Febrile Neutropaenia

Title of Guideline (must Guideline for the management of children

include the word “Guideline” with febrile neutropaenia
Contact Name and Job Title Adam Henderson, Nottingham Children’s Hosp
(author) + CYPICS.
Ghazala Javid Leicester Royal Infirmary
Beverly Harwood , Nottingham Children’s Hosp
Paediatric Oncology Pharmacists
Directorate & Speciality Family Health; Haematology/Oncology
Date of submission August 2013
Date on which guideline must
be reviewed (this should be August 2018
one to three years)
Explicit definition of patient This guideline applies to all children and young
group to which it applies (e.g. people under the age of 19 years who are
inclusion and exclusion assessed as having neutropaenic fever
criteria, diagnosis)
Abstract Advice on assessment and management of
those under 19 years presenting febrile and
found to be neutropaenic
Key Words Fever neutropaenia
Statement of the evidence base of the guideline – has the guideline been peer
reviewed by colleagues?
1a meta analysis of randomised
controlled trials
2a at least one well-designed See references
controlled study without
randomisation
2b at least one other type of well-
designed quasi-experimental
study
3 well –designed non-experimental
descriptive studies (ie
comparative / correlation and
case studies)
4 expert committee reports or NICE Guidelines
opinions and / or clinical
experiences of respected
authorities
5 recommended best practise
based on the clinical experience
of the guideline developer
Consultation Process
Target audience
This guideline has been registered with the trust. However, clinical guidelines
are guidelines only. The interpretation and application of clinical guidelines will
remain the responsibility of the individual clinician. If in doubt contact a senior
colleague or expert. Caution is advised when using guidelines after the review
date.

Adam Henderson 1 of 11 August 2013 1

Document Control

Document Amendment Record

Issue Status Version Issue Lead Author Description

Date
V1 Dr Shaun Wilson SpR Developed from
previous guidelines
V2 Aug 2012 Beverly Harwood and
Ghazala Javid,
Paediatric Oncology
Pharmacists.
V3 Aug 2013 Adam Henderson Reviewed and updated
Paediatric Oncology
Pharmacists.

General Notes;

This guideline is part of the CYPICS* documentation from 2012.

*Children’s and Young Peoples Integrated Cancer Service

Adam Henderson 2 of 11 August 2013 2

Introduction

The most commonly encountered cause of neutropenia in the paediatric population is marrow
suppression secondary to chemotherapy. Oncology patients are immunosuppressed due to a
combination of:
 Neutropaenia
 Splenic dysfunction
 T and B-cell dysfunction – quantitative and qualitative dysfunction
 Destruction of normal mucosal barriers
 Alteration of normal body flora

New patients with possible new leukaemia (or relapsed leukaemia) are functionally
immunosupressed regardless of their neutrophil count. Any child with a fever should also be
started on broad spectrum intravenous antibiotics as below.

Neutropenia can also be seen in non-malignant conditions (see table).

Decreased Marrow Production

Congenital – Kostmann’s syndrome, Reticular dysgenesis, Fanconi’s anaemia
Acquired – Sepsis, Post-viral, Drug suppression, Cyclical neutropaenia, benign chronic
neutropaenia, myelofibrosis
Associated with phenotypically abnormal syndromes
Schwachmann’s, Chediak-Higashi, Cartilage hair hypoplasia, Dyskeratosis congenita
Increased destruction of neutrophils
Sepsis, endotoxaemia, Autoimmune antibodies, Neonatal isoimmune haemolytic disease
Sequestration of neutrophils
Immune complexes – Viral, SLE, Sjorgen’s syndrome
Hypersplenism
Associated with immunodeficiency
X-linked hypogammaglobulinaemia
Selective immunoglobulin deficiency states
Metabolic Problems
Propionic isovaleric, Methylmalonic acidaemia, Hyperglycinaemia

As the immune system is not working properly, the normal inflammatory responses are muted.
This may lead to infection without fever and also a greater tendency to dissemination of
pathogens.

The initial management of a child with febrile neutropenia is the same irrespective of the
cause of the neutropenia.

The microbiological aetiology of the fever in febrile neutropaenic patients is found in only 30 – 40
% of cases (1). Bacteraemia is present in 10 – 20% of febrile neutropaenic patients with
neutrophils below 0.1 (2). The most likely infective pathogens are endogenous bacteria from skin
and gut flora with gram-positive organisms (Streptococci, coagulase-negative staphylococci,
Staphylococcus aureus, Enterococci) now more common agents than gram-negative organisms
(Escherichia coli, Klebsiella spp, Pseudomonas aeruginosa) (3). Fungal infections are always a
diagnostic possibility in immunosuppressed patients. These usually occur in patients with
prolonged neutropaenia (> 7 days) and those who have had a course of broad-spectrum
antibiotics.

