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Fever - neutropenic

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Shared care information

All children who are under the care of a paediatric oncology unit who phone or present with fever need urgent review. Systems need to be in place in all shared care centres for these children to be fast tracked through ED and have a complete history, examination and appropriate investigations as listed below done rapidly so that antibiotic therapy for neutropenic patients with suspected infection can be started within 1 hour. (30 minutes if systemic compromise present).

Risk factors

The risk and pattern of infection in children with cancer and/or neutropenia depends on the primary diagnosis and the type, duration and intensity of the treatment. Some or all of the following factors may influence the type and risk of infection:

Treatment related

  • Duration and severity of neutropenia
  • Associated gut toxicity due to cytotoxic drugs and/or irradiation
  • Previous radiotherapy, particularly TBI or whole neuoraxis irradiation
  • Chronic graft-versus host disease
  • Long-term immunosuppressive treatment, as in continuing (maintenance) therapy for ALL
  • Presence of central venous catheter
  • Hypogammaglobulinaemia
  • Steroids (Dexamethasone > Prednisone)

Disease related

  • AML, haemopoietic stem cell transplant, infant ALL, intensive B-NHL protocols and very severe aplastic anaemia - high risk of bacterial and fungal infection
  • Allogeneic stem cell transplantation and/or profound T cell immunosuppression from drugs such as ATG, campath - high risk of bacterial, fungal and viral infection (e.g., CMV, adenovirus, RSV, parainfluenza) and, if chronically immunosuppressed by GVHD, pneumococcal infection
  • ALL during maintenance - measles, varicella zoster and pneumocystis.

Patient related

  • Cahexia and malnutrition
  • Prophylactic and prior antibiotic usage
  • Previous latent infections/colonisations (e.g., CMV, HSV)
  • Home situation (hygiene, building works, etc).

Teaching points

  • The symptoms and signs of infection may be minimal or absent in the presence of neutropenia due to the lack of the neutrophil mediated inflammatory response. The majority of patients who present with febrile neutropenia have few clinical findings apart from fever. There is no certain way of telling which febrile neutropenic patients have a potentially life-threatening infection; therefore, all such patients require prompt investigation and empirical treatment with antibiotics.
  • The most frequent blood culture isolates are Staph. Epidermidis (coagulas negative staphylococcus), various Streps, G-ve rods, Staph. aureus but the most rapidly lethal are E coli, Klebsiella and Pseudomonas. Hence empirical antibiotic therapy is often weighted towards G-ve organisms although they are not the most common isolates.
  • The origin of most bacterial sepsis in neutropenic patients is from the host themselves, i.e., not from transmission by contact with an infected individual. Therefore, neutropenic children are generally not withdrawn from social contact such as schooling.
  • The risk of viral infection e.g., chickenpox is independent of the neutrophil count and more related to lymphocyte number and function. Any child receiving chemotherapy is at risk regardless of their neutrophil count.
  • A minority of patients have evidence of localised infection and may then require specific investigation and therapy e.g., interstitial pneumonia.

Prevention of infection

The following measures may be taken in an attempt to avoid infection:

  • minimising exposure to contacts known to be infected, especially chickenpox
  • passive immunisation after exposure to varicella zoster or measles
  • encouraging immunisation of parents and siblings with normal childhood immunisation schedule, influenza, etc
  • dietary advice
  • protecting mucosal and epithelial barriers
    • mouth care
    • avoidance of rectal medications or procedures if patient is neutropenic
    • strict aseptic technique with IV sites and central venous catheters
    • avoidance of routine surgical procedures when patient is neutropenic e.g., dental extractions
  • prophylactic antibiotics
  • G-CSF (see indications for Cytokines).

Management of Febrile Neutropenia in Shared Care Centres

Antibiotic therapy should start with one hour of presentation. In patients who present very unwell or with septic shock then bloods should be taken while the line is being accessed for the first antibiotic dose which should not be delayed for blood results. Shock should be treated with IV fluids as per APLS guidelines. History and examination can occur concurrently. Patients on Steroids may need replacement therapy. See Addisonian Crisis.

If the patient is very unwell or there are any other concerns then the paediatric oncologist on call should be contacted at the time of admission. The local paediatrician should be contacted as they have responsibility for the patient until they are handed over to the shared care paediatrician.

Contact with the paediatric oncology unit should be made to inform them of the admission as soon as possible during working hours otherwise.

Antibiotics

Antibiotics usage should follow the antibiotic guidelines. If blood cultures are positive it may be possible to rationalise the antibiotics but this needs to be discussed with the paediatric oncologist on call.

Ongoing care

Well patients can be managed in the shared care centre with regular (daily) contact with the oncology unit. Any changes in a patient's clinical state should be discussed with the oncology unit and any positive blood culture results should be e-mailed or discussed. In most cases, patients admitted with febrile neutropenia should stop oral and IV chemotherapy but this needs to be discussed with the paediatric oncologist.

