Neutropenic fever is a medical emergency defined as a single oral temperature of > 38.3 °C (101 °F) or a temperature of >38.0 °C (100.4 °F) sustained for >1 hour in neutropenic patients a patient with an absolute neutrophil count (ANC) < 1500 or 1000 cells/μL (also known as neutropenic patients). If the neutrophil count falls < 500 cells/μL (called “severe neutropenia”) and/or if the duration of neutropenia is >7 days, the risk of clinically important infection rises significantly. Neutropenic fever is a common life-threatening complication of hematologic malignancies and in patients undergoing chemotherapy. Patients are often asymptomatic, and the only sign is the presence of fever. Diagnosis should include a detailed history, physical examination, and routine laboratory tests, in addition to symptom-directed workup with cultures. Initial management includes the administration of empiric antibiotics adjusted according to clinical response and culture results.
Last updated: Sep 5, 2023
Neutropenic fever Neutropenic fever Neutropenic fever is a medical emergency defined as a fever > 38.3°C (100.9°F) or higher than 38.0°C (100.4°F) for more than 1 hour in neutropenic patients. Neutropenic fever is a common life-threatening complication of hematologic malignancies and in patients undergoing chemotherapy. Neutropenic Fever is defined as a single oral temperature > 38.3 ℃ (101 ℉) or a temperature > 38.0℃ (100.4℉) for at least 1 hour with an absolute neutrophil count Absolute neutrophil count The number of neutrophils (as opposed to the percentage of WBCs) circulating per µL of blood . Neutropenia (ANC) of < 1,500 cells/µL or an ANC that is expected to decrease to < 500 cells/µL during the next 48 hours.
In most cases, the source of infection is unknown (referred to as fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever of unknown origin (FUO)). The majority of documented infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease are bacterial.
The common sources of bacteremia Bacteremia The presence of viable bacteria circulating in the blood. Fever, chills, tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. Glycopeptides are:
Common bacterial pathogens:
Common fungal pathogens:
Common viral pathogens:
Other common pathogens:
The combination of the following factors contribute to the development of neutropenic fever Neutropenic fever Neutropenic fever is a medical emergency defined as a fever > 38.3°C (100.9°F) or higher than 38.0°C (100.4°F) for more than 1 hour in neutropenic patients. Neutropenic fever is a common life-threatening complication of hematologic malignancies and in patients undergoing chemotherapy. Neutropenic Fever:
Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia may minimize symptoms and signs of infection:[2,6,9]
The presence of fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever may be the only sign of an infection.
Measuring the temperature accurately is important, but clinical judgment Judgment The process of discovering or asserting an objective or intrinsic relation between two objects or concepts; a faculty or power that enables a person to make judgments; the process of bringing to light and asserting the implicit meaning of a concept; a critical evaluation of a person or situation. Psychiatric Assessment is crucial since fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever may not be present in all cases of infection.
All patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with febrile neutropenia Febrile neutropenia Fever accompanied by a significant reduction in the number of neutrophils. Neutropenic Fever should undergo a detailed history and physical examination, and diagnostic studies should be performed.
A detailed history should include:
A thorough physical examination should include an evaluation of:
The following information is based on current US, UK, and European literature and guidelines for adult patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship. Exact management protocols may vary based on location and institution.
|Burden of illness: no or mild symptoms||5|
|Burden of illness: moderate symptoms||3|
|Burden of illness: severe symptoms||0|
|No hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension||5|
|No chronic obstructive pulmonary disease Pulmonary disease Diseases involving the respiratory system. Blastomyces/Blastomycosis||4|
|Solid tumor Tumor Inflammation or hematologic malignancy Malignancy Hemothorax with no previous fungal infection||4|
|No dehydration Dehydration The condition that results from excessive loss of water from a living organism. Volume Depletion and Dehydration requiring parenteral fluids||3|
|Age < 60 years||2|
|Risk-stratification tool||NCCN guidelines||IDSA and ASCO guidelines||NICE guidelines|
Empiric antibiotic therapy:[1,2,6,8,10]
Repeat cultures if:
Low-risk patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are treated as outpatients or initially as inpatients and then transferred to outpatient with close follow-up (oral antibiotic therapy).
