Neutropenic Sepsis

Introduction

Neutropenic sepsis is defined by NICE as a neutrophil count of 0.5 × 10⁹ per litre or lower, plus one of the following:¹

• Temperature ≥ 38°C or
• Other signs or symptoms consistent with significant sepsis

Neutropenic sepsis is the most common medical emergency amongst oncology and haematology patients, who can present with, or rapidly progress to haemodynamic instability. Therefore, rapid assessment and administration of empirical antibiotic therapy can be lifesaving.²

The definition of neutropenic sepsis varies between sources. In some hospitals, neutropenic sepsis is diagnosed in patients with a neutrophil count of 1 × 10⁹ per litre or lower. Therefore, local guidelines for the diagnosis and management of neutropenic sepsis should always be followed.

The terms neutropenic sepsis, febrile neutropenia, and neutropenic fever are often used interchangeably. In this article, neutropenic sepsis shall be used as a standard.

Aetiology

How neutropenia predisposes to infection

Neutrophils are a key component of the innate immune system and act as the first line of defence against pathogens. Neutropenia impairs the initial inflammatory response to foreign pathogens allowing them to proliferate.³

The impaired inflammatory response may result in a lack of signs or symptoms, leading to many neutropenic patients presenting with isolated pyrexia as the only clinical evidence of infection.³

Causes of neutropenia

Recent chemotherapy (most commonly within 7 – 10 days) causes neutropenia through bone marrow suppression and is the major cause of neutropenic sepsis in cancer patients. The risk of neutropenia varies in both severity and timescale between different chemotherapy treatment regimes.⁴

Other causes of neutropenia include:⁴

• Malignant bone marrow infiltration
• Extensive radiotherapy
• Bone marrow failure secondary to non-malignant disease (e.g. aplastic anaemia)
• Hypersplenism
• Megaloblastic anaemia
• Drug-induced (e.g. clozapine)

Risk factors

The following factors increase the risk of developing neutropenic sepsis and associated complications:^3,5,6

• Patients over the age of 60
• Advanced malignancy
• Previous neutropenic sepsis
• Mucositis (chemotherapy can induce mucosal damage and allow bacterial translocation)
• Poor performance status
• Significant co-morbidities (the risk increases further in the presence of multiple co-morbidities)
• Indwelling central venous catheters
• Corticosteroids (causes immunosuppression)
• Prolonged hospital admission
• Severe or prolonged neutropenia

Severity of neutropenia

There is a clear relationship between both the severity and duration of neutropenia and the risk of developing neutropenic sepsis.³

The Common Terminology Criteria for Adverse Events (CTCAE) grading system can be used to grade the severity of neutropenia.⁷

Table 1. CTCAE neutropenia grading⁷

Clinical features

Patients receiving chemotherapy will be informed of the risk of neutropenic sepsis and advised to contact the oncology team if they develop a fever. Therefore, many patients will present from home with isolated pyrexia.

Alternatively, neutropenic sepsis may present without fever in some patients, including older patients and those taking immunosuppressive medications such as steroids. Therefore, neutropenic sepsis should be considered in any patient at risk of neutropenia who presents unwell, irrespective of temperature.⁵

History^2,5

Symptoms of neutropenic sepsis may be non-specific symptoms of sepsis or reflect the underlying source of infection.

Typical non-specific symptoms of sepsis include:

• Fatigue
• Feeling warm or cold
• Rigors or shaking
• Feeling sweaty or clammy
• Palpitations
• Dizziness
• Subjective confusion or disorientation

Symptoms that reflect a specific infective source include:

• Chest source: shortness of breath, cough, chest pain, sore throat.
• Urine source: dysuria, increased frequency, urgency or any other lower urinary tract symptoms.
• Skin source: rashes, blisters, pain.
• Gastrointestinal source: diarrhoea, nausea, vomiting, rectal bleeding, abdominal pain, sore mouth (due to mucositis).
• Indwelling line source: pain around the line or rigors after use of the line.

