J Vet Intern Med 2006;20:20–31

Toxic Neutrophils in Cats: Clinical and Clinicopathologic Features,

and Disease Prevalence and Outcome—A Retrospective Case
Control Study
Gilad Segev, Eyal Klement, and Itamar Aroch

Toxic neutrophils exhibit a variety of nuclear and cytoplasmic abnormalities in Romanowsky-stained blood smears, and are
associated with inflammation and infection. The purpose of the retrospective study reported here was to investigate the
association of toxic neutrophils with clinicopathologic characteristics, diseases, and prognosis in cats. Cats with toxic
neutrophils (n 5 150) were compared with negative-control cats (n 5 150). Statistical analyses included Fisher exact,
independent t-, nonparametric Mann-Whitney, and x2 tests. Cats with toxic neutrophils had significantly (P , .05) higher
prevalence of fever, icterus, vomiting, diarrhea, depression, dehydration, weakness, and cachexia, as well as leukocytosis,
neutrophilia, left shift, neutropenia, anemia, hypokalemia, and hypocalcemia. The prevalence of shock, sepsis, panleukopenia,
peritonitis, pneumonia, and upper respiratory tract diseases was significantly higher among these cats, as were infectious (viral
and bacterial) and metabolic disorders. Control cats had a significantly higher prevalence of feline asthma, as well as allergic,
idiopathic, and vascular disorders. Hospitalization duration and treatment cost were significantly (P , .001) higher in cats
with toxic neutrophils. In 53 and 47% of the cats with toxic neutrophils, the leukocyte and neutrophil counts were normal,
respectively, whereas in 43%, both abnormalities and left shift were absent, and toxic neutrophils were the only hematologic
evidence of inflammation or infection. In conclusion, toxic neutrophils were found to be associated with certain
clinicopathologic abnormalities, and when present, may aid in the diagnosis, as well as the assessment of hospitalization
duration and cost. The evaluation of blood smears for toxic neutrophils provided useful clinical information.
Key words: Hematology; Hospitalization duration; Inflammation; Leukocytes.

he term ‘‘toxic neutrophil’’ refers to a neutrophil
T with certain specific morphologic abnormalities
observed on examination of Romanowsky-stained
peripheral blood smears. These changes occur during
the maturation process in the bone marrow under
certain conditions or in association with certain dis-
eases.1 Most of these changes are cytoplasmic, but
nuclear changes and changes in cell size or shape also
may occur.2,3 Cytoplasmic changes are most prevalent
and important, and include Döhle bodies, increased
basophilia, toxic granulation, and vacuolation.2,3 Döhle
bodies are grayish-to-blue cytoplasmic inclusions that
are the result of lamellar retention and aggregation of
rough endoplasmatic reticulum.4,5 Remnants of RNA
and ribosomes lead to increased basophilia that appears
as a bluish-gray to dark-blue cytoplasm, as opposed to
the normal neutral-staining cytoplasm of the cell. Toxic
granulation refers to the presence of azurophilic
granules in the neutrophil’s cytoplasm, and is attributed
to acid mucopolysaccharide retention, and increased
permeability of primary granules to Romanowsky
stains.4,5 Toxic granulation is uncommon in cats, but
its prevalence is unknown, and it must be differentiated
from the eosinophilic granules present in some Birman
cats, granules in animals with certain lysosomal storage
disorders, and other congenital or infectious disease
inclusions.6 Vacuolation appears as mildly reticulated
From the School of Veterinary Medicine (Segev, Klement,
Aroch); and the Section of Epidemiology (Klement), School of
Veterinary Medicine, The Hebrew University of Jerusalem, Israel.
Reprint requests: Itamar Aroch, School of Veterinary Medicine,
The Hebrew University of Jerusalem, Rehovot 76100 Israel; e-mail:
aroch@agri.huji.ac.il.
Submitted November 30, 2004; Revised March 8, 2005; Accepted
July 25, 2005.
Copyright E 2006 by the American College of Veterinary Internal
Medicine
0891-6640/06/2001-0003/$3.00/0
cytoplasm, with loss of granule uniformity up to an
intensively foamy cytoplasm, and is thought to be
a result of autodigestion or disruption of cell membrane
integrity, or both.2,3 Vacuolation may occur as a conse-
quence of potassium ethylenediaminetetracetic acid
(EDTA) storage artifact, but it rarely occurs in freshly
obtained samples. Nuclear toxic changes include vacu-
olation, polyploidy, hyposegmentation and ring forma-
tion, karyorhexis, and karyolysis. Formation of giant
neutrophils represents additional toxic change, and is
a result of skipped cellular divisions during the
maturation process.2,3
Observation of toxic neutrophils in peripheral blood
may precede changes in the leukogram.7 Therefore, their
presence may serve as an early sensitive indicator of
disease, and aid in the prediction of disease course and
outcome. Evaluation of toxic neutrophils is simple and
cost effective; a Romanowsky staining solution and light
microscope are the only necessary pieces of equipment.
This procedure can be performed quickly in any facility,
and the results may be obtained before a CBC is
available. Evaluation of blood smears for toxic neu-
trophils potentially may provide the clinician with
valuable information concerning the components of
the differential diagnosis to be considered, as well as
severity of the disease, and it may be useful in the
assessment of prognosis. Evaluation of neutrophil
morphology provides additional, complementary data
to that of the CBC.
The morphology of toxic neutrophils is well docu-
mented, under light and electron microscopy,7,8 but was
only described in several isolated feline case reports.9 To
our knowledge, studies of its clinical relevance and
association with disease conditions in cats have not been
published. The objective of the study reported here was
to investigate the association of toxic neutrophils in cats
with clinical findings and disease prevalence and out-
come.
 Feline Toxic Neutrophils 21