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Prior to empirical antibiotic regimens mortality rates with infections were as high as 80%.
Aggressive and early broad-spectrum antibiotic policies have decreased these rates to less than
3%. All febrile neutropaenic patients should initially be considered infected, however non-
infectious causes that also need to be considered are:
 Malignant process
 Cytotoxics – cytosine, bleomycin
 Blood products
 Allergic reactions

Any child showing signs of Infection and considered Immunosupressed should be started on
antibiotics and reviewed by a senior staff member regardless of their neutrophil count.

Normal range of neutrophils for children at different ages

AGE TOTAL WBC NEUTROPHILS PERCENTAGE

Mean Range Mean Range
Birth 18 9 – 30 11 6 – 26 61
1 week 12 5 – 21 5.5 1.5 – 10 45
1 month 10.8 5 – 19.5 3.8 1.0 – 9 35
6 months 11.9 6 – 17.5 3.8 1.0 – 8.5 32
1 year 11.4 6 – 17.5 3.5 1.5 – 8.5 31
6 years 8.5 5 – 14 4.3 1.5 – 8 51
16 years 7.8 4.5 – 13 4.4 1.8 – 8 57

Definitions
Neutropaenia:
 Absolute neutrophil count (ANC) less than 500/ml (< 0.5 x 109)
Fever:
 Temperature > 38.50 C on one occasion
OR
 Temperature > 380C on 2 or more occasions recorded at least 1 hour apart

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History on Admission

It is important to pay attention to the following:

1. Concomitant use of nephrotoxic drugs (e.g. Cisplatin, Ifosfamide, Vancomycin,
Amphotericin, Amiloride).

2. Relation of symptoms to central line flushing or usage

 Rigors associated within an hour of a line manipulation is strongly suggestive of a line
infection

3. All patients that have received prolonged or intensive chemotherapy and repeated
courses of antibiotics (e.g. patients with relapsed cancer) should be discussed
with senior staff. More aggressive empiric antibiotic cover (e.g. meropenem) may be
required as first line therapy.

4. History of previous resistant Gram Negative bacteria, e.g. especially those with
resistant E Coli or Klebsiella, Enterobacter, Citrobacter, Morganella. Discuss these
patients with Microbiology – consider use of meropenem as first line therapy.

5. History of other bacteria, e.g. history of MRSA, VRE or Clostridium difficile. Discuss
patient with Microbiology.

Examination on Admission

All patients with a temperature need a detailed and full examination. Areas that need special
attention are:
1. Mouth – teeth, gums, pharynx, consider herpetic stomatitis or gingival candidiasis.
2. ENT – especially examining for tenderness over the sinuses and mastoid sites in
older children. Take an NPA or nose and throat swab in viral transport medium for
patients with coryzal symptoms
3. Respiratory – respiratory rate and oxygen saturations and requirements must be
recorded and documented. Hypoxaemia / signs of respiratory distress and normal
auscultation may be associated with Pneumocystis pneumonia (PCP).
4. Cardiovascular – Blood pressure must be documented.
5. Upper gastrointestinal – painful swallowing may be suggestive of herpetic or
candidal oesophagitis.
6. Abdominal tenderness +/- diarrhoes or bowel stasis – right lower quadrant pain /
tenderness / distension may suggest typhilitis (neutropaenic colitis), as well as
appendicitis investigate with abdo x ray to look for perforation (NB steroids may mask
signs) abdo USS, if diarrhoes send stool for C. Diff toxin– discuss with experienced
registrar / consultant, - consider surgical review.
7. Perineum – symptoms of perianal discomfort or pain should always be asked about.
If there are symptoms, the perineum should be inspected.
8. Skin lesions – look for petechiae and purpura (evidence of thrombocytopaenia or
DIC), consider Pseudomonas, herpetic, fungal aetiology
9. Central venous line (CVL) sites – erythema, swelling, tenderness are suggestive of
infection tracking along the line
10. Procedure sites – e.g. Gastrostomy sites, lumbar puncture, posterior superior iliac
crests

