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Neutropenic Sepsis

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9
Neutropenic sepsis\: de≤0.5 × 10 /L plus temperature ≥38°C or other signs of signi
sepsis.
Medical emergency\: common in oncology/haematology patients; requires rapid assessment and empirical antibiotic
therapy.
Neutropenia and infection\: Neutrophils are key in the innate immune response; neutropenia impairs this, leading to
potential isolated pyrexia as the only infection sign.
Causes\: Recent chemotherapy (7-10 days), malignant bone marrow in
hypersplenism, megaloblastic anaemia, drug-induced (e.g. clozapine).
Risk factors\: Age >60, advanced malignancy, previous neutropenic sepsis, mucositis, poor performance status, signi
co-morbidities, indwelling central venous catheters, corticosteroids, prolonged hospital admission, severe/prolonged
neutropenia.
Symptoms\: Non-speci
abdominal pain, mucositis, line pain).
Examination
output, altered consciousness, mottled/ashen appearance; minimal signs of infection source.
Di
hypothalamic dysfunction, thyroiditis; common infective agents (Gram-negative bacilli, Gram-positive bacilli, fungi).
Investigations\: FBC, U&Es, CRP, LFTs, lactate, blood cultures, ABG, urinalysis, chest/abdominal X-ray, high-resolution chest
CT, abdominal ultrasound/CT, microbiological cultures, viral respiratory swab.
Management\: Empirical antibiotic therapy within 1 hour (e.g., piperacillin with tazobactam), sepsis six care bundle, G-CSF
(e.g.,
Complications\: Multi-organ failure, venous thromboembolism, DIC, opportunistic/hospital-acquired infections, delirium,
psychological issues, chemotherapy delays, in-hospital mortality rate ~10%.
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A comprehensive topic overview

Introduction

Neutropenic sepsis is de9 1
per litre or lower, plus one of the following\:
Temperature ≥ 38°C or
Other signs or symptoms consistent with signi
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 de
with a neutrophil count of 1 × 10 9
per litre or lower. Therefore, local guidelines for the diagnosis and management of
neutropenic sepsis should always be followed.
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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
Neutropenia impairs the initial in
3
The impaired in
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 di
4
Other causes of neutropenia include\:
4
Malignant bone marrow in
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
Signi
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 grading
7
Grade 9
Neutrophil count (× 10 per litre)
1 >1.5
2 1.0 – 1.5
3 0.5 – 1.0
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4 \<0.5

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
History2,5
Symptoms of neutropenic sepsis may be non-speci
Typical non-speci
Fatigue
Feeling warm or cold
Rigors or shaking
Feeling sweaty or clammy
Palpitations
Dizziness
Subjective confusion or disorientation
Symptoms that re
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 identi
Clinical examination2,5
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
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 speci
that examination
Chest source\: increased work of breathing, crepitations, dullness to percussion, reduced air entry.
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Urine source\: suprapubic or
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

Di

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.

Di

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
In
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 sepsis
4
Gram-negative bacilli Gram-positive bacilli Fungi
E . c o l i
K l e b s i e l l a spp.
P s e u d o m o n a s
a e r u g i n o s a
E n t e r o b a c t e r spp.
P r o t e u s spp.
S t a p h y l o c o c c u s a u r e u s
C o r y n e b a c t e r i u m
S t a p h y l o c o c c u s
e p i d e r m i d i s
S t r e p t o c o c c u s
p n e u m o n i a e
V i r i d a n s s t r e p t o c o c c i
Enterococci
C a n d i d a spp.
A s p e r g i l l u s spp.
M u c o r a l e s
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.
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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 P n e u m o c y s t i s j i r o v e c i i .

Management

Patients with suspected or con
arrival at hospital. Antibiotic therapy must not be delayed to wait for con
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 speci
regimens. An example of a G-CSF drug is
1,11
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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
Risk of mortality
The European Society for Medical Oncology (ESMO) estimate an in-hospital mortality rate for patients with
neutropenic sepsis of approximately 10%. However, this mortality rate will vary with di
sepsis used and whether additional risk factors are present.
5,6

References

National Institute for Health and Care Published in 2012. Available from\: [LINK]
Excellence. N e u t r o p e n i c s e p s i s \: p r e v e n t i o n a n d m a n a g e m e n t i n p e o p l e w i t h c a n c e r .
The Newcastle upon Tyne Hospitals NHS Foundation Trust. I n i t i a l M a n a g e m e n t o f N e u t r o p e n i c S e p s i s . Published in 2018.
Crawford J, Dale D, Lyman, G. C h e m o t h e r a p y_‐_i n d u c e d n e u t r o p e n i a . Available from\: [LINK]
t h
Cassidy J, Bissett D, Spence R, Payne M, Morris-Sti
Available from\: [LINK]
Klastersky J, de Naurois J, Rolston K, et Published in 2016. Available from\: [LINK]
al. Man a g e m e n t o f f e b r i l e n e u t r o p e n i a \: E S M O C l i n i c a l P r a c t i c e G u i d e l i n e s .
National Institute for Health and Care Excellence. N e u t r o p e n i c s e p s i s . Published in 2019. Available from\: [LINK]
Institute. C o m m o n T e r m i n o l o g y C r i t e r i a f o r A d v e r s e E v e n t s ( C T C A E ) V e r s i o n 5 .0 . Published in National Cancer Available from\: [LINK]
2017.
Fernandez C, Beeching NJ. P y r e x i a o f u n k n o w n o r i g i n . Published in 2018. Available from\: [LINK]
The Christie NHS 2013. Available from\: [LINK]
Foundation Trust. G u i d e l i n e s f o r t h e M a n a g e m e n t o f S e p s i s ( I n c l u d i n g N e u t r o p e n i c S e p s i s ) . Published in
t h
Ramrakha P, Moore K, Sam A. O x f o r d H a n d b o o k o f A c u t e M e d i c i n e ( 4 e d i t i o n ) . Published in 2019. Available from\: [LINK]
Northern Cancer Alliance. G u i d e l i n e f o r t h e u s e o f g r a n u l o c y t e-c o l o n y s t i m u l a t i n g f a c t o r ( G-C S F ) i n a d u l t o n c o l o g y a n d
h a e m a t o l o g y p a t i e n t s . Published in 2018. Available from\: [LINK]

Reviewer

Dr Adam Hassani
Consultant Clinical Oncologist

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Contents

Introduction
Aetiology
Risk factors
Clinical features
Di
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