Materials and Methods

Selection of Cases and Collection of Data
Clinical records of cats presented to the Department of Small
Animal Internal Medicine at the Hebrew University Veterinary
Teaching Hospital (HUVTH) were reviewed retrospectively. One-
hundred fifty cats with evidence of toxic neutrophils (eg, Döhle
bodies, basophilia, vacuolation or foaminess, toxic granulation,
giant toxic neutrophils) on examination of Mäy-Grünwald-Giemsa
(MGG)-stained peripheral blood smears were included in the study
(defined as cats with toxic neutrophils). These cats were compared
with a randomly selected equal number of cats from the same
period (the next cat within a 14-day interval after a cat with toxic
neutrophils was presented), admitted to the Department of Small
Animal Internal Medicine at the HUVTH that presented with no
evidence of toxic neutrophils on examination of MGG-stained
peripheral blood smears. The examination of all blood smears was
performed by a single clinician (IA) before case selection for the
study.
The data collected from hospital records included signalment,
history, physical examination findings, clinicopathologic findings,
diagnosis, hospitalization duration, treatment cost, and 30-day
survival. Nonsurvivor cats included those that died naturally or
were euthanized within the hospitalization period or within 30 days
from discharge. The total number of diagnoses in each group
exceeded the number of cats, because a cat may have had more
than 1 diagnosis during a single visit. Specific diseases were
classified into the following categories: allergic, anatomic, de-
generative, developmental, infectious-bacterial, infectious-viral, Fig 1. Cytoplasmic toxic morphologic changes in feline neutro-
infectious-parasitic, inflammatory (presumed noninfectious), im- phils. (a) Toxic neutrophils from a cat with Mycoplasma hemofelis
mune-mediated, idiopathic, iatrogenic, metabolic, neoplastic, infection. Neutrophils contain Döhle bodies (solid arrows) and
nutritional, traumatic, toxic, and vascular. In all cats of this study, moderate cytoplasmic basophilia. Notice band neutrophil (open
hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy arrowheads) with mild cytoplasmic basophilia (solid arrowhead).
(DCM) were classified as idiopathic, because the history excluded (b) Large toxic neutrophil with marked cytoplasmic basophilia
familial causes (for both diseases) or taurine deficiency (for DCM). from the cat in a. (c) Neutrophil from a cat with acute pancreatitis,
Obstructive and nonobstructive feline lower urinary tract diseases Notice ring-shaped nucleus and moderate cytoplasmic basophilia.
(FLUTD) also were classified as idiopathic, when urinary tract (d) Two neutrophils with moderate cytoplasmic basophilia (open
infection (classified as infectious), and crystalluria or urolithiasis arrowheads), a large Döhle body (solid arrow), and a normal
(both classified as metabolic) were excluded. Feline asthma was monocyte (asterisk) from the cat in a. (e) Neutrophils from the cat
classified as allergic, whereas acute renal failure (ARF) was in a, with mild (solid arrow), moderate (open arrowhead), and
regarded as a metabolic disorder. High rise syndrome, bite wounds, marked (white arrowhead) cytoplasmic basophilia. The last was
head trauma, and road traffic car accident were classified as defined as a toxic giant band neutrophil. Giemsa stain; bars 5
mechanical trauma. 10 mm (original magnification, 6003).

