Changes

August 2024 — reviewed.  A literature search was conducted in June to August 2024 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of the topic. There have been no major changes to the recommendations. Quality statements temporarily removed from this topic due to ongoing updates to NICE guidelines on sepsis, which underpin the quality statements.

Update

Goals

To support primary healthcare professionals to:

• Be aware of when to suspect a diagnosis of neutropenic sepsis in primary care.
• Arrange emergency transfer to hospital for all people with suspected neutropenic sepsis.
• Provide appropriate emergency management in primary care, if necessary, prior to hospital transfer.
• Provide advice and information to survivors of neutropenic sepsis and their families/carers, and arrange follow-up as needed.

Outcome measures

Audit criteria

No audit criteria applicable to primary care were found during the review of this topic.

QOF indicators

QIPP - Options for local implementation

No QIPP indicators were found during the review of this topic.

NICE quality standards

No current NICE quality standards were found during the review of this topic. 

What is it?

• Sepsis is a syndrome defined as life-threatening organ dysfunction due to a dysregulated host response to infection, according to the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) [Shankar-Hari, 2016; Singer, 2016].
  • Septic shock is a subset of sepsis, which describes circulatory, cellular, and metabolic abnormalities which are associated with a greater risk of mortality than sepsis alone.
    • In a hospital setting, septic shock can be identified using the clinical criteria of persisting hypotension requiring vasopressor therapy to maintain a mean arterial pressure of 65 mmHg or more, and serum lactate level of greater than 2 mmol/L, despite adequate volume resuscitation [Singer, 2016; NICE, 2024].
  • See the CKS topic on Sepsis for more information.
• Neutropenic sepsis describes sepsis which develops in people with low neutrophil levels. The precise diagnostic definition varies in the literature.
  • Neutropenia is defined as a reduction in absolute neutrophil count below the normal range, however that range varies with age, ethnic origin and local policy [Fioredda, 2023]. 
  • The National Institute for Health and Care Excellence (NICE) defines neutropenic sepsis in people having anticancer treatment as a neutrophil count of 0.5 x 10⁹/L or lower and either a temperature higher than 38°C or any symptoms and/or signs of sepsis [NICE, 2020].
  • Neutropenic sepsis is a potentially life-threatening complication of anticancer and other immunosuppressive drug treatments, and may also be a complication of other conditions where there is neutropenia.
  • The term neutropenic sepsis should only be used for people with neutropenia relating to an underlying condition or treatment who develop new infection-related organ dysfunction [AoMRC, 2022]. Sepsis itself may induce neutropenia, but this would not be classified as neutropenic sepsis.
• Febrile neutropenia is the most common complication of anticancer treatment and describes the presence of fever in a person with neutropenia [Morgan, 2018]. The exact definition of febrile neutropenia varies in the literature.
  • The European Society for Medical Oncology (ESMO) defines febrile neutropenia as an oral temperature of more than 38.3°C, or two consecutive readings of more than 38°C for 2 hours, and an absolute neutrophil count of 0.5 x 10⁹/L or lower, or expected to fall below this level [Klastersky, 2016].
  • The Infectious Disease Society of America (IDSA) defines fever in people who are neutropenic as a single oral temperature of greater than 38°C for more than one hour [Taplitz, 2018].
  • People with febrile neutropenia are at risk of sepsis and septic shock [BMJ Best Practice, 2023].

What are the causes?

Neutrophils are the first-line defence against infection, destroying invading micro-organisms and acting as part of the body's inflammatory response [BSI, 2022]. There are multiple possible causes that affect neutrophil function and/or result in a reduced neutrophil count (neutropenia), including [Kochanek, 2019; Fioredda, 2023; BMJ Best Practice, 2024a]:

