Fever and neutropenia
Fever in a neutropenic patient is an emergency and should be addressed immediately. Fever may be the only symptom of infection in neutropenic patients.[42]Heinz WJ, Buchheidt D, Christopeit M, et al. Diagnosis and empirical treatment of fever of unknown origin (FUO) in adult neutropenic patients: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO). Ann Hematol. 2017 Nov;96(11):1775-92.
https://www.doi.org/10.1007/s00277-017-3098-3
http://www.ncbi.nlm.nih.gov/pubmed/28856437?tool=bestpractice.com
See Febrile neutropenia.
Sepsis
Patients with febrile neutropenia are at risk of sepsis and septic shock.[43]Kochanek M, Schalk E, von Bergwelt-Baildon M, et al. Management of sepsis in neutropenic cancer patients: 2018 guidelines from the Infectious Diseases Working Party (AGIHO) and Intensive Care Working Party (iCHOP) of the German Society of Hematology and Medical Oncology (DGHO). Ann Hematol. 2019 May;98(5):1051-69.
http://www.ncbi.nlm.nih.gov/pubmed/30796468?tool=bestpractice.com
[44]Clarke RT, Jenyon T, van Hamel Parsons V, et al. Neutropenic sepsis: management and complications. Clin Med (Lond). 2013 Apr;13(2):185-7.
https://www.rcpjournals.org/content/clinmedicine/13/2/185
Sepsis is a spectrum of disease, where there is a systemic and dysregulated host response to an infection.[45]Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10.
https://jamanetwork.com/journals/jama/fullarticle/2492881
http://www.ncbi.nlm.nih.gov/pubmed/26903338?tool=bestpractice.com
Presentation ranges from subtle, non-specific symptoms (e.g., feeling unwell with a normal temperature) to severe symptoms with evidence of multi-organ dysfunction and septic shock. Patients may have signs of tachycardia, tachypnoea, hypotension, fever or hypothermia, poor capillary refill, mottled or ashen skin, cyanosis, newly altered mental state, or reduced urine output.[46]National Institute for Health and Care Excellence. Sepsis: recognition, diagnosis and early management. Mar 2024 [internet publication].
https://www.nice.org.uk/guidance/NG51
Sepsis and septic shock are medical emergencies.
Risk factors for sepsis include: age under 1 year, age over 75 years, frailty, impaired immunity (due to illness or drugs), recent surgery or other invasive procedures, any breach of skin integrity (e.g., cuts, burns), intravenous drug misuse, indwelling lines or catheters, and pregnancy or recent pregnancy.[46]National Institute for Health and Care Excellence. Sepsis: recognition, diagnosis and early management. Mar 2024 [internet publication].
https://www.nice.org.uk/guidance/NG51
Early recognition of sepsis is essential because early treatment improves outcomes.[46]National Institute for Health and Care Excellence. Sepsis: recognition, diagnosis and early management. Mar 2024 [internet publication].
https://www.nice.org.uk/guidance/NG51
[47]Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021 Nov 1;49(11):e1063-143.
https://journals.lww.com/ccmjournal/fulltext/2021/11000/surviving_sepsis_campaign__international.21.aspx
[Evidence C]862cc978-2e83-4095-9382-6fbc3767c00aguidelineCWhat are the effects of early versus late initiation of empiric antimicrobial treatment in children with or at risk of developing sepsis or severe sepsis?[46]National Institute for Health and Care Excellence. Sepsis: recognition, diagnosis and early management. Mar 2024 [internet publication].
https://www.nice.org.uk/guidance/NG51
[Evidence C]00c00649-f907-49dc-85e3-cf84bbcf7383guidelineCWhat are the effects of early versus late initiation of empiric antimicrobial treatment in adults with or at risk of developing sepsis or severe sepsis?[46]National Institute for Health and Care Excellence. Sepsis: recognition, diagnosis and early management. Mar 2024 [internet publication].
https://www.nice.org.uk/guidance/NG51
However, detection can be challenging because the clinical presentation of sepsis can be subtle and non-specific. A low threshold for suspecting sepsis is therefore important. The key to early recognition is the systematic identification of any patient who has signs or symptoms suggestive of infection and is at risk of deterioration due to organ dysfunction. Several risk stratification approaches have been proposed. All rely on a structured clinical assessment and recording of the patient’s vital signs.[46]National Institute for Health and Care Excellence. Sepsis: recognition, diagnosis and early management. Mar 2024 [internet publication].
https://www.nice.org.uk/guidance/NG51
[48]Royal College of Physicians. National Early Warning Score (NEWS) 2. Dec 2017 [internet publication].
https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2
[49]American College of Emergency Physicians (ACEP) Expert Panel on Sepsis. DART: an evidence-driven tool to guide the early recognition and treatment of sepsis and septic shock [internet publication].
https://poctools.acep.org/POCTool/Sepsis(DART)/276ed0a9-f24d-45f1-8d0c-e908a2758e5a
[50]Academy of Medical Royal Colleges. Statement on the initial antimicrobial treatment of sepsis. May 2022 [internet publication].