Laboratory Tests
On admission, blood samples for a CBC were collected in
potassium EDTA-containing tubes, and analyses were performed
within 15 minutes of sample collection (to avoid EDTA storage
artifacts) by automatic impedance cell analyzers,a,b calibrated for
feline blood. Blood smears for differential leukocyte counting and
morphologic evaluation were prepared within 30 minutes of sample
collection. The differential count was obtained by manually
counting 100 leukocytes in MGG-stained blood smears. Hemato-
logic variables in the automated CBC included red blood cell
(RBC) count, hemoglobin concentration, hematocrit, mean cor-
puscular volume (MCV), mean corpuscular hemoglobin (MCH),
mean corpuscular hemoglobin concentration (MCHC), and white
blood cell (WBC) count. Nucleated red blood cells (NRBC) were
counted manually (as NRBC/100 WBC) when observed, and the
WBC count was corrected for them.10
Blood for biochemical analysis, when performed, was collected
in plain tubes, and serum was separated by centrifugation of the
sample within 1 hour after collection. Sera were stored at 4uC
pending analysis, which was performed within 24 hours of sample
collection by means of a wet chemistry autoanalyzer.c The
measured biochemical variables included alanine transaminase
(ALT), alkaline phosphatase (ALP), albumin, amylase, aspartate
transaminase (AST), calcium, chloride, creatinine, creatine kinase
(CK), c-glutamyltranferase (c-GT), glucose, lactate dehydrogenase
(LDH), phosphorus, potassium, sodium, total protein (TP), total
bilirubin, triglycerides, and urea. Ionized calcium and ionized
magnesium concentrations were measured by an electrolyte
analyzer.d
Definition of Toxic Neutrophils
The severity of toxic neutrophil presence was assessed sub-
jectively and semiquantitatively on the basis of cytoplasmic toxic
changes (eg, foaminess, basophilia, Döhle bodies, toxic granula-
tion, giant toxic neutrophils) on examination of a single MGG-
stained blood smear for each case (Figs 1, 2). Each individual type
of toxic change was assigned 1 of 3 final grade scores of
morphologic abnormality: mild, moderate, or marked (scores 1,
2, and 3, respectively). The final grade of each type of toxic change
was a combination of a quantitative assessment of the percentage
of affected neutrophils (,10% 5 mild, 10–30% 5 moderate, .30%
5 marked), and a qualitative grade of the intensity of each of the
individual toxic scores for each morphologic change (Table 1).
22 Segev, Klement, and Aroch

Table 1. Grade of individual toxic changes in

neutrophils.a
Cells affected in peripheral blood
smear (%)
Morphologic change
intensityb ,10 10–30 .30
Döhle bodies
Mild 1 1 1
Moderate 1 1 2
Marked 2 2 3
Cytoplasmic basophilia
Mild 1 1 2
Moderate 2 2 3
Marked 2 3 3
Cytoplasmic vacuolation
Mild 1 1 2
Moderate 2 2 3
Marked 2 3 3
Giant toxic neutrophils 3 3 3
a
Overall toxic score is the sum of all individual toxic grades.
b
See text for details.

Mild cytoplasmic basophilia was defined as presence of a non-

uniform grayish to light-blue cytoplasm in the neutrophils (Figs 1a,
2b), whereas a uniformly light-blue cytoplasm was judged as
a moderately abnormal change (Figs 1a, c, d, e). The presence of
a uniformly blue to dark-blue cytoplasm was considered a marked
abnormality (Figs 1a, b, e); presence of 1–2 small Döhle bodies/cell
was judged as a mild abnormality (Fig 1a), whereas presence of 3–4
Döhle bodies was ranked as a moderate abnormality (Fig 2a); and
a large prominent Döhle body (Figure 1d), more than 4 Döhle
bodies per cell (Fig 2a), or both were judged as a marked
abnormality.
The presence of cytoplasmic vacuolation was classified into 3
categories. Mild vacuolation was defined as loss in cytoplasm
clarity and neutral-stained granules, whereas a moderate change
was defined as observation of small cytoplasmic vacuoles.
Appearance of intense vacuolation with grayish reticulation was
classified as severe cytoplasmic vacuolation. The presence of giant
toxic neutrophils was considered a marked abnormality (Fig 1e).
For assessment of overall neutrophil toxic change in a smear, the
sum of all scores of the individual morphologic abnormalities in
neutrophils was calculated. Mild overall neutrophil toxic change
included a sum of scores of 1–6. Moderate toxic change included
a total score of 7–12, whereas a total score .12 was classified as
marked toxic change.

Fig 2. Cytoplasmic toxic morphologic changes in feline neutro-
phils. (a) Toxic neutrophils from a cat with septicemia. Notice
two (solid arrow) and multiple (solid arrowhead) Döhle bodies
and mild cytoplasmic basophilia. (b) Toxic neutrophils from
a cat with panleukopenia. Notice mild basophilia (solid arrowhead)
and toxic granulation (open arrowheads). (c) Normal feline
Statistical Analysis
Normality of interval variables was assessed with P-P plots.
Descriptive statistics are presented as median with interquartile
range (IQR) for all variables. The prevalence for each variable was
calculated separately within the study and the control groups.
Prevalence ratio with its 95% confidence interval was calculated for
each variable. Results for nominal variables from the 2 groups were
compared by means of the x2 (clinicopathologic data) and Fisher
exact (all other data) tests. Interval variables were compared by an
independent t-test (if they were normally distributed) or by the
nonparametric Mann-Whitney test (if they were not normally
r
neutrophils. Giemsa stain; bars 5 10 mm (original magnification,
6003).
 Feline Toxic Neutrophils 23

