Neutropenic Fever

Neutropenia: An absolute neutrophil count less than 500 cells/mm3 or less than 1000 cells/mm3 with a predicted decline to less than 500 cells/mm3

ANC = WBC x (neutrophil% + band%)

Mild: 1000 – 1500

Mod: 500 – 1000

Severe: 100 – 500

Profound: <100

Background:

Neutrophils directly combat infection and are important to coordinating the body’s overall immune response.

The loss of these cells leads to immunosuppression as well as decreased responsiveness of the immune system as a whole

Patients with neutropenia will not only get very sick very quickly, but also will have blunted immune response and may not localize signs of infection well

Fever or malaise may be their only presenting symptoms.

Patients with hematologic malignancies are at highest risk for suffering profound and prolonged neutropenia. Particularly high risk are those undergoing induction chemotherapy or stem cell transplant. Allogeneic stem cell grafting is higher risk than autologous.

Neutropenic Fever: Fever (one reading of 38.3C or sustained 38.0C) + ANC < 500 cells/mm3 or expected to fall to < 500 cells/mm3 within the next 48 hours

Common problem during chemotherapy:

10-50% of patients with solid malignancy and >80% of patients with hematologic malignancy will experience at least one episode of neutropenia IDSA 2010 , Klastersky 2004 )

Associated with high morality:

Causes of Neutropenia Gibson 2014 ) :

Overconsumption Sepsis Autoimmune disease (SLE, rheumatoid arthritis, etc)

Underproduction by bone marrow Malnutrition – alcoholism, anorexia, etc Myelodysplastic syndrome Post-viral: varicella, measles, rubella, influenza, hepatitis, Epstein-Barr virus, HIV Drug induced: clozapine, methimazole, sulfasalazine, bactrim, b-lactam antibiotics, NSAIDs, ticlopidine, cephalosporins, chemotherapy



Chemotherapy:

Includes many drugs and drug regimens, all with the goal of killing rapidly dividing cells. Of note, this particularly affects: Cancer cells – this is the reason chemotherapy works as treatment Neutrophils – with a life cycle of only 1-6 days, their numbers are impacted dramatically by chemotherapy Mucosa – destruction of dividing cells thins mucosal barriers, putting these patients at high risk for mucositis and bacterial invasion



This creates a dangerous situation where the body’s barriers against bacterial invasion are broken down and, thus, the ability to combat infection is severely blunted. Antibiotics are effectively the only thing standing between these patients and overwhelming sepsis

Pathogens ( Gudiol 2013 ) :

The pathogens responsible for neutropenic fever have changed over time.

Initially, Gram (-) organisms translocated from the gut caused majority of cases of neutropenic fever

This changed in the 1990s. Gram(+) infections became more common due to more fluoroquinolone prophylaxis against Gram (-) organisms and due to more prevalent use of indwelling catheters for outpatient treatment

Over the past decade, there has been a resurgence of Gram (-) organisms due to increasing antibiotic resistance, particularly multidrug resistant E coli and klebsiella

Given the increasing rates of antibiotic resistance, antibiotic stewardship is becoming increasingly important

In the ED, we can contribute to antibiotic stewardship by checking old cultures and obtaining new ones prior to initiation of antibiotics

ED Evaluation and Management:

Resuscitate if necessary Patients with neutropenic fever may rapidly progress to septic shock Give appropriate fluids, vasopressors, and antibiotics Antibiotics need to be given as quickly as possible if unstable

Perform a complete review of systems and physical exam looking for signs of focal infection Basic Blood Work CBC, BMP, LFTs, bilirubin levels Blood cultures If indwelling catheter present: 1 set from each line of indwelling catheter + 1 peripheral set If no indwelling catheter present: 2x peripheral sets Additional testing based on signs and symptoms: Respiratory symptoms Chest X-Ray Sputum cultures Dysuria Urinalysis Urine culture Abdominal pain CT abdomen and pelvis If diarrhea present, consider C difficile PCR (if available)

Isolation Good hand hygiene is the most effective way to prevent these patients obtaining nosocomial infections Use standard barrier precautions Keep anyone with potentially communicable illness out of the patient’s room – visitors, other patients, or healthcare workers Any stem cell transplant patient should be in a private room. If they have an allogenic transplant, use a HEPA filter with >12 air exchanges per hour Isolation is important for neutropenic patients, but do not let waiting on an isolation room delay obtaining cultures and initiating antibiotics

Specific Pathologies Mucositis Mucositis is a high risk feature indicative of bacterial invasion through thinned mucus membrane barriers Signs and Symptoms Oral pain, erythema, edema, or lesions Sinus pain or pressure Rectal pain or lesions, any swelling suggestive of perirectal abscess Abdominal pain Inspect the rectum for swelling possibly indicative of perirectal abscess. Digital rectal exam is generally discouraged due to concern of inducing bacteremia if mucus membranes are damaged in the process ( CDC 2005 )