• Drugs and treatments
  • Cytotoxic chemotherapy — febrile neutropenia is one of the most frequent and serious complications of chemotherapy [Klastersky, 2016; Morgan, 2018].
    • Chemotherapy causes bone marrow suppression, leading to a temporary reduction in the production of blood cells, including neutrophils, which take time to be replaced. This 'nadir' when the neutrophil count is at its lowest is typically 5–10 days after the last chemotherapy dose, and recovery is usually 5 days later, but this may vary depending on the individual drug regimen.
  • Haematopoietic stem cell transplantation.
  • Immunosuppressive drugs such as azathioprine, methotrexate, sulfasalazine, adalimumab, rituximab, and infliximab. See the CKS topic on DMARDs for more information.
  • Other drugs such as penicillin, carbimazole, phenytoin, valproic acid, clozapine, olanzapine, allopurinol, and nonsteroidal anti-inflammatory drugs (NSAIDs).
  • Radiotherapy — can cause neutropenia by radiation damage of dividing lymphoid stem and progenitor cells.
• Infections
  • Viral — such as HIV, influenza, hepatitis A, B or C, respiratory syncytial virus (RSV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) may cause transient bone marrow suppression and neutropenia. See the CKS topics on HIV infection and AIDS, Influenza - seasonal, Hepatitis A,  Hepatitis B, Hepatitis C  Common cold, and Glandular fever (infectious mononucleosis) for more information.
  • Bacterial — such as tuberculosis, brucella, typhoidal salmonella and shigella. See the CKS topics on Tuberculosis and Gastroenteritis for more information.
  • Parasites — such as malaria and leishmaniasis. See the CKS topic on Malaria for more information. 
• Autoimmune or chronic inflammatory conditions
  • Conditions such as Crohn's disease, rheumatoid arthritis, and systemic lupus erythematosus (SLE) increase the risk of neutropenia through varying mechanisms. See the CKS topics on Crohn's disease and Rheumatoid arthritis for more information.
• Bone marrow disease or failure 
  • May be caused by conditions such as aplastic anaemia, haematological malignancies and metastatic disease.
  • Hypersplenism (Felty's syndrome).
• Nutritional deficiencies
  • May be associated with vitamin B12, folate and copper deficiencies. See the CKS topic on Anaemia - B12 and folate deficiency for more information.
• Others (rare)
  • Genetic conditions causing congenital bone marrow failure syndromes such as Kostmann's syndrome (an autosomal recessive disorder causing severe chronic neutropenia) or congenital isolated neutropenia syndromes such as Cohen syndrome (characterized by developmental delay, microcephaly, and hypotonia).
  • Primary or idiopathic neutropenia.

People with neutropenia are at risk of infection from a wide range of potential pathogens [Morgan, 2018; BMJ Best Practice, 2023; Punnapuzha, 2023]:

• Neutropenic sepsis is commonly caused by bacterial infection with Gram-positive pathogens such as Staphylococcus aureus, Enterococcus sp, Streptococcus pneumoniae and S. pyogenes, and Gram-negative pathogens such as Escherichia coli, Klebsiella sp, Enterobacter sp, and Pseudomonas aeruginosa.
• Viral or fungal infection (such as Candida or Aspergillus species) may also be involved, either causing or complicating infection.

What are the risk factors?

Neutropenia itself is an independent risk factor for the development of infection and sepsis.

• In a person with neutropenia, risk factors for the development of febrile neutropenia and neutropenic sepsis include:
  • Characteristics of neutropenia —  the risk of infection and/or sepsis increases with severe neutropenia (absolute neutrophil count of 0.5 x 10⁹/L or lower) and prolonged neutropenia lasting more than 7 days.
    • People receiving high-intensity chemotherapy regimens to treat acute myeloid leukaemia and people undergoing haematopoietic stem cell transplantations are at increased risk of invasive fungal infections due to severe and prolonged neutropenia.
    • In addition, a rapid decline in the neutrophil count increases infection risk.
  • Age — infants and people over 60 years of age are at higher risk of febrile neutropenia following chemotherapy.
  • Chemotherapy — affects immune cellular function and may reduce mucosal barrier protection by causing mucositis and epithelial damage, which increases the risk of bacterial translocation across the gut wall.
  • Corticosteroids — causes additional immunosuppression.
  • Antibiotics — antibiotics at the time of onset of febrile neutropenia increases the risk of serious complications by disrupting the normal body flora.
  • Haematological malignancy — there is approximately a 5 times increased risk of febrile neutropenia compared to people being treated for solid tumours or lymphoma.
  • Advanced malignancy.
  • History of previous febrile neutropenia.
  • Prolonged hospital admission.
  • Previous surgery.
  • Comorbidities such as diabetes mellitus, liver disease, renal disease; poor nutritional status — the risk of complications increases in people with more than one significant comorbidity.
  • Central venous access device.
  • Total parenteral nutrition — increases the risk of invasive fungal infection.