Table 2. Prevalence of selected clinical signs of disease in cats with toxic neutrophils and in controls.
Clinical sign Toxica Controlb PR CI95% P-value
Tachypnea (.30 breaths/min) 80 88 0.91 0.74–1.11 .42
Anorexia 49 35 1.40 0.97–2.03 .09
Depression* 34 19 1.78 1.07–2.99 .03
Dyspnea 30 31 0.97 0.62–1.51 1.00
Vomiting* 30 13 2.31 1.25–4.25 .008
Hypothermia #37.5uC) 29 27 1.07 0.67–1.72 .88
Weakness* 28 13 2.15 1.16–3.99 .02
Dehydration* 24 10 2.4 1.19–4.84 .02
Diarrhea* 21 9 2.33 1.11–4.93 .03
Fever ($39.5uC)* 21 9 2.33 1.11–4.93 .03
Pale mucus membranes 19 13 1.46 0.75–2.85 .35
Salivation* 10 1 10.00 1.30–77.15 .01
Icterus* 9 1 9.00 1.15–70.16 .02
Increased lung sounds 9 6 1.50 0.55–4.11 .60
Cachexia* 8 1 8.00 1.01–93.18 .04
Skeletal fracture 8 2 4.00 0.86–18.53 .10
Polyuria/polydipsia 8 11 0.73 0.30–1.76 .64
Abdominal mass 7 3 2.33 0.61–8.85 .34
Cough 7 5 1.40 0.45–4.31 .77
Abdominal pain 6 2 3.00 0.62–14.63 .28
Constipation 5 3 1.67 0.41–6.85 .73
Lymphadenopathy 5 2 2.50 0.49–12.69 .45
Hematuria 4 5 0.80 0.22–2.92 1.00
Stranguria 3 8 0.38 0.10–1.39 .22
Heart murmur 2 6 0.33 0.07–1.63 .28
Dysuria* 0 12 NA NA , .001

PR, Prevalence ratio; CI95%, 95% confidence interval; NA, not applicable.
a
Number of cats with toxic neutrophils.
b
Number of control cats.
*
Significant difference by the Fisher exact test (P , .05).

distributed). Differences in hospitalization duration were evaluated
for all surviving cats in both groups by survival analysis, and were
tested for statistical significance by the Gehan test.11 The same
comparison was performed separately for each specific diagnosis,
when at least 5 surviving cats in each group were present (eg,
enteritis, feline immunodeficiency virus infection, mechanical
trauma, pneumonia). Multivariate analysis was performed with
the Cox proportional hazards model. This model was applied to
control for disease effect on hospitalization duration. For all tests
applied, differences were considered statistically significant when P
# .05. Statistical analysis was performed by means of 2 statistical
software programs.e,f
Results
Differences in age and sex between cats with toxic
neutrophils and control cats were not found. Differences
were not found in mean body temperature, pulse, or
respiratory rate between groups (38.3uC versus 38.1uC,
175 beats/min [bpm] versus 176 bpm, and 48 bpm versus
51 bpm, respectively). However, cats with toxic neutro-
phils had significantly (P , .05) higher prevalence of
increased body temperature (.39.5uC, 17.2% versus
8.3%).
Depression, dehydration, weakness, cachexia, diar-
rhea, icterus, salivation, and vomiting were significantly
(P , .05) more prevalent in cats with toxic neutrophils.
Dysuria was the only clinical sign of disease that was
significantly more prevalent in the control group
(Table 2).
Cats with toxic neutrophils had significantly (P , .05)
lower RBC count, hemoglobin concentration, and
hematocrit (6.82 3 106/mL versus 7.72 3 106/mL,
10.45 g/dL versus 11.75 g/dL, and 31.7% versus 35.2%,
respectively), and higher prevalence of anemia (hemat-
ocrit ,24%, 22.8% versus 7.7%, P 5 .0353 [Table 3]).
Cats with toxic neutrophils also had significantly (P ,
.05) higher prevalence of macrocytosis (MCV .55 fL,
6.71% versus 1.3%, P , .001), although there was no
significant difference in mean MCV between groups.
Cats with toxic neutrophils had significantly (P , .05)
higher WBC and absolute neutrophil counts (18.52 3
103/mL versus 13.16 3 103/mL, and 14.08 3 103/mL
versus 9.85 3 103/mL, respectively). The prevalence of
neutrophilia and neutropenia also was significantly (P 5
.001) higher in cats with toxic neutrophils, compared
with controls (45.0% versus 25.5% and 10.1% versus
2.7%, respectively). Normal leukocyte and neutrophil
counts were observed in 53 and 47% of cats with toxic
neutrophils, respectively, whereas leukocytosis with
neutrophilia and left shift were absent in 43% of cats
with toxic neutrophils. In 45% of affected cats,
leukocytosis and left shift or neutrophilia and left shift
were absent. Mean absolute band neutrophil counts
tended to be higher in cats with toxic neutrophils, but
did not achieve statistical significance (P 5 .082), and
prevalence of left shift was significantly higher in those
cats (28.9% versus 7.4%, P , .001).
24 Segev, Klement, and Aroch

