Neutropenia means a low neutrophil count. The normal range for neutrophils is 2.5-7.5 x 109/L. Moderate neutropenia is defined as neutrophil count of 0.5-1.0 x 109/L. Severe neutropenia is a count of <0.5 x 109/L.
As the neutrophil count falls, especially once neutrophils are <1 x 109/L, a patient becomes immunocompromised and at risk of serious infections which may be fatal.
When faced with a patient with neutropenia it is important to answer the following questions:
- What is the underlying cause of neutropenia?
- What is the cause of neutropenic sepsis if present?
Neutropenic patients can therefore be divided into three clinical groups:
- Otherwise well patients with neutropenia. These patients may be known to be neutropenic previously or presenting de novo and require investigation to look for an underlying diagnosis.
- Immunocompetent patients presenting with neutropenia and compromised, requiring urgent treatment.
- Immunocompromised patients presenting with neutropenia and compromised, requiring urgent treatment.
Neutropenia is a common finding on routine FBC. Patients may have recurrent infections, autoimmune diseases, a previously diagnosed haematological disease or solid tumour indicating an obvious disease-related state. However, when the finding is unexpected, thorough consideration of possible underlying causes is the first step.
- Rare disorders of neutrophil production (present from birth) - eg, Kostmann's syndrome, X-linked agammaglobulinaemia, Shwachman-Diamond syndrome, Chédiak-Higashi syndrome, myelokathexis and cyclical neutropenia.
- Ethnic variation - particularly in patients of African descent.
- Cyclical neutropenia in children (rare - recurring episodes of severe neutropenia accompanied by malaise, fever, adenopathy, anorexia and ulceration of mucous membranes).
- Decreased or ineffective neutrophil production:
- Bone marrow infiltration with malignancy.
- Aplastic anaemia.
- Vitamin B12 or folate or iron deficiency.
- Chemotherapy - cytotoxics and immunosuppressants.
- Exposure to chemical agents - eg, benzene, organophosphate.
- Drugs - eg, phenytoin, chloramphenicol, alcohol (abuse).
- Autoimmune neutropenia.
- Infections - eg, infectious mononucleosis, hepatitis B or C, human immunodeficiency virus, cytomegalovirus infection, typhoid.
- Accelerated neutrophil turnover in the blood:
- Felty's syndrome (rheumatoid arthritis, splenomegaly, and granulocytopenia).
- Malaria and acute bacterial infections.
- Changes in shifts of cells from the circulating to the marginal blood pools:
- Dengue fever, measles and viral infections.
- Unclear or combination of mechanisms:
- Toxoplasmosis, malaria, kala-azar.
- Treatment with a wide variety of analgesics, anti-inflammatories, anticonvulsants, antibiotics, antihistamines, diuretics, hypoglycaemics and antidepressants.
- Thyroid dysfunction.
- Autoimmune neutropenia.
An initial approach may therefore include history, examination and blood tests, guided by clinical suspicion. Initial additional tests (if not already tested) may reasonably include U&Es, serum folate, vitamin B12, iron and ferritin, serum liver enzymes, serum proteins, antinuclear and anti-DNA antibodies and rheumatoid factor and TFTs.
Many of the cases will be transient, or will resolve when the underlying cause is treated or removed. Approximately 34% of cases will be chronic and idiopathic. There is currently no evidence to support prophylactic antibiotics for asymptomatic patients with idiopathic neutropenia.
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Febrile neutropenia (FN) is defined as an oral temperature ≥38.5°C or two consecutive readings of ≥38.0°C for two hours and an absolute neutrophil count ≤0.5 x 109/L, or expected to fall below 0.5 x 109/L.
Successful management depends on early recognition. Patients should be educated to monitor their symptoms (including body temperature), and be given clear written instructions on when and how to contact the appropriate service in the event of concerns.
- History to include:
- Does the patient belong to a high-risk group - eg, active neoplastic disease, a recent course of chemotherapy, immunosuppressant therapy (eg, azathioprine, steroids) or immunosuppressive illnesses such as HIV?
- Renal failure.
- Include duration since last chemotherapy cycle if applicable.
- Any recent blood products.
- Any intravascular devices - eg, cannulae, central lines, urinary catheter.
- Checking past microbiology results for history of resistant organisms.
- Cardiac and respiratory systems (and resuscitate where necessary). NB: signs and symptoms of infection in neutropenic patients can be minimal.
- General examination: pyrexia, stigmata of infective endocarditis, lymphadenopathy, skin rashes.
- Potential foci of infection:
- Ear, mouth and nose examination.
- Gastrointestinal tract (avoid digital rectal examination until antibiotics have been given).
- Respiratory system.
- Genitourinary tract.
- Neurological - eg, neck stiffness.
- FBC (current neutrophil level).
- Two sets of blood cultures from a peripheral vein, and any indwelling venous catheters.
- Other investigations to consider in a neutropenic septic patient:
- Blood film, D-dimer and fibrinogen testing (to look for disseminated intravascular coagulation).
- U&E, creatinine.
- CRP and ESR.
- Coagulation screen.
- Serology or polymerase chain reaction for viruses - eg, cytomegalovirus.
- More specialised investigations such as bronchoscopy and CT scans.
- Sputum, urine, skin swabs and stool specimens where clinically indicated.
The next step is to use a risk assessment tool. The most widely used instrument is the Multinational Association for Supportive Care in Cancer (MASCC) index. It uses the following characteristics:
- Burden of illness.
- No, or mild symptoms - 5 points.
