Neutrophils are a part of the granulocytic cell line and play an essential role in initiating an immune response to invading
pathogens, such as bacteria, and releasing chemotactic substances that attract other inflammatory cells, such as monocytes.1 Neutropenia (< 3,000 neutrophils/μl in dogs, < 2,500 neutrophils/μl in cats) as a solitary laboratory finding is often not
associated with clinical signs and may be detected on routine screening of otherwise apparently healthy patients. Alternatively,
neutropenic dogs may present with a fever or lethargy or other signs associated with infection. Prompt recognition and treatment
are vital because if the neutropenia is not resolved, infections may be persistent or recurrent and may result in death.2-6
Immune-mediated neutropenia, also called steroid-responsive neutropenia, is a primary disorder or may occur secondary to infection, neoplasia, or the effects of certain drugs. It results when antibodies
directed against neutrophil surface antigens or potentially against growth regulators of granulopoiesis develop.7,8 It can occur concurrently with other immune-mediated diseases, such as rheumatoid arthritis or systemic lupus erythematosis
in dogs and people.9-11 Immune-mediated neutropenia is a well-recognized cause of neutropenia in people, primarily affecting infants.12 Much of the available information about immune-mediated neutropenia in animals is extrapolated from the disease in people.12
Immune-mediated neutropenia is a relatively uncommon cause of neutropenia in cats and dogs, and recognizing it is challenging.
It can only be identified by understanding the pathophysiology of neutropenia in general and ruling out its differential diagnoses.
PATHOPHYSIOLOGY OF NEUTROPENIA
Several mechanisms of neutropenia must be considered before diagnosing immune-mediated neutropenia.13 Neutropenia can occur because of
- Increased margination or egress of neutrophils from the circulating pool to the marginated pool as may occur with infection,
immune-mediated disorders, or hypersplenism
- Decreased production resulting from bone marrow injury, such as that caused by certain drugs, or infiltration as in myelophthisis
(normal hemopoietic tissue is replaced with fibrous tissue or a nonhemopoietic tissue such as carcinoma), myeloproliferative
disorders, and lymphoproliferative disorders
- Increased consumption or destruction of neutrophils as in immune-mediated destruction or severe infection in which use or
destruction is in excess of bone marrow production and release of neutrophils.
These causes of neutropenia are not mutually exclusive, and multiple mechanisms are frequently concurrent.
Immune-mediated neutropenia represents the least common cause of neutropenia and results primarily from increased destruction
of neutrophils when they become coated with anti-neutrophil antibodies.14 The spleen also sequesters antibody-coated blood cells, so increased margination may concurrently be present (Felty syndrome:
neutropenia, rheumatoid arthritis, and splenomegaly).
DIFFERENTIAL DIAGNOSES FOR NEUTROPENIA
Neutropenia can occur for a variety of reasons including infections, drug reactions, and bone marrow and genetic diseases.
Overall, infections with bacteria, viruses, and fungi are the most common causes of decreased neutrophils. In the case of
endotoxemia, sepsis, or localized infections, increased margination may be noted. If the infectious process is overwhelming,
increased destruction may exceed bone marrow production. Some infections, such as canine monocytotropic ehrlichiosis, impair
bone marrow proliferation.15 Neutropenia may also be associated with systemic mycosis (histoplasmosis, cryptococcosis) if myelophthisis occurs and results
in subsequent cytopenias.16
In dogs, the most common infection consistently associated with neutropenia is parvovirus. In both dogs and cats, parvovirus
targets tissues with high mitotic rates such as the bone marrow, leading to cytotoxic hematopoietic cell death as well as
ineffective hematopoiesis. Parvovirus infection will also lead to increased neutrophil margination and consumption associated
with gastrointestinal damage and endotoxemia.
In cats, feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) infections are the most common infectious causes
of neutropenia. FeLV infection causes the destruction of hematopoietic stem cells and ineffective maturation of neutrophils
associated with an altered microenvironment. Secondary infections cause increased consumption. A cyclic neutropenia has been
reported in association with FeLV infection.17 With FIV infection, neutropenia is also common but is usually mild and transient, occurring in the first few weeks after
infection. Neutropenia seems to result from impaired monocyte and granulocyte differentiation.18