Table 3. CBC results for cats with toxic neutrophils and for controls.
Cats with toxic neutrophils Control cats

Parameter Median IQR % ,RI % .RI Median IQR % ,RI % .RI RI

3 *
WBC count (10 /mL) 14.0 14.1 8.05 38.9 11.5 7.0 2.0 22.8 5.0–16.0
Corrected WBC count (103/mL)* 13.5 13.3 8.05 38.3 11.4 6.8 2.0 22.8 5.0–16.0
RBC count (106/mL)* 7.05 3.09 22.8 6.0 7.67 2.45 4.1 13.5 5.0–10.0
Hemoglobin (g/dL)* 10.6 5.1 27.5 8.1 11.8 3.9 8.7 13.4 8.0–15.0
Hematocrit (%)* 33.1 12.7 22.8 7.4 35.4 9.4 6.7 10.7 24.0–45.0
MCV (fL) 47.0 10.0 2.01 6.7 46.0 5.0 0.0 1.3 39.0–55.0
MCH (pg) 15.2 2.9 6.7 30.9 15.2 2.5 6.7 11.4 12.5–17.5
MCHC (g/dL) 32.3 3.5 20.1 10.1 32.5 3.0 12.2 13.5 30.0–36.0
Neutrophils (103/mL)* 10.07 12.21 10.1 45.0 8.33 6.41 2.7 25.5 3.0–11.5
Band neutrophils (103/mL) 0.00 0.50 0.0 28.9 0.00 0.00 0.0 2.0 0.0–0.3
Nucleated RBC (103/mL) 0.00 4.00 0.0 16.0 0.00 0.00 0.0 9.3 0.0–0.0
Monocytes (103/mL) 0.44 0.56 12.8 8.1 0.39 0.43 17.4 3.4 0.15–1.3
Lymphocytes (103/mL) 1.19 1.45 38.9 6.0 1.58 1.86 30.2 6.7 1.0–4.8
Eosinophils (103/mL) 0.18 0.60 38.9 10.7 0.40 0.81 24.8 12.1 0.10–1.25
Basophils (103/mL) 0.00 0.00 0.0 0.0 0.00 0.00 0.0 0.00 0.00–0.24

RI, reference interval; IQR, interquartile range; RBC, red blood cell; MCV, mean cell volume; MCH, mean cell hemoglobin; MCHC,
mean cell hemoglobin concentration.
*
Significant difference by the x2 test (P , .05).

Cats with toxic neutrophils had significantly higher
mean serum activity of AST and significantly (P , .05)
lower mean serum activity of ALP, as well as
significantly lower mean concentration of total calcium
and potassium. Compared with control cats, those with
toxic neutrophils tended to have higher mean serum CK
and LDH activities, but the differences did not achieve
statistical significance (P 5 .056 and P 5 .071,
respectively). Mean sodium concentration tended to be
lower in cats with toxic neutrophils, but the value did
not achieve statistical significance (P 5 .072 [Table 4]).
Cats with toxic neutrophils also had a significantly (P ,
.05) higher prevalence of hyperbilirubinemia (P 5 .002),
hypocalcemia (P 5 .038), hypokalemia (P 5 .012), and

Table 4. Serum biochemical values in cats with toxic neutrophils and in controls.
Cats with neutrophil toxicity Control cats