|Levofloxacin Levofloxacin The l-isomer of ofloxacin. Fluoroquinolones||500–750 mg daily|
|Ciprofloxacin Ciprofloxacin A broad-spectrum antimicrobial carboxyfluoroquinoline. Fluoroquinolones||500–750 mg 2 times daily|
|Moxifloxacin Moxifloxacin A fluoroquinolone that acts as an inhibitor of DNA topoisomerase II and is used as a broad-spectrum antibacterial agent. Fluoroquinolones||400 mg daily|
|Amoxicillin Amoxicillin A broad-spectrum semisynthetic antibiotic similar to ampicillin except that its resistance to gastric acid permits higher serum levels with oral administration. Penicillins–clavulanate||Either:
|Clindamycin Clindamycin An antibacterial agent that is a semisynthetic analog of lincomycin. Lincosamides||Either:
High-risk patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship must be treated as inpatients (IV antibiotic therapy).
|Typical initial options||Cefepime Cefepime A fourth-generation cephalosporin antibacterial agent that is used in the treatment of infections, including those of the abdomen, urinary tract, respiratory tract, and skin. It is effective against pseudomonas aeruginosa and may also be used in the empiric treatment of febrile neutropenia. Cephalosporins||2 g every 8 hours|
|Ceftazidime Ceftazidime Semisynthetic, broad-spectrum antibacterial derived from cephaloridine and used especially for pseudomonas and other gram-negative infections in debilitated patients. Cephalosporins||2 g every 8 hours|
|Imipenem Imipenem Semisynthetic thienamycin that has a wide spectrum of antibacterial activity against gram-negative and gram-positive aerobic and anaerobic bacteria, including many multiresistant strains. It is stable to beta-lactamases. Clinical studies have demonstrated high efficacy in the treatment of infections of various body systems. Its effectiveness is enhanced when it is administered in combination with cilastatin, a renal dipeptidase inhibitor. Carbapenems and Aztreonam– cilastatin Cilastatin A renal dehydropeptidase-i and leukotriene d4 dipeptidase inhibitor. Since the antibiotic, imipenem, is hydrolyzed by dehydropeptidase-i, which resides in the brush border of the renal tubule, cilastatin is administered with imipenem to increase its effectiveness. The drug also inhibits the metabolism of leukotriene d4 to leukotriene e4. Carbapenems and Aztreonam||500 mg every 6 hours|
|Meropenem Meropenem A thienamycin derivative antibacterial agent that is more stable to renal dehydropeptidase I than imipenem, but does not need to be given with an enzyme inhibitor such as cilastatin. It is used in the treatment of bacterial infections, including infections in immunocompromised patients. Carbapenems and Aztreonam||Either:
|Piperacillin Piperacillin Semisynthetic, broad-spectrum, ampicillin derived ureidopenicillin antibiotic proposed for pseudomonas infections. It is also used in combination with other antibiotics. Penicillins– tazobactam Tazobactam A penicillanic acid and sulfone derivative and potent beta-lactamase inhibitor that enhances the activity of other anti-bacterial agents against beta-lactamase producing bacteria. Cephalosporins||Either:
|For MRSA MRSA A strain of Staphylococcus aureus that is non-susceptible to the action of methicillin. The mechanism of resistance usually involves modification of normal or the presence of acquired penicillin binding proteins. Staphylococcus coverage||Vancomycin Vancomycin Antibacterial obtained from streptomyces orientalis. It is a glycopeptide related to ristocetin that inhibits bacterial cell wall assembly and is toxic to kidneys and the inner ear. Glycopeptides||15 mg/kg every 12 hours|
|Daptomycin Daptomycin A cyclic lipopeptide antibiotic that inhibits gram-positive bacteria. Lipopeptides and Lipoglycopeptides||6 mg/kg/day (higher doses for specific infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease)|
|Linezolid Linezolid An oxazolidinone and acetamide derived anti-bacterial agent and protein synthesis inhibitor that is used in the treatment of gram-positive bacterial infections of the skin and respiratory tract. Oxazolidinones||600 mg every 12 hours|
|Aminoglycosides Aminoglycosides Aminoglycosides are a class of antibiotics including gentamicin, tobramycin, amikacin, neomycin, plazomicin, and streptomycin. The class binds the 30S ribosomal subunit to inhibit bacterial protein synthesis. Unlike other medications with a similar mechanism of action, aminoglycosides are bactericidal. Aminoglycosides for complicated disease/ resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing||Amikacin||15 mg/kg/day IV|
|Gentamicin Gentamicin Aminoglycosides||Either:
|Tobramycin||2 mg/kg IV every 8 hours|
|Antifungal Antifungal Azoles coverage||Amphotericin B Amphotericin B Macrolide antifungal antibiotic produced by streptomyces nodosus obtained from soil of the orinoco river region of venezuela. Polyenes liposomal complex||3–5 mg/kg every 24 hours|
|Voriconazole Voriconazole A triazole antifungal agent that specifically inhibits sterol 14-alpha-demethylase and cytochrome p-450 cyp3a. Azoles|
|Posaconazole Posaconazole Azoles|
|Caspofungin Caspofungin A cyclic lipopeptide echinocandin and beta-(1, 3)-d-glucan synthase inhibitor that is used to treat internal or systemic mycoses. Echinocandins|
|Micafungin Micafungin A cyclic lipo-hexapeptide echinocandin antifungal agent that is used for the treatment and prevention of candidiasis. Echinocandins|
|Antiviral Antiviral Antivirals for Hepatitis B coverage||Acyclovir Acyclovir A guanosine analog that acts as an antimetabolite. Viruses are especially susceptible. Used especially against herpes. Herpes Zoster (Shingles)|
Source of infection is identified:[1,2,6,7]
|Organism||Type of infection||Treatment duration|
|Bacterial||Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and soft tissue Soft Tissue Soft Tissue Abscess||5–14 days|
|Bloodstream||S. aureus S. aureus Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications. Staphylococcus||≥ 4 weeks after 1st negative blood culture|
|Other gram-positive Gram-Positive Penicillins organisms||7–14 days|
|Gram-negative organisms||7–14 days|
|Sinusitis Sinusitis Sinusitis refers to inflammation of the mucosal lining of the paranasal sinuses. The condition usually occurs concurrently with inflammation of the nasal mucosa (rhinitis), a condition known as rhinosinusitis. Acute sinusitis is due to an upper respiratory infection caused by a viral, bacterial, or fungal agent. Sinusitis||7–14 days|
|Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia||5–14 days|
|Fungal||Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis||≥ 2 weeks after 1st negative blood culture|
|Aspergillus Aspergillus A genus of mitosporic fungi containing about 100 species and eleven different teleomorphs in the family trichocomaceae. Echinocandins||12 weeks, minimum|
|Viral||HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 and 2||7–10 days|
|Influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza||5 days, minimum|
Source of infection unknown:[1,2,7]
|Factors||Associated with ↑ risk|
|Patient characteristics||Advanced age (≥ 65 years)|
|↓ Performance status|
|Previous neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia|
|Presence of mucositis Mucositis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis (GI and/or oral)|
|Comorbidities Comorbidities The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. St. Louis Encephalitis Virus|
|Lab findings||↓ Albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests|
|Type of malignancy Malignancy Hemothorax||Acute leukemia|
|High-grade lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum|
|Soft tissue Soft Tissue Soft Tissue Abscess sarcoma|
|Non-Hodgkin lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum|
|Advanced-stage malignancy Malignancy Hemothorax|
|Malignancy Malignancy Hemothorax that is not in remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches|
|Relapsed malignancy Malignancy Hemothorax|
|Treatment||High-dose therapy with:
|Rescue chemotherapy Chemotherapy Osteosarcoma|
|Remission-induction chemotherapy Chemotherapy Osteosarcoma|
Particular organisms to consider covering:[1,9]
|Antibiotics||Levofloxacin Levofloxacin The l-isomer of ofloxacin. Fluoroquinolones||500–750 mg daily|
|Ciprofloxacin Ciprofloxacin A broad-spectrum antimicrobial carboxyfluoroquinoline. Fluoroquinolones||500–750 mg 2 times daily|
|Antifungals||Fluconazole Fluconazole Triazole antifungal agent that is used to treat oropharyngeal candidiasis and cryptococcal meningitis in aids. Azoles||400 mg daily|
|Posaconazole Posaconazole Azoles||Either:
|Voriconazole Voriconazole A triazole antifungal agent that specifically inhibits sterol 14-alpha-demethylase and cytochrome p-450 cyp3a. Azoles||200 mg 2 times daily|
|Antivirals||Acyclovir Acyclovir A guanosine analog that acts as an antimetabolite. Viruses are especially susceptible. Used especially against herpes. Herpes Zoster (Shingles)||400–800 mg 2 times daily|
|Valacyclovir Valacyclovir A prodrug of acyclovir that is used in the treatment of herpes zoster and herpes simplex virus infection of the skin and mucous membranes, including genital herpes. Herpes Zoster (Shingles)||500 mg 2 times daily|
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