- Neutrophils are the most prevalent white blood cells in circulation. They are a type of polymorphonuclear (PMN) leukocyte, with 3-5 nuclear lobes and fine granules within the cytoplasm.
- Mature neutrophils exhibit 3-5 nuclear lobes, with immature forms exhibiting less lobes and hypersegmented exhibiting more. Females may display a 'drumstick' that protrudes from the nucleus.
- Neutrophils contain primary and secondary granules. The primary granules are azurophilic (Burgundy-coloured) and contain toxic mediators such as elastase and myeloperoxidase. The secondary granules are pink-staining and contain proteins such as lactoferrin; these are not usually visible by light microscopy.
Roles of Neutrophils
- Neutrophils make up part of the innate immune system, and as such act immediately and are non-specific in their action. They migrate to a site of infection and phagocytose pathogens such as bacteria, fungi and protozoa.
The Neutrophil Life Cycle
- Neutrophils are of granulocyte origin. They mature in the bone marrow and are then released into blood and tissues. Neutrophil proliferation and maturation is stimulated by granulocyte colony stimulating factor (G-CSF).
Stages of Neutrophil Development
- Banded neutrophil (<8% normally) - U-shaped nucleus
- Mature neutrophil - 3-5 nuclear lobes
- Neutrophilia is the presence of increased circulating neutrophils, and is a common finding in the full blood count of acutely unwell patients.
- Neutrophilia is classically caused by bacterial infection (or in fact any pyogenic infection), though there are several other important causes. Inflammation of any cause may result in neutrophilia, including the post-surgical state, burns and autoimmune disease. Long-term smoking can also cause a chronic low-grade neutropaenia.
- Acute stress or exertion can cause shift of neutrophils into the circulation, resulting in pseudoneutrophilia. Corticosteroids may cause neutrophilia through demargination of neutrophils from the endothelial lining, delayed migration from the circulation into tissues and delayed apoptosis. After splenectomy patients will develop neutrophilia.
- Myeloproliferative disorders are a less common cause of neutrophilia that are important not to miss.
Causes of Neutrophilia
- Pseudoneutrophilia (granulocyte shift) - vigorous exercise, emotional stress, vomiting, seizure, paroxysmal tachycardia
- Acute infection (particularly pyogenic) - bacterial, viral, fungal, parasitic
- Inflammation - e.g. surgery, burns, infarction, autoimmune disease
- Myeloproliferative neoplasms - CML, polycythaemia, essential thrombocytosis
- Solid tumours
- Post splenectomy
- Heavy smoking
- Neutrophilia should be correlated with the patient’s clinical state and other markers of inflammation
- Most often the history and examination will reveal the most likely cause of neutrophilia
- Neutrophilia with left shift of granulocytes on blood film is highly suggestive of acute bacterial infection
- Neutropaenia refers to reduced circulating neutrophils.
- Neutropaenia confers increased risk of infections - particularly bacterial and fungal - and fevers in these patients (febrile neutropaenia) are medical emergencies that require prompt investigation and treatment.
Severity of Neutropaenia
- Mild: 1.0 - 1.5 x 10⁹/L
- Moderate: 0.5 - 0.9 x 10⁹/L
- Severe: <0.5 x 10⁹/L
- Acute neutropaenia is commonly caused by viral infections and certain other infectious states. Dietary deficiency, and in particular B12 and folate deficiency, can cause neutropaenia.
- Bone marrow pathologies tend to cause pancytopaenia more commonly than isolated neutropaenia, as does cytotoxic chemotherapy. Other medications may cause dose-related or idiosyncratic neutropaenia.
- Any condition that induces hypersplenism (including cirrhosis, certain infections, myeloproliferative disorders and chronic haemolytic anaemia), can cause sequestrational loss of neutrophils. Felty's syndrome is the triad of rheumatoid arthritis, splenomegaly and neutropaenia, and is associated with poorer prognosis in the RA patient. Other autoimmune conditions such as SLE may also cause neutropaenia and should be considered.
- There are many congenital syndromes that cause chronic neutropaenia; these range from benign to severe and progressive.
Causes of Neutropaenia
- Congenital - benign familial neutropaenia, cyclic neutropaenia, severe congenital neutropaenia, certain congenital syndromes
- Bone marrow pathology - aplastic anaemia, myelofibrosis, myelodysplasia, acute leukaemia, LGL leukaemia, lymphoma, cancer metastasis
- Infection - viruses, mycobacteria, typhoid, brucellosis, rickettsia, severe sepsis
- Autoimmune - primary autoimmune neutropaenia, SLE, rheumatoid arthritis (Felty’s syndrome)
- Drugs - cytotoxic chemotherapy, NSAIDs, sulfasalazine, clozapine, many others
- Dietary deficiency - B12, folate, copper, alcohol abuse, severe malnutrition
- Chronic idiopathic neutropaenia
- Ask about family history of low white blood cells
- Ask about high risk features such as fevers, poor appetite, weight loss and night sweats
- Examine for lymphadenopathy and splenomegaly
- Correlate the onset of the patient’s neutropaenia with the commencing and cessation of certain medications
- Do not delay investigation and treatment of febrile neutropaenia!
Left Shift of Granulocytes
- Left shift refers to increased numbers of circulating neutrophil precursors (band forms, metamyelocytes, myelocytes, promyelocytes or even blasts).
- This may be physiologic in response to a stress on the body such as pregnancy, infection or inflammation; it may occur with administration of granulocyte colony stimulating factor (G-CSF); or it may be a sign of bone marrow infiltration.
Causes of Left Shift of Granulocytes
- Infection / inflammation
- G-CSF administration
- Bone marrow infiltration - MPNS, leukaemias, lymphomas, myeloma, metastatic cancer
- The presence of nucleated red blood cells and left shift is referred to as a leukoerythroblastic blood film. If left shift is present then look for nucleated red cells.
- "Right shift" refers to the presence of hypersegmented neutrophils, with five or more nuclear lobes.
- This finding is characteristic of megaloblastic anaemia, though may also occur with myelodysplastic syndrome.
Toxic Granulation of Neutrophils
- Toxic granulation is present when there is an increase in the number of large basophilic granules within circulating neutrophils.
- Levels of toxic granulation are highly correlated with C-reactive protein (CRP) values in patients with infection or inflammation.
Causes of Toxic Granulation
- Bacterial infection
- Recovery post bone marrow suppression
- Hypogranular neutrophils have less granules than normal.
- This finding is highly suggestive of myelodysplastic syndrome.
- The presence of vacuoles within neutrophils on a blood film is highly suggestive of infection.
Causes of Vacuolated Neutrophils
- Acute heavy alcohol intake