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. REBEL Core Cast 122.0 – Neutropenic Fever Click here for Direct Download of the Podcast. Neutropenia and 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: 80% of patients with hematologic malignancy will experience at least one episode of neutropenia (IDSA 2010, Klastersky 2004) Associated with high morality: ~90% without antibiotics (Perron 2014, Klastersky 2009) ~2-21% when treated with early antibiotics (Clarke 2011, Kruderer 2006) Higher mortality rates with co-morbidities and hematologic malignancies Time to antibiotic administration has been shown to directly impact mortality (Perron 2014, Rosa 2014, Marín 2015) 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 CXR 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 No plants in the treatment room or nurse’s station 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 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 7 days of ANC 500 Neutropenia expected to last 4 days of fever unresponsive to antibiotic treatment with no clear source identified Low risk 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 follow-up 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. Read More: Infectious Disease Society of America 2010 Clinical Practice Guidelines Life in the Fast Lane: Febrile Neutropaenia Uptodate: overview of neutropenic fever syndromes EMRAP: Risk stratification of neutropenic fever MDCalc: MASCC Score MDCalc: CISNE Score References: Ahn S, Rice TW, Yeung SJ, Cooksley T. Comparison of the MASCC and CISNE scores for identifying low-risk neutropenic fever patients: analysis of data from three emergency departments of cancer centers in three continents. Support Care Cancer. 2018 May;26(5):1465-1470. doi: 10.1007/s00520-017-3985-0. Epub 2017 Nov 22. Clarke, R. T., Warnick, J., Stretton, K., Littlewood, T. J., Improving the immediate management of neutropenic sepsis in the UK: Lessons from a national audit. British Journal of Haematology. 2011 Jun;153(6):773-9. doi: 10.1111/j.1365-2141.2011.08693.x. Epub 2011 Apr 22 Coyne CJ, Le V, Brennan JJ, Castillo EM, Shatsky RA, Ferran K, Brodine S, Vilke GM. Application of the MASCC and CISNE Risk-Stratification Scores to Identify Low-Risk Febrile Neutropenic Patients in the Emergency Department. Ann Emerg Med. 2017 Jun;69(6):755-764. doi: 10.1016/j.annemergmed.2016.11.007. Epub 2016 Dec 29. Ellis M. Febrile Neutropenia. Annals of New York Academy of Sciences. 2008 Sep;1138:329-50. doi: 10.1196/annals.1414.035. Freifeld, A. G., Bow, E. J., Sepkowitz, K. A., Boeckh, M. J., Ito, J. I., Mullen, C. A., Raad, II, et al., Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america, Clinical Infectious Diseases, 2011, 52(4):e56-93. Gibson C, Berliner N. How we evaluate and treat neutropenia in adults. Blood. 2014 Aug 21;124(8):1251-8; quiz 1378. doi: 10.1182/blood-2014-02-482612. Epub 2014 May 28. Gorschlüter M, Mey U, Strehl J, et al. Neutropenic enterocolitis in adults: systematic analysis of evidence quality. Eur J Haematol 2005; 75:1. Gudiol C, Bodro M, Simonetti A, et al. Changing aetiology, clinical features, antimicrobial resistance, and outcomes of bloodstream infection in neutropenic cancer patients. Clin Microbiol Infect 2013; 19:474 Klastersky J. The changing face of febrile neutropenia-from monotherapy to moulds to mucositis. Why empirical therapy? J Antimicrob Chemother. 2009;14(Suppl 1):i14–i15 Klastersky J. Management of fever in neutropenic patients with different risks of complications. Clin Infect Dis. 2004;39(Suppl. 1):S32–S37 Ku