Parameter n Median IQR % ,RI % .RI n Median IQR % ,RI % .RI RI

Albumin (g/dl) 45 3.10 0.75 17.8 0.0 42 3.10 0.53 7.1 0.0 2.6–4.0
ALP (U/L)* 44 28 35 9.1 0.0 42 44 44 9.5 4.8 13–140
ALT (U/L) 73 45 51 2.7 42.5 69 49 56 1.4 40.4 10–50
Amylase (U/L) 43 608 399 11.6 23.3 41 607 403 4.9 31.7 340–800
AST (U/L)* 45 45 63.5 4.4 44.4 42 30 39 2.4 12.9 14–50
Chloride (mEq/L) 38 113.4 9.1 2.6 28.9 38 115.2 5.6 5.3 31.6 102–117
Cholesterol (mg/dL) 44 127 93 38.6 15.9 42 153 87 23.8 4.8 120–260
Creatine kinase (U/L) 42 476 1339 2.4 81.0 42 218 540 0.0 66.7 13–100
Creatinine (mg/dL) 76 1.29 1.7 2.7 37.3 80 1.36 1.0 0.0 38.7 0.5–1.6
Total calcium (mg/dl)* 43 9.2 1.2 25.6 2.3 42 9.7 1.1 7.1 2.4 8.7–11.8
c-GT (U/L) 44 1.8 1.8 22.7 0.0 41 1.7 1.9 29.3 0.3 1.0–10.0
Globulin (g/dL) 44 4.3 1.0 0.0 79.5 41 3.8 1.2 4.8 64.3 1.9–3.5
Glucose (mg/dL) 37 122.0 60 8.1 73.0 38 143.0 98 5.3 65.8 70–110
LDH (U/L) 43 738 918 0.0 82.1 41 516 634 0.0 61.0 34–360
Potassium (mEq/L)* 69 3.91 0.93 42.9 1.4 62 4.24 0.91 22.6 11.3 3.8–5.6
Total protein (g/dL) 44 7.3 1.6 2.3 40.9 41 7.0 1.4 4.9 29.3 5.5–7.5
Phosphate (mg/L) 42 4.10 7.00 16.7 14.3 38 4.72 6.00 2.6 21.1 2.5–6.2
Sodium (mEq/L) 66 148.0 9.7 9.0 28.4 58 151.60 5.57 3.4 24.1 140.0–154.0
Total bilirubin (mg/dL) 47 0.39 0.92 2.1 40.4 39 0.24 0.18 2.6 10.3 0.10–0.60
Triglycerides (mg/dL) 38 86 110 13.2 31.6 35 57 68 14.3 25.7 40–100
Urea (mg/dL) 86 55.3 59.2 1.2 71.4 90 57.6 56.0 2.2 80.0 21–40
Ionized calcium (mmol/L) 43 1.17 0.18 30.2 2.3 30 1.16 0.16 26.7 3.3 1.1–1.4
Ionized magnesium (mmol/L) 41 0.54 0.17 9.8 31.7 30 0.52 0.18 13.3 33.3 0.4–0.6

IQR, Interquartile range; RI, reference interval; ALP, alkaline phosphatase; ALT, alanine transaminase; ASP, aspartate transaminase; c-
GT, c-glutamyltransferase; LDH, lactate dehydrogenase.
*
Significant difference by the x2 test (P , .05).
 Feline Toxic Neutrophils 25

Table 5. Prevalence of selected diagnoses in cats with toxic neutrophils and in controls.
Diagnosis Toxica Controlb PR CI95% P-value
Mechanical trauma 19 23 0.83 0.47–1.45 .63
Pneumonia* 16 6 2.67 1.07–6.63 .04
Chronic renal failure 14 13 1.08 0.52–2.21 1.00
Enteritis 12 8 1.50 0.63–3.56 .49
Skeletal fracture 12 9 1.33 0.58–3.07 .65
Feline immunodeficiency virus infection 11 7 1.57 0.63–3.94 .47
Hypertrophic cardiomyopathy 10 12 0.83 0.37–1.87 .82
Upper respiratory tract disease* 10 1 10.00 1.30–77.15 .01
Bite wounds 7 5 1.40 0.45–4.31 .77
Hepatic lipidosis 7 2 3.50 0.74–16.57 .17
Diabetic ketoacidosis 6 2 3.00 0.62–14.63 .28
Gastritis 6 3 2.00 0.51–7.85 .50
Gingivitis 6 6 1.00 0.33–3.03 1.00
Intestinal foreign body 6 2 3.00 0.62–14.63 .28
Peritonitis* 6 0 NA NA .03
Pleural effusion 6 1 6.00 0.73–49.24 .12
Acute renal failure 5 1 5.00 0.59–42.29 .21
Congestive heart failure 5 9 0.56 0.19–1.62 .41
Lymphoma 5 3 1.67 0.41–6.85 .72
Panleukopenia 5 0 NA NA .06
Sepsis 5 0 NA NA .06
Shock 5 0 NA NA .06
Nonobstructive FLUTD 4 9 0.44 0.14–1.41 .26
Obstructive FLUTD 4 12 0.33 0.11–1.01 .07
Pancreatitis 4 0 NA NA .12
Pneumothorax 4 4 1.00 0.25–3.92 1.00
Poisoning 4 3 1.33 0.30–5.86 1.00
Eosinophilic granuloma 3 4 0.75 0.17–3.29 1.00
Diabetes mellitus 0 5 NA NA .06
Feline asthma* 0 6 NA NA .03
Lung contusion 0 5 NA NA .06
Thromboembolism 0 5 NA NA .06