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 Patients with following signs/symptoms need antibiotics to be commenced immediately
AND URGENT assessment by a senior staff member regardless of neutrophil count:
 Shock
 Respiratory distress
 Coagulopathy
 More than one organ system involvement
Use PEWS Scoring System for monitoring

Investigations on Admission

All patients with a temperature on admission need:

1. Temperature/fever confirmed
2. Full blood count – differential to confirm neutropaenia
3. Biochemistry – U+E’s, LFT’s
4. Blood cultures – each sample must be labelled from where it is taken (e.g. red lumen)
a. 1 culture from each lumen of the CVL (red and white) – ideal volume 5ml each
b. If no CVL – 1 peripheral culture

Investigations to perform if any clinical indications:

1. CXR if signs or symptoms of respiratory disease

2. Nasopharyngeal aspirate if signs or symptoms of respiratory disease or coryza. Nose and
throat swab in a viral transport medium is an alternative (request PCR for CMV, EBV and
respiratory viruses as appropriate; please note 9.30am cut off for respiratory viruses).
3. Stool culture if diarrhoea – MC+S, virology, Clostridium difficile toxin (discuss C difficile
with microbiology if patient under 5 years)
4. Coagulation screen if septic – APPT, INR, fibrinogen
5. Urine culture – clean catch for urine dipstix and urgent MC+S
5. Throat swab – bacterial (in charcoal) and viral cultures (in viral transport medium)
6. Skin lesions:
a. Bacterial skin swab
b. CVL site
c. Gastrostomy site
7. If CVL in situ consider septic embolic phenomena – ECHO CVL
8. Abdo X ray / USS if signs of abdo distension / tenderness

Subsequent Investigations
1. FBC – repeated at least twice weekly
2. Biochemistry as clinically indicated
3. At 48 hours and still febrile – Discuss patient with Experienced Registrar or
Consultant
a. Repeat examination, including perianal region
b. Repeat blood cultures
4. At 96 hours and still febrile – Discuss patient with Experienced Registrar / Consultant
a. Repeat full clinical examination, including perineum
b. Repeat blood cultures
c. Discuss performing echocardiogram of heart and line tip
d. Discuss abdominal ultrasound for fungal lesions in liver and spleen plus
galactomannan test

Discuss performing x-rays of sinuses if clinical signs are present and the patient is in right age
group – late childhood and older.

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General measures
 If the duration of neutropaenia is predicted to be prolonged, preventative measures need to
be instituted:
 Stop immunosuppressive agents if appropriate
 Do not routinely give any medication via PR route
 Support haematological requirements appropriately
 Do not routinely use NSAIDs as an anti-pyretic
 Good mouth care and dental hygiene
 Prophylaxis against pneumocystis (Co-trimoxazole) in patients expected to have
prolonged myelosuppression (particularly lymphopenia) - to continue throughout
treatment (except in close relation to high dose methotrexate)
 Prophylaxis against fungal infections (Fluconazole)
 If exposed to building/construction work there is an increased risk of mould infections.
If this exposure cannot be avoided, fungal prophylaxis should include an agent active
against aspergillus species.

 GCSF – institution of GCSF therapy is a consultant decision.

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EMPIRICAL ANTIBIOTIC REGIME

IF AT ANY TIME DURING ADMISSION A CHILD APPEARS SEPTIC, DISCUSS THE

CONDITION WITH THE ONCOLOGY CONSULTANT ON-CALL
Antibiotics must be administered within ONE HOUR of arrival to hospital.
Decision to change antibiotics at any time will be a Consultant decision.

Prescribe paracetamol 15mg/kg every six hours alongside antimicrobials to control fever

First line antimicrobials:

1. IV piperacillin/tazobactam (Tazocin) 90mg/kg every 6 hours (max 4.5 grams qds)

 Use meropenem if meningitis suspected.
2. IV Gentamicin 7mg/kg stat dose (prescribe on front of drug chart)
 If pre-existing renal impairment then consider dose reduction – see gentamicin
guideline
 After senior review if this is continuing then levels should be taken according to
local guidelines
3. Oral fluconazole prophylaxis 3mg/kg once daily – continue while neutropaenic

Additional to first line antibiotics:

1. Add IV Teicoplanin (a glycopeptide) 10mg/kg (max 400mg) every 12 hours for 3

doses, then once daily) as first line agent if:
 CVL related infection suspected (line or tunnel infection)
 pain/inflammation round an endoprosthesis
 Severe mucositis
 Previous MRSA isolate