All patients need:

  • Daily FBC while neutropenic
  • Biochemistry if on nephrotoxic drugs
  • Daily blood cultures while febrile or for 48 hours after a positive blood culture until culture is negative. If culture fails to clear after 48 hours, line removal may be indicated. Discuss with the oncology unit.
  • Therapeutic drug monitoring if on Gentamicin, Vancomycin etc
  • Continuing mouth cares
  • Daily review and full examination
  • Platelet transfusion threshold for febrile patients is 20 x109/L rather than 10 x109/L.

Use of antipyretics - once a child has been started on antibiotics, paracetamol can be used to treat symptoms of fever on a prn basis but should not be used regularly. Aspirin and NSAIDs should be avoided.

When to transfer

Some patients may require transfer to the tertiary unit on presentation while others may require transfer after some time in a shared care centre.

Reasons to consider transfer at presentation may include (but are not limited to):

  • Septic shock - after initial resuscitation consider if the patient requires paediatric intensive care, in which case they should be transferred to Starship by a retrieval team after discussion with a paediatric oncologist from the child's oncology centre.
  • Moderate or severe mucositis
  • Soft tissue infection
  • Port pocket infection
  • Leukaemia during induction or reinduction therapy
  • Bone marrow ablative therapy - following allogeneic or autologous haematopoietic stem cell rescue (6 months for autologous and 12 months for allogeneic regardless of neutrophil count).
  • Abdominal pain or tenderness
  • Recent major surgery
  • Pneumonia or CXR suggestive of infective change
  • Dexamethasone - patient either on this medication or a) within two days of completing five day course or b) within a week of completing a course longer than five days
  • Concern by the shared care centre about any aspect of the patient's care, e.g., ability to supply platelets, etc. It is the decision of the shared care centre whether they feel happy to keep a child.

Reasons to consider transfer in a current inpatient include (but are not limited to):

  • Ongoing fever >48 hours in an otherwise well child
  • Worsening clinical state regardless of fever
  • Development of potential surgical problems
  • Ongoing positive blood cultures
  • Probable or proven fungal or significant viral infection (e.g., CMV, RSV).

Management of Febrile Neutropenia in Oncology Unit

Initial management

Once a history, examination, and investigations have all been taken, antibiotics should be started without delay within 1 hour of presentation. In patients who present very unwell or with septic shock, then bloods should be taken while the line is being accessed for the first antibiotic dose, which should not be delayed for blood results. Shock should be treated with IV fluids as per APLS guidelines. History and examination can occur concurrently.

Antibiotics

Antibiotics usage should follow the antibiotic guidelines. If blood cultures are positive it may be possible to rationalise the antibiotics later but this needs to be discussed with the paediatric oncologist on call.

Specific issues

  • Septic shock - after initial resuscitation consider if the patient requires nurse specialing, intensive care
  • Moderate or severe mucositis (may need the addition of metronidazole and investigation for underlying HSV infection)
  • Abdominal pain or tenderness (consider paediatric surgical opinion).
  • Soft tissue infection - may have localised pain without erythema or tenderness. Different antibiotic coverage or surgical intervention may be required.
  • Port pocket infection (may need surgical drainage or removal)
  • Recent CVL insertion - add flucloxacillin
  • Renal impairment or on nephrotoxic drugs e.g., cisplatin, high dose methotrexate - see antibiotics in renal impairment
  • Bone marrow ablative therapy - following allogeneic or autologous haematopoietic stem cell rescue (6 months for autologous and 12 months for allogeneic regardless of neutrophil count). These patients should be treated as neutropenic regardless of neutrophil count
  • Recent major surgery
  • Pneumonia or CXR suggestive of infective change.

Ongoing care

In most cases patients admitted with febrile neutropenia should stop oral and IV chemotherapy but this needs to be discussed with the treating oncologist. Exceptions include:

  • ALL and AML during induction treatment
  • dose-intense rapid treatments (e.g., rapid COJEC).
  • All patients need:
    • Daily FBC (+/- CRP)
    • Electrolytes and Cr if on nephrotoxic drugs
    • Daily blood cultures while febrile or for 48 hours after a positive blood culture if CVL present
    • Therapeutic drug monitoring if on Gentamicin, Vancomycin etc
    • Continuing mouth cares
    • Daily review and full examination
    • Platelet threshold for febrile patients is 20 x109/L rather than 10 x109/L.

Use of antipyretics - once a child has been started on antibiotics, paracetamol can be used to treat symptoms of fever on a prn basis but should not be used regularly.

References

Tam CS, O'Reilly M, Andresen D et al. Use of empiric antimicrobial therapy in neutropenic fever. IMJ 2011;41:90-101.

Freifeld AG, Bow EJ, Sepkowitz KA et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. CID 2011:52:e56-e93.

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  • Date last published: 03 March 2014
  • Document type: Clinical Guideline
  • Services responsible: National Child Cancer Network