Principles of Leukogram Interpretation

As noted previously, the absolute numbers of leukocyte subtypes are interpreted in the context of appropriate reference intervals. If there are questions about the validity of available reference intervals, clinicians should consider the option of submission of samples for comparison from one or more age- and sex-matched unaffected individuals sharing the husbandry conditions and genet­ics of the patient of interest.

Neutrophilia

Although bacterial infection is the most common cause of neutrophilia in large animal species, nonbacterial infectious agents such as Blastomyces dermatitidis infection in alpaca,¹⁶ noninfectious inflammatory processes such as traumatic tissue damage, surgery, foaling in horses,¹⁷ and immune-mediated hemolytic anemia can also cause increased neutrophil concentra­tions (Boxes 25.1 and 25.2).¹⁸ A left shift and toxic change provide additional evidence of an inflammatory cause for neutrophilia, but they may not always be present, especially with mild or chronic compensated inflammation. In fact, normal neutrophil numbers do not exclude infectious or inflammatory diseases because the numbers of circulating cells do not reflect tissue activity in all conditions. Neutrophilia can signal the presence of otherwise difficult-to-detect processes such as extra- pulmonary Rbodococcus equi infection in foals,¹⁹ musculoskeletal Corynebacterium pseudotuberculosis infection,²⁰ meningitis or meningoencephalomyelitis in horses,²¹ liver abscesses and cholangiohepatitis in dairy cattle,^22,23 leukoencephalomalacia and eosinophilic myocarditis in horses,^24,25 and endocarditis in rams.²⁶ Stress resulting from causes such as transport and changes in housing can be another important cause of neu­trophilia in cattle.²⁷ Marked neutrophilia occasionally follows

■ BOX 25.1

Causes of Neutrophilia in Horses

Common Causes

Excitement, exercise

Stress, exogenous corticosteroid administration

Chronic pneumonia, pleuritis

Strangles (Streptococcus equi infection)

Chronic peritonitis, abdominal abscess

Other internal abscessation

Chronic salmonellosis or colitis

Thrombophlebitis

Purpura hemorrhagica (vasculitis)

Less Common Causes

Bacterial endocarditis

Cellulitis

Pyelonephritis

Chronic hepatitis, cholangiohepatitis

Cholelithiasis

Lymphosarcoma

Meningitis, meningoencephalitis

Other internal neoplasia

Pituitary adenoma (equine Cushing's syndrome)

Autoimmune hemolytic anemia

Granulocytic leukemia

Systemic fungal infections

■ BOX 25.2

Causes of Neutrophilia in Ruminants

Common Causes

Stress, exogenous corticosteroid administration

Chronic pneumonia

Chronic traumatic reticuloperitonitis

Peritonitis

Internal abscessation

Caseous lymphadenitis (O, C)

Mycoplasmal or chlamydial polyarthritis (O, C)

Chronic pyelonephritis

Chronic metritis

Liver abscesses

Enteritis

Umbilical abscessation Chronic salmonellosis Septic arthritis

Uncommon Causes

Autoimmune hemolytic anemia

Toxins

Pregnancy toxemia (O, C) Bovine granulocytopathy syndrome

C, Caprine; O, ovine.

a period of neutropenia induced by inflammation (overshoot effect), and very rare genetic causes such as bovine leukocyte adhesion deficiency have been documented. Some authors advocate the use of a neutrophil/lymphocyte ratio to augment the interpretation of absolute neutrophil and lymphocyte numbers on the basis that ruminants have been described to have greater numbers of lymphocytes than neutrophils in the circulation under normal circumstances. Recent information on bovine leukocyte reference intervals suggests that clini­cians should exercise caution with that approach and consider laboratory- and herd-specific information when interpreting the ratio.²⁸

Neutropenia

Endotoxemia results in rapid redistribution of neutrophils from the circulating pool to marginal pool and tissues, resulting in neutropenia followed by fast-onset neutrophilia.⁸ Neutropenia resulting from bone marrow depletion is often observed in large animal species during the first 24 to 48 hours of an acute inflammatory episode, especially in cattle (Boxes 25.3 and 25.4).²9 Persistent neutropenia is a poor prognostic sign or may indicate bone marrow pathology if other peripheral cytopenias are present. Neutropenia at a single time point may also have prognostic significance; for example, neutropenia in foals 2 weeks of age or younger when admitted to an intensive care unit (ICU) was associated with nonsurvival.³⁰ Transient viral infections in cattle, such as bovine viral diarrhea virus and bluetongue virus, can cause neutropenia, as can some tick- borne diseases. As for any species, toxic damage to the marrow or bone marrow necrosis, fibrosis, or neoplasia can result in generalized peripheral cytopenias, including neutropenia. Recent work identified neutropenia without toxic change in 10 of 12

■ BOX 25.3

Causes of Neutropenia in Horses

Common Causes

Acute salmonellosis

Acute toxic colitis

Acute peritonitis (ruptured viscus)

Gram-negative septicemia, endotoxemia

Neonatal septicemia

Acute pleuritis

Acute metritis

Proximal enteritis (duodenitis, proximal jejunitis)