2. Consider using antibiotic (NUH and UHL only) or ethanol line locks (UHL only) for
gram positive line infections – instil appropriate volume into each lumen and aspirate
after 24hours
 vancomycin 20mg in 2ml for Gram positive organisms
 gentamicin 3mg in 2ml for Gram negative organisms (always in liaison with a
medical microbiologist)
 line removal strongly recommended for infections caused by staph aureus,
MRSA, Coliforms, Pseudomonas and Candida species

Second line antibiotics: If febrile at 48 hours – Discuss possible second line antibiotics with
Consultant
Consider adding:
 IV Teicoplanin 10mg/kg (max 400mg) every 12 hours for 3 doses, then once daily

Third line antibiotics: If febrile at 96 hours – Discuss possible third line antibiotics with
Consultant:
Consider empirical treatment for possible fungal infection (Experienced Registrar / Consultant
decision only):
 IV Liposomal amphotericin (Ambisome)
 Dose 1mg/kg once daily (remember to prescribe test dose as per cBNF)
 Increase to 3mg/kg once daily if fever does not settle or high suspicion of fungal
infection

Discuss change of antibiotic with Consultant on call:

 IV meropenem 20mg/kg (max 1g) every 8 hours

Adam Henderson 8 of 11 August 2013 8

Discharge

Patients can be considered for discharge once 48 hour cultures are reported if ALL of the
following criteria are met:
1. No signs of sepsis
2. Blood cultures negative at 48 hours
3. Temperature settling or afebrile
4. Experienced Registrar / Consultant is aware of plan and agrees to discharge

Discharge medications:
 Fluconazole antifungal prophylaxis if still neutropaenic (to continue until
neutrophil recovery).

Some children may be sent home on oral antibiotics. This is a Experienced Registrar /
Consultant decision only.

Assessment of febrile patients with neutrophils > 0.5 who are

immunosuppressed ie chemotherapy / immunodeficiency
All patients should have the same history and examination and initial investigations
instituted as per Febrile Neutropaenic Guideline.

 ADMISSION AND ANTIBIOTIC THERAPY SHOULD BE INSTITUTED IN ANY

PATIENT WHO SHOWS SIGNS OF INFECTION REGARDLESS OF THEIR
NEUTROPHIL COUNT (Coryza alone is not an indication for starting iv antibiotics)
 Identifiable source of infection – treat with appropriate antibiotics, can discharge home if
well
 No obvious source of infection – careful observation. Antibiotics may not be necessary.
 If in doubt, contact Experienced Registrar / Consultant.

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 FEBRILE NEUTROPAENIA MANAGEMENT ALGORITHM
IF ANY PATIENT SHOWS SIGNS OF INFECTION COMMENCE ANTIBIOTICS AND
ARRANGE FOR URGENT SENIOR REVIEW

Confirm neutropaenia and fever:

 Neutrophils < 0.5
 Temperature > 38.50 once OR
 > 380 x 2, 1 hour apart

First line antibiotics

Relevant immediate investigations:  Tazocin General measures:
 Blood cultures  Stat dose of  Stop immunosuppressive agents
 Urine dipstix and culture
Gentamicin  if appropriate
 Throat swab – bacterial and viral  Fluconazole while neutropaenic
Teicoplanin
 Biochemistry – UE, LFT, CRP  Antipyretics – no PR medications
 Haematology – DIC screen if septic  Mouth care
Blood Culture @ 480

Positive Negative

Febrile

Continue appropriate
antibiotics – discuss length Yes No
with microbiology

Discuss with senior staff Discharge:

 Repeat FBC, blood cultures  WELL CHILD
 Consider adding Teicoplanin  D/W Consultant
 Fluconazole

Blood Culture @ 960

Negative and febrile Negative and afebrile > 480

Important Points to Consider:
 Discuss antibiotic choice for all
relapsed patients with Investigate for
experienced registrar / systemic fungal
consultant infection Stop antibiotics
 CVL infection suspected –
discuss addition of Glycopeptide
 If abdominal signs or symptoms DISCUSS WITH CONSULTANT
see specific guidance  Repeat FBC at least twice weekly
 ALWAYS CHECK INSIDE  Repeat blood culture
COVER OF PATIENT FOLDER  CXR
FOR SUGGESTED FIRST LINE o Possible: Abdominal ultrasound – hepatic and splenic masses
DRUG THERAPY OR KNOWN ECHO – cardiac valve and line thrombi
RESISTANCE
Empirical Ambisome
 Test dose, then 1-3mg/kg OD
Adam Henderson 10 of 11 August 2013 10
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