Molecular Medicine: A Case of Febrile Neutropenia

Question 1

Diagnose

Mrs KT is a 36 year old married woman with two children aged 4 and 6 years

She has noticed:

• Slowly worsening tiredness for six weeks
• Unusually severe bruising for two weeks
• Unusual bleeding from her gums for three days

Her GP sees that she is pale and has multiple bruises. She organizes a full blood count:

• Hb 81g/L (115–150)
• White cell count 8.6 10⁹/L (4–11)
  
  • Blasts 6.5 10⁹/L
  • Neutrophils 0.9 10⁹/L (2.2–7.5)
  • Lymphocytes 1.2 10⁹/L (1.5–2.5)
• Platelets 33 10⁹/L (150–400)

Answer 1

She is referred to the haematology department and a bone marrow examination is performed.

Diagnosis is acute myleoid leukaemia.

Question 2

Describe Treatment for AML

Answer 2

Chemotherapy for acute myeloid leukaemia is recommended. In course 1, DA3+10 include:

• Daunorubicin 50mg/m² daily by slow (1 hour) IV infusion on days 1,3 and 5 (3 doses).
• Cytosine arabinoside 100mg/m² 12-hourly by IV push on days 1-10 inclusive (20 doses).

Chemotherapy has prompt effects on her marrow and her peripheral blood (decreased haemoglobin, platelets, white blood cells)

Question 3

What would you find in the history and examination in people with febrile neutropenia?

Answer 3

• Nothing in history suggests the site of infection
• No cough or shortness of breath (SOB), abdominal pain, urinary frequency or dysuria, skin lesions
• Nothing in examination suggests the site of infection
• Temp is 39.3^oC, nil else are abnormal

Question 4

What is Acute Myeloid Leukaemia?

Answer 4

Acute myeloid leukaemia (AML) is a type of cancer that affects immature blood cells on the myeloid line. AML causes an overproduction of abnormal blast cells (immature white cells) which crowd bone marrow and prevent it from making normal blood cells. Because the bone marrow cannot function properly, it cannot produce adequate numbers of red cells, normal white cells and platelets.

This makes people with AML more susceptible to anaemia, recurrent infections, bruising and bleeding easily.

The _abnormal blast cells (_leukaemic blasts) eventually spill out into the blood stream and can accumulate in various organs including the spleen and liver.

Question 5

11 days after starting her chemotherapy, Mrs KT phones the hospital to report two episodes of uncontrollable shivering, each lasting about 30minutes and a fever of 39.9^oC. Then, 2 days ago:

• Her total WBC count was <0.1 (4-11 10⁹/L)
• Her platelet count was 15 (150-400 10⁹/L)
• Her haemoglobin was 114g/L (115-150g/L)

Therefore, she acquired______________

Answer 5

Febrile Neutropenia

Question 6

Describe Febrile Neutropenia

Answer 6

Febrile neutropenia is the development of fever, often with other signs of infection, in a patient with neutropenia, an abnormally low number of neutrophil granulocytes (a type of white blood cell) in the blood.

1. Common in severely neutropenic patients
2. H_igh rate of bacteraemia_
3. Infections arise from e_ndogenous gut and skin flora_
   
   • ​​e.g. e-coli and staph
4. Very high mortality in patients with Gram-negative bacteraemia (without empiric Rx)
5. _Improved outcome with empiric antibiotic treatmen_t (started at presentation)

Question 7

Decsribe the risk of infection and low neutrophil count

Answer 7

Risk of infection is related to neutrophil count:

• Risk rises below 0.5 10⁹/L.
• >1% daily risk of bacteraemia with neutrophil count <0.1 10⁹/L.

Risk of infection is greatest in patients with prolonged, severe neutropenia.

Risk of infection related to neutropenia, if n_eutrophils <0.1,_ duration and risk of severe infection is:

• For 1 week, ~33%
• For 6 weeks, ~100%

Question 8

• ____ patients with febrile neutropenia have no evidence of infection
• ____ patients with febrile neutropenia are bacteraemic

Answer 8

• 40% no evidence of infection
• 30% patients with febrile neutropenia are bacteraemic

Question 9

What is the aetiology of Febrile Neutropenia?

Answer 9

• Infections arise from damaged barriers in the gut and the skin
• It is predominantly caused by
  
  • staphylococci,
  • streptococci
  • aerobic gram-negative bacilli

Question 10

What are the initial and further clinical management of Febrile Neutropenia?

Answer 10

Initial Clinical Course

Commenced on gentamicin and tazocin as empiric antibiotic therapy (treatment without all information based on educated guess)

• Antibiotics with a broad spectrum and quite strong

Gram-negative bacilli from catheter blood cultures identified as E. coli

• Sensitive to tazocin, ceftriaxone, gentamicin
• Resistant to augmentin

Gram-positive cocci from peripheral blood cultures identified as coagulase negative staphylococcus

• Sensitive to vancomycin
• Resistant to flucloxacillin

Further Clinical Course

• Continued on gentamicin and tazocin
• Recovery of neutrophil count observed from day 18 onwards with resolution of fever
  
  • Changed to monotherapy with tazocin alone
  • Repeat bone marrow examination at day 29 confirms morphologic remission of AML

Question 11

What is e-coli sensitive to and resistant to?

Answer 11

E. coli

• Sensitive to
  
  • tazocin,
  • ceftriaxone,
  • gentamicin
• Resistant to
  
  • augmentin

Question 12

What is coagulase negative staphylococcus sensitive to and resistant to?

Answer 12

Coagulase negative staphylococcus

• Sensitive to vancomycin
• Resistant to flucloxacillin

Question 13

Mrs KT’s results

• Blood cultures from central line: Gram negative bacilli
• Blood cultures from peripheral vein: Gram positive cocci
• Swab skin and mouth lesions: normal skin and oral flora
• Chest X-ray: lung-fields clear, normal cardiac and medias0nal contours

What is Mrs KT’s initial management?

Answer 13

• Tazocin (piperacillin and tazobactam) (active against almost all aerobic bacteria); and
• Gentamicin (aminoglycoside) (active against almost all aerobic Gram-negative bacilli)

Question 14

What are some strategies to reduce risk of neutropenic fever with further therapy?

Answer 14

Strategies To Reduce Risk Of Neutropenic Fever With Further Therapy

• Should we nurse the patient in isolation?
  
  • Patients with severe neutropenia can benefit somewhat from being nursed in isolation (hepa-filtered, sterilised environment).
    • It reduces the _duration o_f neutropenic fever
    • It r_educes infection_ risk from externally introduced organism, but does not reduce infection from patient’s own bacterial flora
    • I_t does not i_mpact overall survival rates
• Use of prophylactic antibiotics?
  
  • ​Not currently used in The Auckland Hospital.
• Role of haematopoietic growth factors
• Consider reducing intensity of subsequent course of chemotherapy (might compromise the patient outcome)