 [Klastersky, 2016; Morgan, 2018; Kochanek, 2019; BMJ Best Practice, 2023]

How common is it?

The prevalence of febrile neutropenia and neutropenic sepsis varies in the literature, depending on the definitions used, study populations of different causes of neutropenia, types of malignancy (if any), and different statistical methods of analysis [Kochanek, 2019; NICE, 2020].

• The incidence of neutropenic sepsis is increasing over time, possibly reflecting the increasing use of anticancer and other immunosuppressive drug therapies [NICE, 2020]
• The incidence of neutropenic sepsis among people with cancer ranges from three cases a month in general hospitals in the UK to over 20 cases a month in specialist haematology/oncology units [NICE, 2020].  
• The German Society of Hematology and Medical Oncology guidelines state that 7–45% of people with neutropenia develop sepsis or septic shock in different study populations of neutropenic people with cancer, and note that epidemiology data from non-specialised centres is lacking [Kochanek, 2019].
• The European Society for Medical Oncology (ESMO) guidelines state that febrile neutropenia is observed in about 8 cases per 1000 people receiving cancer chemotherapy [Klastersky, 2016].
• A prospective observational study of febrile episodes during chemotherapy-induced neutropenia in children with cancer or after haemopoietic stem cell transplantation (n = 1792 neutropenic periods) found a rate of 0.76 episodes of febrile neutropenia per 30 days at risk [Castagnola, 2007].

What are the complications?

Many cases of febrile neutropenia have no significant complications and up to 50% have no definable infection [Morgan, 2018]. If neutropenic sepsis develops, possible complications include:

• Death
  • Sepsis and septic shock are leading causes of death in people with haematological or solid tumours with chemotherapy-induced neutropenia. Neutropenia is an independent risk factor for increased mortality in this population [Kochanek, 2019].
• Organ failure
  • This may be multi-system (due to tissue damage secondary to the inflammatory response and impaired perfusion) and includes acute kidney injury (AKI), hepatic encephalopathy, heart failure, central nervous system dysfunction, and acute respiratory distress syndrome (ARDS) or acute respiratory failure [Clarke, 2013; Morgan, 2018; Kochanek, 2019; BMJ Best Practice, 2024b; Daniels, 2024]. See the CKS topics on Acute kidney injury, Jaundice in adults, Delirium, and Heart failure - chronic for more information.
    • Neutropenia is independently associated with a higher risk for AKI compared with non-neutropenic sepsis [Reilly, 2016].
    • Multiple previous chemotherapy treatments may independently increase the risk of developing heart failure, depending on the regimens used [Kochanek, 2019].
    • A higher SOFA (Sequential Organ Failure Assessment) score is associated with an increased risk of death [Singer, 2016].
• Invasive and atypical infection
  • People with neutropenic sepsis may develop opportunistic or hospital-acquired infections with atypical organisms such as Legionella sp and Mycoplasma sp, and may have reactivation of latent viruses, due to an impaired ability to mount an appropriate immune response [Gotts, 2016; Klastersky, 2016; Cecconi, 2018].
  • People receiving chemotherapy for acute myeloid leukaemia and undergoing haematopoietic stem cell transplantation are at risk of prolonged neutropenia and invasive fungal or atypical infections, such as systemic candidiasis and aspergillosis [Clarke, 2013; Klastersky, 2016]. See the CKS topic on Candida - oral for more information.
• Coagulopathy
  • This may cause thromboembolism or disseminated intravascular coagulation (DIC) characterized by microthrombosis and haemorrhage [Clarke, 2013; Cecconi, 2018; BMJ Best Practice, 2024b]. Microvascular changes and DIC can result in loss of digits or limbs [Daniels, 2024]. See the CKS topics on Deep vein thrombosis and Pulmonary embolism for more information.
• Post-sepsis syndrome affects 40% of people admitted to hospital with sepsis and may include physical, cognitive and psychological problems [Daniels, 2024].
  • Physical impairments, which may be specific (for example neurological or neuromuscular, loss of digits or limbs, long term respiratory or renal dysfunction), affecting mobility or function, or a reduced quality of life may result from chronic pain and fatigue.
  • Cognitive impairments range from difficulty with complex tasks to inability to remember everyday things, affecting relationships, work and everyday function.
  • Psychological sequelae may include anxiety about recurrent infection and sepsis, post-traumatic stress disorder, loss of confidence and self-esteem, and social isolation due to fear of infection from others. See the CKS topics on Generalized anxiety disorder and Post-traumatic stress disorder for more information.
• Treatment delays and reductions in dose intensity
  • Neutropenic sepsis may affect drug regimens of chemotherapy or other immunosuppressive drug therapy, leading to reduced drug efficacy and impact on cancer treatment outcomes, including disease-free intervals and survival rates [Klastersky, 2016; Morgan, 2018].