PR, prevalence ratio; CI95%, confidence interval; NA, not applicable; FLUTD, feline lower urinary tract disease.
a
Number of cats with toxic neutrophils.
b
Number of control cats.
*
Significant difference by the Fisher exact test (P , .05).

increased LDH activity (P 5 .038), whereas control cats
had a higher prevalence of hyperkalemia (P 5 .019).
Cats with toxic neutrophils had a significantly (P ,
.05) higher prevalence of pneumonia, sepsis, shock, and
upper respiratory tract infections. Panleukopenia tended
(P 5 .06) to be more prevalent in cats with toxic
neutrophils, but the value did not achieve statistical
significance. Controls had a significantly (P 5 .03)
higher prevalence of feline asthma, and tended to have
higher prevalence of thromboembolism and lung con-
tusions, but this difference did not achieve statistical
significance (P 5 .06 [Table 5]). Cats with toxic
neutrophils had a significantly higher prevalence of
metabolic disorders (P 5 .05) and bacterial (P , .001)
and viral (P 5 .003) infections, whereas controls had
a significantly (P # .05) higher prevalence of allergic,
idiopathic, and vascular diseases (Table 6).
Differences in mortality were not found between cats
with toxic neutrophils and controls (20.0% versus 15.3%,
respectively, P 5 .29). However, there was a significant
(P , .001) difference between cats with toxic neutrophils
and controls in median hospitalization duration for
surviving cats (3.0 days versus 1.1 days, respectively,
Fig 3), and treatment cost ($357.1 versus $252.8,
respectively). This difference in hospitalization duration
also was highly significant when controlled for disease
type by means of the Cox proportional hazards model
(adjusted hazards ratio 5 .32, P , .001). Comparison of
hospitalization duration between cats with toxic neu-
trophils and controls also was done for specific diseases,
if the number of cases in each group was $5. These
diseases included pneumonia (median 2.75 days versus
0.83 days, respectively, P 5 .011), enteritis (median
3.00 days versus 0.70 days, respectively, P 5 .002),
feline immunodeficiency virus infection (median
3.17 days versus 0.75 days, respectively, P 5 .013),
and mechanical trauma (median 3.33 days versus
1.25 days, respectively, P , .001).
Differences in mortality and treatment cost between
cats with moderate-to-marked (total toxic score .6),
compared with mild (total toxic score ,6) neutrophil
toxic changes, were not found. However, significantly (P
5 .007) longer hospitalization duration was found in
cats with moderate-to-marked (total toxic score .6),
compared with mild (total toxic score ,6) neutrophil
toxic changes (median toxic score, 3.75 versus 2.61).
26 Segev, Klement, and Aroch

Table 6. Disease category prevalence in cats with toxic neutrophils and in controls.
Disease category Toxic (n)a Control (n)b PR CI95% P-value
*
Allergic 3 11 0.27 0.08–0.96 .05
Degenerative 13 7 1.86 0.76–4.52 .25
Developmental 2 3 0.67 0.11–3.93 1.00
Metabolic* 20 9 2.22 1.05–4.72 .05
Neoplasia 10 10 1.00 0.43–2.33 1.00
Nutritional 0 4 NA NA .12
Infectious bacterial* 67 30 2.23 1.55–3.22 , .001
Infectious viral* 28 10 2.80 1.41–5.56 .003
Infectious parasitic 4 5 0.80 0.22–2.92 1.00
Inflammatory 14 11 1.27 0.60–2.71 .67
Immune 0 0 NA NA 1.00
Idiopathic* 17 35 0.49 0.28–0.83 .009
Iatrogenic 0 1 NA NA 1.00
Traumatic 27 27 1.00 0.62–1.62 1.00
Anatomic 9 7 1.29 0.49–3.36 .80
Toxic 5 4 1.25 0.34–4.56 1.00
Vascular* 0 6 NA NA .03

PR, prevalence ratio; CI95%, 95% confidence interval; NA, not applicable.
a
Cats with toxic neutrophils.
b
control cats.
*
Significant difference by the Fisher exact test (P , .05).

