Neutrophils are white blood cells and are plentiful in a normal circulation. They are crucial for a normal functioning immune system. They phagocytose organisms and their numbers increase in infections and inflammation, especially bacterial infections.

Neutropenia means a low neutrophil count. The normal range for neutrophils is 2.5-7.5 x 10⁹/L. In the 1960s it was first discovered that as the neutrophil count falls, especially once neutrophils <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 two questions:

1. What is the cause of neutropenic sepsis if present?
2. What is the underlying cause of neutropenia?

The causes of neutropenic sepsis can be bacterial, viral, or fungal (see below). In terms of the underlying cause of neutropenia, this can be divided into congenital or acquired. Acquired causes include chemotherapy, bone marrow infiltration, e.g. malignancy and viral infections (see box headed 'Some underlying causes of neutropenia', below).

Neutropenic patients can be divided into 3 clinical groups

1. Immunocompetent patients presenting with neutropenia and compromised, requiring urgent treatment.
2. Immunocompromised patients presenting with neutropenia and compromised, requiring urgent treatment.
3. 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).

Approach to a patient with neutropenia

The most important concern is to determine whether the neutropenic patient is septic - this will require urgent and prompt management. A summary of this is as follows:

• Resuscitate the patient, e.g. if hypovolaemic or septic shock is present.
• Does the patient have signs of sepsis, e.g. fever, tachycardia, hypotension?
• Full history and examination (see below).
• Send cultures (see below for full list of investigations).
• Antibiotics - begin with broad spectrum according to local guidelines, e.g. Tazocin® and an aminoglycoside.
• Look for clues to the source of infection - if found then alter the antibiotic regimen to more specific therapy
  Some causes of neutropenic sepsis:
  • Bacteria:
    • Gram-positive cocci - S. aureus and viridans group streptococci.
    • Gram-negative bacilli - Pseudomonas spp. and coliforms.
  • Viruses:
    • These are more usually associated with problems in defects of cellular immune function.
    • The most common viruses that cause problems in neutropenic patients are herpes viruses.
    • Other viruses include CMV, human herpes virus type 6 (HHV-6), VZV and respiratory syncytial virus.¹
  • Fungi:
    • Invasive fungal infections are associated with a high morbidity and mortality rate.²
    • Organisms include invasive candidiasis and aspergillosis.
    • Aspergillosis presents as pyrexia with pulmonary infiltrates and is difficult to treat.^3,4
  Therapy can even be tailored from the outset, e.g. vancomycin in patients with known meticillin-resistant Staphylococcus aureus (MRSA) or acyclovir in cases of varicella zoster virus (VZV)/herpes simplex virus (HSV) infection.
• Discover the underlying cause for the neutropenia and treat if possible (see box below).
  

  Some underlying causes of neutropenia Congenital: Rare, present from birth, e.g. Kostmann's syndrome. Acquired: Bone marrow infiltration with malignancy. Aplastic anaemia. Vitamin B12 or folate deficiency. Chemotherapy. Radiotherapy. Felty's syndrome. Hypersplenism. Drugs, e.g. phenytoin, chloramphenicol. Autoimmune neutropenia. Infections, e.g. viral, typhoid.

• If the patient is well or once the patient has improved, there may be a need to consider prophylactic antibiotics and vaccinations. It might be necessary to liaise with haematology and microbiology specialists.
• Immunosuppressed patients will need careful consideration of further management issues, e.g. prophylactic antibiotics.

• Acute respiratory distress syndrome - commonly associated with viridans group streptococci.
• Disseminated intravascular coagulation (DIC).
• Multiple organ failure.

History in neutropenic patients

Aim to find the cause of neutropenia and the source of sepsis - include a full systems' review and sexual history.

• Does the patient belong to a high-risk group, e.g. active neoplastic disease, a recent course of chemotherapy, immunosuppressant therapy, e.g. 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, e.g. cannulae, central lines, urinary catheter.

Examination in neutropenic patients

Looking for a source of the sepsis:

• General examination: pyrexia, stigmata of infective endocarditis, lymphadenopathy, skin rashes.
• Ear, mouth and nose examination.
• Fundoscopy.
• Gastrointestinal tract (avoid digital rectal examination until antibiotics have been given).
• Respiratory system.
• Genitourinary tract.
• Cardiovascular system.
• Neurological, e.g. neck stiffness.

Remember immunosuppressed patients may not be able to mount clinical signs.