What is the prognosis?

Neutropenic sepsis is a major cause of death in people with neutropenia, and is a potentially life-threatening, time-critical medical emergency [NICE, 2020].

• People who are immunocompromised with neutropenia have lower survival rates from sepsis than people who are immunocompetent [Kochanek, 2019].
  • There was a doubling of the annual mortality rate from neutropenic sepsis between 2001 and 2010, with a peak of 700 deaths in 2010, particularly in the 15–24 years age group. Possible contributing factors include increases in cancer diagnoses, increased intensity of chemotherapy regimens, and more inclusive eligibility criteria for chemotherapy treatments [NICE, 2020].
  • The Sepsis Manual from the UK Sepsis Trust quotes mortality rates from neutropenic sepsis in adults of up to 21% or higher [Daniels, 2024].
• The European Society for Medical Oncology (ESMO) guidelines state that people with febrile neutropenia and complications have an overall in-hospital mortality rate of about 10% [Klastersky, 2016].
• Mortality rates for febrile neutropenia vary with the Multinational Association of Supportive Care in Cancer (MASCC) prognostic index, which is a clinical prediction rule incorporating factors such as the burden of illness, presence of hypotension, chronic obstructive pulmonary disease (COPD), history of previous fungal infection, dehydration, performance status, and age to identify people at low risk of complications from febrile neutropenia [Klastersky, 2016]. Mortality rates are lower than 5% in low-risk patients and estimated at 40% for people at high risk of complications from febrile neutropenia.
• In a meta-analysis of 7512 critically ill cancer patients (1702 of whom were neutropenic), neutropenia was found to be independently associated with a poor outcome and increased mortality, unrelated to type of malignancy, duration of intensive care unit admission, and use of mechanical ventilation [Georges, 2018].
• Around 40% of people who survive sepsis have long-term sequelae, which may be physical, psychological and/or cognitive impairments [Singer, 2016; Daniels, 2024].

When should I suspect neutropenic sepsis?

People who are neutropenic and have an infection are at increased risk of sepsis compared with immunocompetent people, as their ability to respond to infection is compromised. Be aware that sepsis can be challenging to identify in people who are neutropenic, as there may be minimal or atypical symptoms and/or signs of infection or sepsis. This is due to the fact that the neutropenia may interfere with development of the inflammatory response.