Other important areas to cover in the history include:

• Past medical history (e.g. details of cancer diagnosis including previous treatments)
• Chemotherapy history (e.g. type of chemotherapy, date of the most recent cycle)
• Drug history (e.g. steroids, antibiotic prophylaxis, granulocyte-colony stimulating factor use and details of any allergies)
• Recent procedures which may predispose to infection (e.g. placement of an indwelling vascular access device)
• Previous episodes of pyrexia or neutropenic sepsis (to guide the identification of a source or causative organism)

Clinical examination^2,5

All patients should be examined with an ABCDE approach. See the Geeky Medics guide here for further information.

Patients with neutropenic sepsis are at risk of sudden deterioration. The initial examination should focus on determining how unwell the patient is and establishing what immediate care they require.

General clinical findings in neutropenic sepsis may include:

• Haemodynamic instability (e.g. hypotension, tachycardia, tachypnoea, hypoxia)
• Fever
• Reduced urine output
• Altered conscious level or confusion
• Mottled/ashen appearance

The examination should progress to focus more specifically on identifying a source. However, it is important to remember that examination findings are often minimal in neutropenic sepsis.

• Chest source: increased work of breathing, crepitations, dullness to percussion, reduced air entry.
• Urine source: suprapubic or flank pain, cloudy urine in catheter bag (if applicable).
• Skin source: rashes, blistering, tenderness.
• Gastrointestinal source: abdominal tenderness, dehydration (if reporting vomiting or diarrhoea), evidence of oral mucositis, jaundice.
• Indwelling line source: surrounding erythema, tenderness on palpation, pain or rigors on flushing.

Differential diagnosis

The clinical presentation of neutropenic sepsis is similar to sepsis without neutropenia. Whilst initial management does not depend on the actual neutrophil count, it is critical to establish whether a patient is neutropenic to guide ongoing management and to inform prognosis.

Differential diagnosis of fever

The most common cause of a fever in cancer patients is an infection, with or without neutropenia.

Other causes of fever to consider include:⁸

• Underlying malignancy (both solid and haematological)
• Immunotherapy toxicities
• Inflammatory disorders (e.g. SLE, vasculitis, rheumatoid arthritis)
• Drug-induced
• Hypothalamic dysfunction
• Thyroiditis

Causative organisms

Most cases of neutropenic sepsis are caused by an underlying bacterial infection, but it is important to consider viral and fungal infections. The table below highlights the common infective agents seen in patients with neutropenic sepsis.

Table 2. Infective agents in neutropenic sepsis⁴

Reviewing previous microbiological results should form a critical part of the assessment of a patient with neutropenic sepsis, as this may help identify an underlying cause and guide treatment.

Investigations

Investigations will depend on the clinical context and the suspected source of infection. They may include the following:^1,5,9,10

Bedside investigations

• Urinalysis: to look for urinary tract infection.
• ECG: should be performed in all acutely unwell patients.
• Capillary blood glucose: to exclude hypoglycaemia.

Laboratory investigations

• Baseline blood tests (FBC, U&E, coagulation, CRP, LFTs): white cells may be low or raised and CRP may also be raised.
• Serum lactate: performed as part of the sepsis six care bundle.
• Group and save: the patient may require a blood transfusion.
• Blood cultures: at least two sets from a peripheral vein plus a set from an indwelling line if present to look for a causative organism.
• Arterial blood gas: to assess the extent and severity of any respiratory failure.
• Microbiological cultures: wounds, urine, stool, sputum, and line tip (if indwelling line infection suspected).
• Viral respiratory swab: if viral respiratory infection suspected.

Imaging

• Chest X-ray: to look for evidence of pneumonia.
• High-resolution chest CT: if fungal pneumonia is suspected.
• Abdominal ultrasound or CT abdomen: if biliary or abdominal infection suspected.

Other investigations

• Bronchoalveolar lavage: if an atypical chest source is suspected, such as Pneumocystis jirovecii.

Management

Patients with suspected or confirmed neutropenic sepsis should receive empirical antibiotic therapy within one hour of arrival at hospital.  Antibiotic therapy must not be delayed to wait for confirmation of neutropenia.²

The sepsis six care bundle should be completed. See the Geeky Medics guide here for further information on the acute management of sepsis and the sepsis six bundle.

