patients.[19][20] [Level 3] Infectious disease specialists can coordinate with infectious disease-specialized pharmacists to enact the most effective antimicrobial therapy. Nurses will administer the medication.

All staff members should have a heightened sense of urgency when interviewing patients undergoing chemotherapy presenting with new-onset fever. As mentioned above, the pharmacist should assist the team with antibiotic selection and dosing. The nursing staff should monitor the patient and report any concerns or changes in condition to the team. The best outcomes are achieved by an interprofessional team approach to diagnosing and managing this life-threatening condition. [Level 5]