Equine influenza

Equine herpesvirus type 1 infection

Less Common Causes

Equine ehrlichial colitis (Potomac fever, Ehrlichia risticii infection) Equine ehrlichiosis (Anaplasma phagocytophilum infection) Idiopathic aplastic anemia

Equine viral arteritis

Radiation toxicosis

Myelophthisic disease (e.g., leukemia)

Alloimmune neonatal neutropenia

■ BOX 25.4

Causes of Neutropenia in Ruminants

Common Causes

Gram-negative septicemia, endotoxemia

Septic metritis

Septic (coliform) mastitis

Diffuse peritonitis

Ruptured uterus with peritonitis

Ruptured abomasal ulcer

Acute salmonellosis

Acute pneumonia

Toxemia- or toxin-induced bone marrow suppression Fat cow syndrome (fatty liver)

Clostridial infection

Uncommon Causes

Bovine virus diarrhea

Bracken fern toxicosis

Trichloroethylene toxicosis

Radiation toxicosis

Idiopathic aplastic anemia horses with acute leukemia in conjunction with at least one other cytopenia and circulating blasts.² Alloimmune neonatal neutropenia has been reported in horses.³¹

Eosinophilia

Eosinophilia is not common in large animal species, even when parasitism can be demonstrated (Boxes 25.5 and 25.6). This may be related to the tissue predilection of eosinophils and the relatively short transit time from marrow to target tissue.

Basophilia

Basophilia is rare in large animal species and is often attributed to hypersensitivity responses. It has been reported in associa­tion with certain snake envenomation in horses,³⁵ and acute basophilic leukemia was recently reported in a calf; however, circulating cells in peripheral blood were blasts and not ter­minally differentiated basophils.³⁶ Basopenia is not recognized as clinically significant.

Lymphocytosis

Lymphocytosis characterizes an epinephrine response (especially in young horses) as well as antigenic exposure (Boxes 25.7 and 25.8). The lymphocytosis caused by antigenic stimulation may be accompanied by morphologic changes in lymphocytes, including reactive lymphocytes that have increased amounts of cytoplasm, cytoplasmic basophilia, increased azurophilic granules, or larger cell size. Spontaneous lymphoid leukemias, both acute and chronic in nature, are described sporadically

■ BOX 25.5

Causes of Eosinophilia in Horses Uncommon Causes

Internal parasitism

Cutaneous habronemiasis

Systemic hypersensitivity reaction Lymphosarcoma

Eosinophilic leukemia

■ BOX 25.6

Causes of Eosinophilia in Ruminants

Uncommon Causes

Milk allergy

Atypical interstitial pneumonia Acute bovine pulmonary emphysema Sarcocystosis

Toxoplasmosis

Migrating parasite larvae, such as: Lungworms

Ascarids

Flukes Trichostrongylus spp.

Parelaphostrongylus spp.

■ BOX 25.7

■ BOX 25.11

Causes of Lymphocytosis in Horses Common Cause

Excitement, exercise

Uncommon Causes

Lymphocytic leukemia

Equine infectious anemia

■ BOX 25.8

Causes of Lymphocytosis in Ruminants

Persistent lymphocytosis (bovine leukemia virus infection) Lymphocytic leukemia

Chronic infections (pneumonia, peritonitis, pericarditis, liver abscess)

■ BOX 25.9

Causes of Lymphopenia in Horses

Common Causes

Stress, exogenous corticosteroid administration

Equine influenza

Equine herpesvirus type 1 infection

Endotoxemia, septicemia

Acute peritonitis (gastrointestinal rupture)

Less Common Causes

Malnutrition, starvation

Equine viral arteritis

Combined immunodeficiency disease

■ BOX 25.10

Causes of Lymphopenia in Ruminants

Common Causes

Stress, exogenous corticosteroid administration Gram-negative septicemia, endotoxemia

Septic mastitis Diffuse peritonitis Ruptured abomasal ulcer

Acute pneumonia

Infectious bovine rhinotracheitis

Uncommon Causes

Bovine virus diarrhea Immunodeficiency

in horses, with chronic forms potentially lacking cytopenias³⁷ and bovine leukemia virus causing persistent lymphocytosis in a third of infected cattle and leukemia in approximately 4%.²⁹

Lymphopenia

The most common cause of lymphopenia in large animal species is corticosteroid effects, although the acute phase of systemic infectious diseases may also be associated with a transient period of lymphopenia (Boxes 25.9 and 25.10). Rarely, congenital combined immunodeficiency syndromes, especially in Arabian and Arabian-cross foals, cause severe lymphopenia and global depletion of lymphoid tissues.

Causes of Monocytosis in Large Animals Uncommon Causes

Granulomatous disease

Chronic bacterial infections

Monocytosis

Monocytosis can be seen with inflammation or tissue necrosis, or occasionally as part of a stress leukogram. Because the reference intervals for monocytes approach or include zero, monocytopenia is not a diagnostically useful observation (Box 25.11).