Empirical antibiotic therapy

Local guidelines regarding the choice of antibiotic therapy must always be followed. If in doubt, seek advice from microbiology.

• First-line therapy is usually intravenous piperacillin with tazobactam (tazocin). Some guidelines may also recommend the administration of gentamicin.^1,2,9
• Second-line therapy (e.g. penicillin allergy) may include intravenous meropenem although this will depend on local guidelines.^2,9
• Additional anti-microbial cover (e.g. teicoplanin) for gram-positive organisms may be required for patients with indwelling central venous catheters.
• Anti-fungal treatment may be considered when the fever persists beyond 4 – 6 days.^2,5

Specimens for microbiological culture should ideally be taken before commencing antibiotic therapy however this should not delay treatment.

Antibiotics should not be switched simply due to persistent fever, however, they may be changed in response to clinical deterioration.²

The decision to switch to oral antibiotic therapy depends on various factors, including the degree of clinical response, infective source, local guidelines, and individual patient risk.

Granulocyte-colony stimulating factor

Recombinant granulocyte-colony stimulating factor (G-CSF) may be used for both prophylaxis and treatment of neutropenia to reduce the risk of neutropenic sepsis.

G-CSF works by stimulating the bone marrow to produce neutrophils and may form part of specific chemotherapy regimens. An example of a G-CSF drug is filgrastim.^1,11

Complications

Complications of neutropenic sepsis can include:

• Single or multi-organ failure (e.g. renal failure, heart failure and acute respiratory distress syndrome)
• Venous thromboembolism (e.g. pulmonary embolism)
• Disseminated intravascular coagulation
• Opportunistic or hospital-acquired infections
• Delirium
• Psychological complications (e.g. anxiety regarding future infections and chemotherapy treatment)
• Delays in chemotherapy leading to worse cancer outcomes

Key points

• Neutropenic sepsis is the most common emergency in cancer patients and carries significant morbidity and mortality.
• Empirical antibiotic therapy should be commenced within one hour of admission.
• Administration of antibiotics should not be delayed to wait for confirmation of neutropenia.
• Symptoms of neutropenic sepsis may be minimal and therefore should be considered in any unwell patient at risk of neutropenia.
• All patients with suspected neutropenic sepsis should be assessed with an ABCDE approach.
• Indwelling vascular access devices can be a source of infection.
• Always follow local guidelines for managing patients with neutropenic sepsis.

Reviewer

Dr Adam Hassani

Consultant Clinical Oncologist

Editor

Dr Chris Jefferies

References

1. National Institute for Health and Care Excellence. Neutropenic sepsis: prevention and management in people with cancer. Published in 2012. Available from: [LINK]
2. The Newcastle upon Tyne Hospitals NHS Foundation Trust. Initial Management of Neutropenic Sepsis. Published in 2018.
3. Crawford J, Dale D, Lyman, G. Chemotherapy‐induced neutropenia. Available from: [LINK]
4. Cassidy J, Bissett D, Spence R, Payne M, Morris-Stiff G. Oxford Handbook of Oncology (4^th edition). Published in 2018. Available from: [LINK]
5. Klastersky J, de Naurois J, Rolston K, et al. Management of febrile neutropenia: ESMO Clinical Practice Guidelines. Published in 2016. Available from: [LINK]
6. National Institute for Health and Care Excellence. Neutropenic sepsis. Published in 2019. Available from: [LINK]
7. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Published in 2017. Available from: [LINK]
8. Fernandez C, Beeching NJ. Pyrexia of unknown origin. Published in 2018. Available from: [LINK]
9. The Christie NHS Foundation Trust. Guidelines for the Management of Sepsis (Including Neutropenic Sepsis). Published in 2013. Available from: [LINK]
10. Ramrakha P, Moore K, Sam A. Oxford Handbook of Acute Medicine (4^th edition). Published in 2019. Available from: [LINK]
11. Northern Cancer Alliance. Guideline for the use of granulocyte-colony stimulating factor (G-CSF) in adult oncology and haematology patients. Published in 2018. Available from: [LINK]