Definition

• Neutrophil count <3,000 neutrophils/µL in dogs and <2,500 neutrophils/µL in cats.
• Can develop alone or as a component of pancytopenia.
• Often accompanied by a left shift and toxic changes (e.g., cytoplasmic basophilia, foamy cytoplasmic vacuolation, Döhle bodies, and/or toxic granulation).
• Certain breeds, such as greyhounds or Belgian Tervurens, can normally have a neutrophil count below the reference interval for other dogs.

Pathophysiology

Results from one of four mechanisms-(1) decreased production or release of neutrophils from the bone marrow, (2) a shift of neutrophils from the circulating pool within the large vessels to the marginating pool, adhered to the endothelium of capillaries, (3) increased migration into the tissues from the blood due to severe inflammation/tissue consumption, and (4) immune-mediated destruction.

Systems Affected

• Predisposes the patient to systemic infection by a variety of pathogens.
• Many body systems can be affected in any combination, depending on the site(s) of infection.

Genetics

• Canine cyclic hematopoiesis is autosomal recessive, involving the adaptor protein complex 3 (AP3) -subunit, which redirects neutrophil elastase trafficking from membranes to granules.
• A genetic trait with delayed penetrance seems likely to explain the age-related neutropenia in Belgian Tervurens.
• Selective cobalamin malabsorption is autosomal recessive, resulting in neutropenia due to failure to express the receptor for intrinsic factor-cobalamin complex. A CUBN frameshift mutation is likely causative for Imerslund-Gräsbeck Syndrome (selective cobalamin malabsorption) in border collies.
• An autosomal recessive neutropenia, known as trapped neutrophil syndrome (TNS), has been seen in Australian and New Zealand border collies with a deficiency of segmented neutrophils in the blood and hyperplasia of myeloid cells in the bone marrow due to an alternately spliced transcript of VPS13B, similar to Cohen syndrome in humans.

Signalment

• Nothing specific for generalized infection.
• Schnauzers, beagles, Australian shepherds, Shar-Peis, and border collies with inherited cobalamin malabsorption.
• Gray collies and possibly border collies with canine cyclic hematopoiesis.
• Belgian Tervuren dogs.
• Related border collies in Australia and New Zealand with chronic neutropenia.
• G-CSF deficiency has been reported in a rottweiler with chronic idiopathic neutropenia.

Signs

• Septic animals usually present with nonspecific signs of illness such as lethargy, weakness, and inappetence. They are often febrile, but normothermia does not rule out infection. Other signs can include tachycardia, injected mucous membranes, prolonged capillary refill time, and weak pulses, some of which are related to septicemia and endotoxic shock.
• Gray collies with cyclic hematopoiesis exhibit severe neutropenia every 12–14 days. Episodes of fever, diarrhea, gingivitis, respiratory infection, lymphadenitis, and arthritis occur in association with the neutropenia. These dogs seldom live past 1 year of age.
• No clinical signs in Belgian Tervurens.
• Related border collies in Australia and New Zealand with chronic neutropenia had recurrent bacterial infections manifesting as osteomyelitis and gastroenteritis. A dog with heat stroke demonstrated inappropriate rubricytosis with a high normal PCV, moderate mature neutropenia and lymphopenia, and petechiation despite only mild thrombocytopenia. Numerous leukocytes showed evidence of apoptosis; many neutrophils had botryoid nuclei.

Causes

Risk Factors

• Inherited disease-cyclic hematopoiesis in Gray collies and possibly border collies.
• Inherited cobalamin malabsorption in giant schnauzers, beagles, Australian shepherds, and border collies.
• Drug and chemical exposure-estrogen overdose in dogs (pancytopenia) and chloramphenicol and benzene-ring compounds in cats.
• Exposure to various infectious agents-dogs and cats, overwhelming bacterial infection; dogs, acute infection with Ehrlichia canis, parvovirus, Babesia canis rossi (travel history to/from South Africa), Rangelia vitalii (travel history to/from Brazil), and Anaplasma phagocytophilum (more likely lymphopenic and eosinopenic than neutropenic); cats, panleukopenia, FIV, and FeLV infection.
• Middle-aged and old animals are less effective at repopulating the bone marrow after a severe toxic insult.

Differential Diagnosis

• Most neutropenias are due to non-bacterial infectious diseases such as FeLV, FIV, systemic mycoses, and parvoviruses.
• Bacterial infection with marked inflammation and/or endotoxemia.
• Direct cytotoxic effects of drugs or other toxins on myeloid stem cells and circulating cells.
• Primary bone marrow disease.
• Immune-mediated destruction.
• Breed of dog may promote suspicion of inherited disease.

CBC/Biochemistry/Urinalysis

• Diagnosis is verified by CBC and leukocyte differential counts.
• Multiple CBCs necessary to confirm true neutropenia and/or exclude a diagnosis of cyclic hematopoiesis.
• Urinalysis with bacterial culture and sensitivity to evaluate for urinary tract infection.