• Suspect a diagnosis of neutropenic sepsis in any person with known neutropenia or with risk factors for neutropenia (such as undergoing chemotherapy), and/or with risk factors for neutropenic sepsis, who becomes unwell. For example, suspect sepsis if there are any of the following features:
  • Confirmed infection or symptoms or signs indicating possible infection, such as dysuria, diarrhoea, or productive cough. This includes people who are deteriorating unexpectedly, or failing to improve as expected.
    • Note: sepsis may result from infection with almost any pathogen. Therefore, it may present with a wide range of clinical features depending on the site of infection and host response.
  • Chills, shivers, rigors, and/or a temperature greater than 38°C.
    • Note: people with neutropenic sepsis may not present with fever and may instead present with hypothermia. In addition, medication such as corticosteroids may mask an elevated temperature.
  • Clinical features of possible sepsis.
    • For example, tachycardia, tachypnoea, hypotension, fever or hypothermia, increased capillary refill time, mottled or ashen skin, cyanosis, newly altered mental state, reduced urinary output. 
    • See the CKS topic on Sepsis for more information on symptoms and signs of sepsis.
    • Note: people with sepsis may present with non-specific, non-localized clinical features, for example general malaise, agitation, confusion or behavioural change. In addition, neutropenia may cause changes in behaviour, mental state, or cognition which is independent from the onset of sepsis.
  • The person appears unwell, or there is concern from a relative or carer that there is a change in appearance or behaviour.
• Be aware that local protocols may have different temperature and neutrophil threshold criteria to suspect or diagnose neutropenic sepsis, and these should be followed where appropriate, using clinical judgement.

How should I assess a person with suspected neutropenic sepsis?

If a person presents with suspected neutropenic sepsis, refer immediately for urgent assessment in secondary or tertiary care so that the risk of serious complications can be evaluated, and managed appropriately.

Note that the complete assessment should be made in secondary or tertiary care, and that measurements in community settings should not delay transfer of the patient. Some of the aspects below may be better deferred to the secondary care setting, depending on clinical circumstances and level of suspicion.

• Ask the person/carers about:
  • Any known causes or risk factors for neutropenia.
  • Any recent fever or rigors. Be aware that people with neutropenic sepsis may not present with fever, and may present with hypothermia.
  • Any symptoms suggesting a focus of infection, such as dysuria, diarrhoea, or productive cough.
  • Clinical features suggesting dehydration, such as reduced urine output in the past 18 hours.
  • Any altered behaviour, mental state, or cognition. See the CKS topic on Delirium for more information.
  • If the person is known to have cancer, the type of cancer; timing, duration and intensity of chemotherapy, radiotherapy, or immunosuppressive drug regimen including when the last dose of treatment was given.
  • Any antibiotic prophylaxis or recent antibiotic therapy (increases the risk of antibiotic resistance); granulocyte colony-stimulating factor (G-CSF, may be used prophylactically to reduce the risk of neutropenia during chemotherapy treatment), or corticosteroid use.
  • Any history of bone marrow or stem cell transplantation.
  • Possible risk factors for infection or sepsis, including comorbidities, central venous access device, recent fungal infection, previous hospital admissions, or surgery.
  • Any recent travel, infectious contacts, or animal exposure.
  • Previous episodes of febrile neutropenia or sepsis, or other recent presentations with symptoms or signs which could indicate sepsis (as sepsis may be hard to recognise particularly in early stages).
• Examine the person to assess for:
  • General appearance, level of consciousness, and cognition.
    • Consider using the Glasgow Coma Scale (GCS) or AVPU ('alert, voice, pain, unresponsive') scale, to assess level of consciousness.
  • Temperature.
    • Be aware that people with neutropenic sepsis may not present with fever, and may instead present with hypothermia.
  • Heart rate, respiratory rate, signs of respiratory distress, and blood pressure.
  • Capillary refill time and oxygen saturation (abnormal results may indicate poor peripheral perfusion).
  • Mottled or ashen skin; pallor or cyanosis of the skin, lips or tongue; cold peripheries.
  • Any rash.
    • A non-blanching rash which may suggest meningococcal disease. See the CKS topic on Meningitis - bacterial meningitis and meningococcal disease for more information on assessment and emergency management.
    • Be aware that viral exanthems in people who are immunosuppressed may present atypically.
  • Weak high-pitched or continuous cry (in children under 5 years of age).
  • Any breach of skin integrity (for example cuts, burns, or skin infections) or other skin signs suggesting infection or mucositis. See the CKS topics on Burns and scalds and Cellulitis - acute for more information.
  • Dry mucous membranes or other signs of dehydration. See the CKS topic on Feverish children - risk assessment and management for more information on assessment.
  • The possible underlying source of infection.
    • Be aware that people who are immunosuppressed and/or have neutropenia often lack an obvious source of infection.
• See the CKS topic on Sepsis for more information on the assessment and risk stratification of a person with suspected sepsis.