https://www.aomrc.org.uk/reports-guidance
[51]Schlapbach LJ, Watson RS, Sorce LR, et al. International consensus criteria for pediatric sepsis and septic shock. JAMA. 2024 Feb 27;331(8):665-74.
https://jamanetwork.com/journals/jama/fullarticle/2814297
http://www.ncbi.nlm.nih.gov/pubmed/38245889?tool=bestpractice.com
It is important to check local guidance for information on which approach your institution recommends. The timeline of ensuing investigations and treatment should be guided by this early assessment.[50]Academy of Medical Royal Colleges. Statement on the initial antimicrobial treatment of sepsis. May 2022 [internet publication].
https://www.aomrc.org.uk/reports-guidance
Treatment guidelines have been produced by the Surviving Sepsis Campaign and remain the most widely accepted standards.[47]Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021 Nov 1;49(11):e1063-143.
https://journals.lww.com/ccmjournal/fulltext/2021/11000/surviving_sepsis_campaign__international.21.aspx
[52]Surviving Sepsis Campaign. Hour-1 bundle: initial resuscitation for sepsis and septic shock. 2019 [internet publication].
https://www.sccm.org/SurvivingSepsisCampaign/Guidelines
Recommended treatment of patients with suspected sepsis is:
Measure lactate level, and remeasure lactate if initial lactate is elevated (>2 mmol/L [>18 mg/dL])
Obtain blood cultures before administering antibiotics
Administer broad-spectrum antibiotics (with methicillin-resistant Staphylococcus aureus [MRSA] coverage if there is high risk of MRSA) for adults with possible septic shock or a high likelihood for sepsis
For adults with sepsis or septic shock at high risk of fungal infection, empirical antifungal therapy should be administered
Begin rapid administration of crystalloid fluids for hypotension or lactate level ≥4 mmol/L (≥36 mg/dL). Consult local protocols
Administer vasopressors peripherally if hypotensive during or after fluid resuscitation to maintain mean arterial pressure (MAP) ≥65 mmHg, rather than delaying initiation until central venous access is secured. Noradrenaline is the vasopressor of choice
For adults with sepsis-induced hypoxaemic respiratory failure, high-flow nasal oxygen should be given.
Ideally these interventions should all begin in the first hour after sepsis recognition.[52]Surviving Sepsis Campaign. Hour-1 bundle: initial resuscitation for sepsis and septic shock. 2019 [internet publication].
https://www.sccm.org/SurvivingSepsisCampaign/Guidelines
For adults with possible sepsis without shock, if concern for infection persists, antibiotics should be given within 3 hours from the time when sepsis was first recognised.[47]Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021 Nov 1;49(11):e1063-143.
https://journals.lww.com/ccmjournal/fulltext/2021/11000/surviving_sepsis_campaign__international.21.aspx
For adults with a low likelihood of infection and without shock, antibiotics can be deferred while continuing to closely monitor the patient.[47]Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021 Nov 1;49(11):e1063-143.
https://journals.lww.com/ccmjournal/fulltext/2021/11000/surviving_sepsis_campaign__international.21.aspx
For more information on sepsis, please see our topics Sepsis in adults and Sepsis in children.
Agranulocytosis (absolute neutrophil count <0.1 x10⁹/L or <100 neutrophils/mm³)
Severe agranulocytosis requires urgent management. If a drug is suspected as the cause, it must be discontinued immediately. The most common drug causes are clozapine, antithyroid drugs (thionamides), and sulfasalazine.[17]Andersohn F, Konzen C, Garbe E. Systematic review: Agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med. 2007 May 1;146(9):657-65.
http://www.ncbi.nlm.nih.gov/pubmed/17470834?tool=bestpractice.com
[18]Theophile H, Begaud B, Martin K., et al. Incidence of agranulocytosis in Southwest France. Eur J Epidemiol. 2004;19(6):563-5.
http://www.ncbi.nlm.nih.gov/pubmed/15330129?tool=bestpractice.com
[19]van der Klauw MM, Goudsmit R, Halie MR, et al. A population-based case-cohort study of drug-associated agranulocytosis. Arch Intern Med. 1999 Feb 22;159(4):369-74.
http://www.ncbi.nlm.nih.gov/pubmed/10030310?tool=bestpractice.com
[20]Andres E, Maloisel F, Kurtz JE, et al. Modern management of non-chemotherapy drug-induced agranulocytosis: a monocentric cohort study of 90 cases and review of the literature. Eur J Intern Med. 2002 Aug;13(5):324-8.
http://www.ncbi.nlm.nih.gov/pubmed/12144912?tool=bestpractice.com
Severe agranulocytosis is also seen in the congenital neutropenias, of which the most common are severe congenital neutropenia and cyclic neutropenia.
Antibiotic prophylaxis, including coverage of gram-negative species, should be administered. The recombinant neutrophil cytokine granulocyte colony-stimulating factor is also used, particularly in the management of congenital neutropenias.
Speciality consultation should be sought if the practitioner is not familiar with treating agranulocytosis.