Other Laboratory Tests

• Serologic test-exclude ehrlichiosis, anaplasmosis, and parvovirus in dogs and panleukopenia, FeLV, and FIV infections in cats.
• Demonstration of anti-neutrophil antibodies by flow cytometry and observation of leukoagglutination-essential for diagnosing immune-mediated neutropenia.
• Consider microbiologic culture of blood or putative sites(s) of bacterial infection or empiric antibiotic administration if occult infection is suspected.

Imaging

Survey radiography and ultrasonography may help locate occult sites of infection not apparent during physical examination.

Diagnostic Procedures/Pathologic Findings

• Examination of a bone marrow aspirate and core biopsy-to evaluate neutrophil production and exclude myelophthisis, myelonecrosis, and myelofibrosis. Animals rebounding from peripheral neutropenia can potentially be misdiagnosed with acute leukemia due to high percentage of myeloblasts in marrows that have extreme left-shifting.
• Cytologic examination of preparations-to document excess tissue demand for neutrophils, verify sequestration of neutrophils in body cavities or between tissue planes, confirm bacterial infection, and identify sites of insensible or occult loss of neutrophils from mucous membranes or skin lesions.
• Culture of infection site or blood culture in febrile animals.
• Provocative exposure to parenteral cobalamin/vitamin B₁₂ should reverse anemia, neutropenia, and neutrophil hypersegmentation in affected breeds.

Appropriate Health Care

• Primary concern is the presence or development of infection.
• In the absence of pyrexia, broad-spectrum oral antibiotics that spare normal anaerobic GI flora should be given prophylactically on an outpatient basis (especially if the count is <1,000 neutrophils/µL).
• Pyrexia-indicates current infection; treated more aggressively; inpatient treatment recommended for administration of parenteral crystalloid fluids and antibiotics that target both anaerobic and aerobic bacteria until the infection is contained.

Drug(s)

• Non-febrile (dogs and cats)-trimethoprim-sulfadiazine (15 mg/kg PO q12h) or cephalexin (30 mg/kg PO q12h) or enrofloxacin (5–20 mg/kg PO q24h; note potential for retinal toxicity in cats at doses >5 mg^/kg).
• Febrile (dogs and cats)-ampicillin (22 mg/kg IV q6–8h) or ampicillin + sulbactam (15 mg/kg IV q8h) or cefazolin (20–30 mg/kg IV q6–8h) and enrofloxacin (5–10 mg/kg IV q24h; note potential for retinal toxicity in cats).
• If clinically warranted, additional anerobic coverage is provided by metronidazole (15 mg/kg IV q12h) and/or a later generation cephalosporin.
• rhG-CSF (dogs and cats) 5–10 mg/kg/day SC for 3–6 doses may be effective to stimulate neutrophilic production short term; however, it is a foreign protein and eventually elicits the production of a neutralizing antibody in 14–21 days, which may then cross-react with endogenous G-CSF.
• Neutrophilia subsides within 5 days after G-CSF is discontinued.
• Immune-mediated neutropenia-prednisolone (1–4 mg/kg PO q12h).

Precautions

Maintain hydration when administering sulfa drugs to prevent renal crystallization.

Patient Monitoring

• Neutropenia is most likely to occur 7–10 days after the administration of most chemotherapeutic drugs but may develop as late as 2–3 weeks following lomustine and carboplatin administration.
• Periodic CBCs; improvement denoted by a rising leukocyte or neutrophil count, resolution of left shift, and disappearance of toxic changes. Seen after appropriate antimicrobial therapy if bacterial sepsis was the initiating cause of the neutropenia.
• Rebound neutrophilic leukocytosis expected during recovery from neutropenia.
• With the accelerated neutrophil production seen with rhG-CSF therapy, toxicity and left-shifting are expected and cannot be interpreted as sepsis.

Possible Complications

Secondary infections

Associated Conditions

Secondary infection, sepsis

Age-Related Factors

Repopulation of bone marrow with hematopoietic cells is more difficult in middle-aged and old animals because of age-related reduction in stem cell numbers.

Pregnancy/Fertility/Breeding

See Also

• Canine Parvovirus Infection
• Ehrlichiosis
• Feline Immunodeficiency Virus Infection
• Feline Leukemia Virus Infection
• Feline Panleukopenia
• Hyperestrogenism (Estrogen Toxicity)

Abbreviations

• FeLV = feline leukemia virus
• FIV = feline immunodeficiency virus
• GI = gastrointestinal
• PCV = packed cell volume
• rhG-CSF = recombinant human granulocyte colony-stimulating factor
• WBC = white blood cell

Author Jennifer L. Owen

Consulting Editor Alan H. Rebar

Acknowledgment The author and editors acknowledge the prior contribution of A. Rick Alleman.