Scenario: Management

From age 1 month onwards.

Search strategy

Scope of search

A literature search was conducted for guidelines and systematic reviews on primary care management of neutropenic sepsis.

Search dates

March 2019 - August 2024

Key search terms

The terms listed below are the core search terms that were used for EBSCOhost MEDLINE (searched 28th March 2019). These were combined with filters to identify guidelines, systematic reviews and primary care relevant literature in EBSCOhost MEDLINE. The strategy was adapted for The Cochrane Library databases.

S6    S1 OR S2 OR S5                                                                              
S5    S3 AND S4                                          
S4    (MH "Sepsis+")                                          
S3    (MH "Neutropenia+")                                  
S2    AB ( ((fever* or febrile or sepsis) N3 (neutropeni* or neutropaenia)) ) OR TI ( ((fever* or febrile or sepsis) N3 (neutropeni* or neutropaenia)) )                                                                              
S1    (MH "Febrile Neutropenia+")     

Sources of guidelines

• National Institute for Health and Care Excellence (NICE)
• Scottish Intercollegiate Guidelines Network (SIGN)
• Royal College of Physicians
• Royal College of General Practitioners
• Royal College of Nursing
• NICE Evidence
• World Health Organization
• Guidelines International Network
• TRIP database
• Agency for Healthcare Research and Quality
• Institute for Clinical Systems Improvement
• National Health and Medical Research Council (Australia)
• Royal Australian College of General Practitioners
• British Columbia Medical Association
• Canadian Medical Association
• Alberta Medical Association
• Michigan Quality Improvement Consortium
• Singapore Ministry of Health
• National Resource for Infection Control
• RefHELP NHS Lothian Referral Guidelines
• Medline (with guideline filter)
• Driver and Vehicle Licensing Agency
• NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

• The Cochrane Library:
  • Systematic reviews
  • Protocols
  • Database of Abstracts of Reviews of Effects
• Medline (with systematic review filter)
• EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

• NIHR Health Technology Assessment programme
• The Cochrane Library:
  • NHS Economic Evaluations
  • Health Technology Assessments
• Canadian Agency for Drugs and Technologies in Health
• International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

• The Cochrane Library:
  • Central Register of Controlled Trials
• Medline (with randomized controlled trial filter)
• EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

• Bandolier
• Drug and Therapeutics Bulletin
• TRIP database
• Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

• Department of Health
• Health Management Information Consortium (HMIC)

Patient experiences

• Healthtalk
• BMJ - Patient Journeys

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

• British National Formulary (BNF)
• electronic Medicines Compendium (eMC)
• European Medicines Agency (EMEA)
• LactMed
• Medicines and Healthcare products Regulatory Agency (MHRA)
• REPROTOX
• Scottish Medicines Consortium
• Stockley's Drug Interactions
• TERIS
• TOXBASE
• Micromedex
• UK Medicines Information

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Our policy

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• Clinical accuracy.
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Our policy

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Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

• Animal studies
• Original research is not written in English

Possible exclusions for reviewed literature:

• Sample size too small or study underpowered
• Bias evident or promotional literature
• Population not relevant
• Intervention/treatment not relevant
• Outcomes not relevant
• Outcomes have no clear evidence of clinical effectiveness
• Setting not relevant
• Not relevant to UK
• Incorrect study type
• Review article
• Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

• Feasibility
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• Organizational and Financial Impact Analysis
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  • Time dependencies
• Cost-effectiveness or cost-benefit analysis studies are identified where available. 

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Competing interests declared for this topic:

None.