Neutropenic Enterocolitis (Typhlitis) A feared complication of neutropenic fever is direct bacterial invasion of the intestinal mucosa causing necrotizing infection Most commonly at the ileocecal junction It presents with classic triad of neutropenia, fever, and RLQ pain . Mortality approaches 50% when present Gorschlüter 2005 ) Surgery is avoided unless the bowel perforates, as these patients have poor wound healing and high surgical complication rates



Determine whether the patient is high or low risk High Risk Factors HD instability Hematologic malignancy Uncontrolled or widespread malignancy Induction chemotherapy / hematopoietic stem cell transplant ANC <100 >7 days of ANC <500 Medical comorbidities (particularly COPD, cardiac disease, or diabetes) Low Risk Factors HD stable Solid tumor malignancy ANC >500 Neutropenia expected to last <7 days No comorbidities MASCC and CISNE risk calculators MASCC ( MASCC Score) Low risk = 21-26 High risk = <21 The MASCC Score will identify more patients as low risk, but will have more treatment failures / bounce-backs than the CISNE score Ahn 2017 , Coyne 2016 )



CISNE Score ( CISNE Score) Low risk = 0 Intermediate risk = 1-2 High risk = 3-8



The CISNE score will identify fewer patients as low risk, but will result in fewer treatment failures/bounce-backs than the MASCC score Ahn 2017 , Coyne 2016 ) Default to using whichever score your oncologist is more comfortable with

Antibiotic Selection Check old cultures for prior infections and sensitivities (if available). Follow your hospital’s protocol (if available). This will have been formulated based on local resistance patterns and likely with input from your institution’s oncologists. High Risk Patients will need hospitalization and IV antibiotics. General approach for IV antibiotic therapy Begin with single broad spectrum agent which includes pseudomonas coverage such as cefepime, piperocillin-tazobactam, or a carbepenem Penicillin allergies other than anaphylaxis are not considered a contraindication to the use of cephalosporins such as cefepime If patient has anaphylactic reaction to penicillins, consider broad coverage with ciprofloxacin plus clindamycin or aztreonam plus vancomycin ( IDSA 2010 ) Do not routinely start vancomycin. Add vancomycin if there is clinical suspicion for Gram (+) infection Signs of mucositis or cellulitis Indwelling catheter present on arrival Prior MRSA infection Patient already on Gram (-) prophylaxis such as fluoroquinolone Consider adding additional agents for unstable patients, or patients in which antibiotic resistant organisms are suspected (patient has known colonization or patient population has high endemic rates) MRSA: vancomycin, linezolid, or daptomycin VRE: linezolid or daptomycin Extended spectrum beta lactamase (ESBL) producing orgamisms: carbapenem Carbapenemase producing organisms (such as klebsiella): polymixin-colistin or tigecycline If there is clinical suspicion for influenza (or positive PCR testing), treatment with oseltamivir is recommended Other antiviral and antifungal agents should NOT be started routinely Antiviral + Antifungal Therapies Only start antiviral or antifungal therapies if the patient has a known viral or fungal infection (ex: patient spikes a fever while already on antifungal treatment) or if they have a clinical picture strongly suggestive of viral or fungal etiology Antifungals are generally not initiated until a patient has had >4 days of fever unresponsive to antibiotic treatment with no clear source identified Low risk patients If the patient has no high risk features, is found to be low risk on MASCC or CISNE scoring, and has good oncology follow-up, it may be preferable to discharge them home with 24hr oncology followup Send patients home ONLY after discussion with the patient’s oncologist and only if there are no high risk features present Outpatient antibiotic choice Ciprofloxacin plus amoxicillin-clavulanate is recommended by IDSA guidelines for oral empiric therapy ( IDSA 2010 ) Levofloxacin or ciprofloxacin monotherapy, or ciprofloxacin plus clindamycin are less well studied but are commonly used Avoid fluoroquinolones if the patient is already on fluoroquinolone prophylaxis



Take Home Points:

There are many causes of neutropenia, chemotherapy being by far the most dangerous

Febrile neutropenia is a condition conveying high mortality. Early administration of antibiotics is the only factor known to reduce this mortality

For a patient with neutropenic fever, remember that the body’s own flora is the greatest danger. Isolate, but do not wait to initiate treatment

Check old blood cultures and obtain new cultures prior to starting treatment

Identify low risk patients and send them home with PO antibiotics and close oncology follow-up in conjunction with your oncologist

Guest Post By

Joseph Bennett, MD

PGY3 Resident

NYU/Bellevue Emergency Medicine Residency

For More on This Topic Checkout:

References:

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Post Peer Reviewed By: Salim R. Rezaie, MD (Twitter: @srrezaie) and Anand Swaminathan, MD (Twitter: @EMSwami)