- Moderate symptoms - 3 points.
- Severe symptoms - 0 points.
- Absence of hypotension (systolic BP ≥90 mm Hg) - 5 points.
- Absence of chronic obstructive pulmonary disease - 4 points.
- Presence of solid tumour/lymphoma with no previous fungal infection - 4 points.
- No dehydration - 3 points.
- Outpatient status (at onset of fever) - 3 points.
- Age ≤60 years - 2 points.
Low-risk cases are those scoring ≥21.
Oral antibacterial therapy can be used safely in some low-risk FN patients although its use in the UK is still low. These are patients who are haemodynamically stable, who do not have acute leukaemia or evidence of organ failure, who do not have pneumonia, an indwelling venous catheter or severe soft tissue infection.
Quinolone with amoxicillin plus clavulanic acid is the preferred choice given the rise in Gram-positive FN episodes. Oral quinolone therapy should not be used in patients who have taken a quinolone antibacterial as prophylaxis.
The National Institute for Health and Clinical Excellence (NICE) recommends that all patients who require intravenous treatment be commenced on beta-lactam monotherapy with piperacillin and tazobactam. Aminoglycosides should NOT be used for initial empirical therapy, unless there are specific patient or local related reasons.
Coverage for meticillin-resistant Staphylococcus aureus (MRSA) or resistant Gram-negative bacteria may be required. If pneumonia is diagnosed, antibiotic cover must be extended to treat atypical organisms such as Legionella spp. and Mycoplasma spp. by adding a macrolide antibiotic.
- The frequency of this should be determined by severity, but may be required every 2-4 hours in cases needing resuscitation.
- Daily assessment of fever trends, bone marrow and renal function is indicated until the patient is apyrexial and neutrophil count is ≥0.5 x 109/L.
- If the patient is apyrexial and the neutrophil count is ≥0.5 x 109/L at 48 hours, low-risk patients with no obvious cause found can be changed to oral antibiotics. High-risk patients with no cause found can have their aminoglycoside discontinued. When a cause has been found they should continue on appropriate specific therapy.
- If the neutrophil count is normal, the patient is asymptomatic and has been afebrile for 48 hours and blood cultures are negative, antibacterials can be discontinued. If the neutrophil count is still low, but the patient has not had complications and has been afebrile for 5-7 days, antibacterials can be discontinued. In some high-risk cases (acute leukaemia and following high-dose chemotherapy) antibiotics are often continued for up to 10 days, or until the neutrophil count is normal.
- Careful consideration may be required (and appropriate microbiological advice sought) regarding future prophylaxis.
Mortality from febrile neutropenia has reduced but remains significant. Aggressive use of in-patient intravenous antibiotics has reduced the need for intensive care management to fewer than 5% of cases in England. Overall mortality rates are approximately 5% in patients with solid tumours but may be as high as 11% in some haematological malignancies. The serious medical complication rate in those with a MASCC risk score of ≥21 is estimated to be 6% and mortality just 1%.
Prognosis is worst in patients with proven bacteraemia, with mortality rates of 18% in Gram-negative and 5% in Gram-positive bacteraemia.
Adult patients (aged over 18 years) with acute leukaemias, stem cell transplants or solid tumours, who undergo chemotherapy which is likely to cause a period of significant neutropenia (ie neutrophil count 0.5 x 109 or lower), should be offered prophylaxis with a fluoroquinolone. This should be taken only during the period of neutropenia.
Granulocyte colony-stimulating factor
G-CSF is a growth factor that can stimulate the bone marrow, thus leading to an increased number of white cells. It is given subcutaneously.
In some cases (but not routinely), G-CSF is used prophylactically - eg, following chemotherapy. In neutropenic patients with an infection, G-CSF can be given to help counteract the infection, along with antibiotics.
Further reading & references
- Lewis MA, Hendrickson AW, Moynihan TJ; Oncologic emergencies: Pathophysiology, presentation, diagnosis, and treatment. CA Cancer J Clin. 2011 Aug 19. doi: 10.3322/caac.20124.
- Godwin JE et al, Neutropenia, Medscape, May 2011
- Lima CS, Paula EV, Takahashi T, et al; Causes of incidental neutropenia in adulthood. Ann Hematol. 2006 Oct;85(10):705-9. Epub 2006 Jun 29.
- Management of febrile neutropenia: ESMO Clinical Practice Guidelines, European Society for Medical Oncology (2010)
- Klastersky J et al, The Multinational Association for Supportive Care in Cancer Risk Index: A Multinational Scoring System for Identifying Low-Risk Febrile Neutropenic Cancer Patients, Journal of Clinical Oncology, Aug 2000
- Paesmans M, Klastersky J, Maertens J, et al; Predicting febrile neutropenic patients at low risk using the MASCC score: does Support Care Cancer. 2011 Jul;19(7):1001-8. Epub 2010 Jul 2.
- Ziglam HM, Gelly K, Olver W; A survey of the management of neutropenic fever in oncology units in the UK. Int J Antimicrob Agents. 2007 Apr;29(4):430-3. Epub 2007 Feb 12.
- Neutropenic sepsis, NICE Clinical Guideline (September 2012)
- Cooper KL, Madan J, Whyte S, et al; Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis BMC Cancer. 2011 Sep 23;11:404.
|Original Author: Dr Gurvinder Rull||Current Version: Dr Hayley Willacy||Peer Reviewer: Dr Colin Tidy|
|Last Checked: 02/11/2012||Document ID: 372 Version: 5||© EMIS|
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