Investigations to consider in a neutropenic septic patient

• FBC, blood film, D-dimer and fibrinogen testing to look for DIC.
• U&E, creatinine testing.
• Liver function tests.
• C-reactive protein and erythrocyte sedimentation rate.
• Coagulation screen.
• CXR.
• Blood cultures (take multiple cultures from peripheral sites and via lines and include mycobacterium blood cultures if suspected).
• Urine dipstick, microscopy, culture and sensitivity (MC&S), and cytology.
• Stool MC&S, ova, cysts and parasites, Clostridium difficile toxin.
• Skin lesions for culture.
• Serology or polymerase chain reaction for viruses, e.g. cytomegalovirus (CMV).
• More specialised investigations such as bronchoscopy and CT scans.

Other points to note

• Over the last few decades the organisms involved in neutropenic sepsis have changed; organisms such as enterococci and legionellae are becoming more frequent.
• Also there is an increased resistance to antibiotics, such as Pseudomonas spp. resistant to imipenem.
• At present there is no role for the use of prophylactic antibiotics in patients with chronic neutropenia in whom there are no symptoms or signs of infection.⁵

Other management issues

• If neutropenia is chronic and the patient is not displaying any infective symptoms then discuss with a haematology specialist.
• Reverse barrier nursing is required.
• Treat all with broad spectrum antibiotics (according to local policy) if there is acute neutropenia or a rapidly falling neutrophil count with fever.
• Some treat all with a neutrophil count <500, even if there is no fever - see local hospital guidelines or discuss with haematologists/microbiologists.
• Dual therapy is mainstay (once all cultures are sent) - but do not delay if the patient has sepsis, e.g. gentamicin and antipseudomonal cover (such as Tazocin®).
• A systematic review and meta-analysis comparing β-lactam and aminoglycoside combination versus β-lactam alone found no difference between the two.⁶ Superinfections were also similar in both groups.
• There is recent evidence for monotherapy with imipenem provided the patient is not shocked or if pseudomonas species grown.²
• If there is ongoing fever, consider other organisms such as fungi and further investigations such as ultrasonography or CT scanning looking for abdominal collections.
• Most patients are admitted and treated for 7-14 days or until the neutrophil count improves. They may be converted to oral therapy once they are apyrexial. Oral therapies include ciprofloxacin and co-amoxiclav.
• Infections associated with chronic neutropenia can be treated on an outpatient basis under specialist advice. Oral antibiotics have also been used in low-risk cancer patients with neutropenia.⁷
• The National Institute for Health and Clinical Excellence (NICE) is in the process of reviewing evidence relating to neutropenic sepsis in cancer patients.

Granulocyte colony-stimulating factor in neutropenia

• Granulocyte colony-stimulating factor (G-CSF) is a growth factor that is given subcutaneously and can stimulate the bone marrow, thus leading to an increased number of white cells.
• In some cases, G-CSF is used prophylactically, e.g. following chemotherapy.
• In neutropenic patients with an infection, G-CSF can be given to help counteract the infection, along with antibiotics.
• G-CSF shortens the time taken for the neutrophil count to recover.^7,8
• Treatment with G-CSF is usually reserved for neutropenia associated with severe (high risk of deterioration) or recurrent infections. However the evidence at present does not show any clear benefit for the use of G-CSF.⁷
• Side-effects of G-CSF include pain and itchiness at the site of injection. It can itself cause fever, diarrhoea and vomiting.

Document references

1. Wood MJ; Viral infections in neutropenia--current problems and chemotherapeutic control. J Antimicrob Chemother. 1998 Jun;41 Suppl D:81-93. [abstract]
2. Donowitz GR, Maki DG, Crnich CJ, et al; Infections in the neutropenic patient--new views of an old problem. Hematology Am Soc Hematol Educ Program. 2001;:113-39. [abstract]
3. Warnock DW; Fungal infections in neutropenia: current problems and chemotherapeutic control. J Antimicrob Chemother. 1998 Jun;41 Suppl D:95-105. [abstract]
4. Kerr KG; The prophylaxis of bacterial infections in neutropenic patients. J Antimicrob Chemother. 1999 Nov;44(5):587-91.
5. Mulinde J, Joshi M; The diagnostic and therapeutic approach to lower respiratory tract infections in the neutropenic patient. J Antimicrob Chemother. 1998 Jun;41 Suppl D:51-5. [abstract]
6. Paul M, Soares-Weiser K, Leibovici L; Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis. BMJ. 2003 May 24;326(7399):1111. [abstract]
7. Oppenheim BA, Anderson H; Management of febrile neutropenia in low risk cancer patients. Thorax. 2000 Aug;55 Suppl 1:S63-9.
8. Berliner N, Horwitz M, Loughran TP Jr; Congenital and acquired neutropenia. Hematology Am Soc Hematol Educ Program. 2004;:63-79. [abstract]

Internet and further reading

• Guidelines for the management of febrile neutropenia in oncology patients, Nottingham University Hospital (2009)

Acknowledgements