Discussion tions.2,3 The results of the study reported here support

Observation of toxic neutrophils has been a well
known phenomenon in humans and animals, and its
morphologic characteristics are well described.2,3,7,8
However, its association with specific disease conditions
has been described mostly in dogs, in a limited number
of clinical case reports or series, and in animals with
experimentally induced inflammation.8,12–18 Recently,
toxic neutrophils in dogs were investigated in a large
retrospective study.20 In recent reports, toxic neutrophils
were associated with chloramphenicol toxicosis and
tularemia in cats.9,15
Toxic neutrophils have been associated with systemic,
rather than localized infection and inflammatory condi-
Fig 3. Comparison of hospitalization duration between cats with
toxic neutrophils (––—) and controls (- - - - -). Rate of cats’
discharge from the hospital is depicted as a function of days after
admission.
this observation, because cats with toxic neutrophils had
a significantly (P , .05) higher prevalence of systemic
infectious conditions, such as peritonitis and pneumo-
nia, as well as a higher tendency, however insignificant
(P 5 .06), toward panleukopenia and sepsis, compared
with controls. Although some of these diseases may
sometimes be localized, in most such cases admitted to
the HUVTH, the animals are systemically ill, requiring
intensive care and hospitalization. Some of these
diseases are characterized by high tissue demands for
neutrophils attributable to inflammation, leading to
accelerated neutrophil production and maturation in the
bone marrow, which may predispose the cells to
disturbances and manifestation of toxic changes.19
Alternatively, inflammatory mediators and cytokines
may influence the neutrophil maturation process in the
bone marrow, resulting in toxic changes.
Cats with toxic neutrophils had more severe clinical
signs of disease and a wider variety of signs on
presentation, compared with controls, probably because
the former had more severe and systemic disorders. This
was manifested by a significantly (P , .05) higher
prevalence of cachexia, dehydration, depression, di-
arrhea, increased body temperature, icterus, salivation,
vomiting, weakness, and signs of shock (Table 2).
Increased body temperature and icterus were also
significantly more prevalent in dogs with toxic neutro-
phils, compared with controls (Table 7).20
Compared with controls, cats with toxic neutrophils
had a significantly (P 5 .01) higher prevalence of icterus.
It is likely that some of the same disorders that led to
icterus also induced formation of toxic neutophils, but
the possibility that increased bilirubin concentration
actually is a cause of toxic neutrophil formation cannot
be ruled out. Bilirubin, especially in the nonconjugated
 Feline Toxic Neutrophils 27

Fig 4. Comparison of hospitalization duration for specific disease entities between cats with toxic neutrophils (––—) and controls
(- - - - -).

form, may lead to cellular disturbances in various body
systems.21–24 Although there was a significantly higher
prevalence of hyperbilirubinemia (P 5 .002) and clinical
icterus (P 5 .01) in cats with toxic neutrophils, mean
total bilirubin concentration only tended to be different
between groups (P 5 .07), probably because hyperbiliru-
binemia in cats with toxic neutrophils was not severe
(mean, 1.05 mg/dL; maximum, 8.76 mg/dL; reference
interval, 0.1–0.6 mg/dL).
The traditional observation that toxic neutrophils are
associated with infection and inflammation2 is further
supported by the hematologic results of the study
reported here. Cats with toxic neutrophils had a signif-
icantly higher prevalence of most hematologic markers
of inflammation, such as leukocytosis, neutrophilia,
neutropenia, and left shift (Table 3), probably because
of a significantly higher prevalence of pneumonia,
peritonitis, and upper respiratory tract infections, and
higher tendency for sepsis in this group (Table 5). In
contrast, control cats had a lower prevalence of these
hematologic markers of inflammation. They tended (P
5 .06) to present with noninflammatory and, presumed,
noninfectious diseases, but this association was not
significant. These conditions included thromboembo-
lism, obstructive FLUTD, diabetes mellitus, and lung
contusions. The same applies to feline asthma, which
was significantly (P 5 .03) more prevalent in control
cats (Table 5).
28 Segev, Klement, and Aroch

Table 7. Results in cats and dogs with toxic neutrophils, compared with their respective controls.*
Dogs with toxic neutrophils versus controls (n 5 248) Cats with toxic neutrophils versus controls (n 5 150)
Clinical signs of disease seen more frequently in animals with toxic neutrophils
Fever, icterus, pale mucous membranes, vaginal discharge, Fever, icterus, vomiting, diarrhea, depression, dehydration, weakness,
abdominal organomegaly, melena cachexia,
Prevalence of hematologic abnormalities in animals with toxic neutrophils, compared with controls
Leukocytosis q Leukocytosis q
Leukopenia q
Neutrophilia q Neutrophilia q
Neutropenia q Neutropenia q
Left shift q Left shift q
Monocytosis q
Anemia q Anemia q
Macrocytosis q Macrocytosis q
Hypochromia q
Prevalence of biochemical abnormalities in animals with toxic neutrophils, compared with controls
Hyperbilirubinemia q Hyperbilirubinemia q
Increased LDH activity q Increased LDH activity q
Hypocalcemia q Hypocalcemia q
Hypoalbuminemia q
Hypoproteinemia q
Hypokalemia q Hypokalemiaq
Hyponatremia q Hyperkalemia Q
Increased ALP activity q
Increased ALT activity q
Increased c-GT activity q
Increased creatinine concentration q
Increased urea concentration q
Increased triglycerides concentration q
Prevalence of diseases in animals with toxic neutrophils, compared with controls
Sepsis q Sepsis q
Parvovirus infection q Panleukopenia q
Pancreatitis q
Peritonitis q Peritonitis q
Acute renal failure q Pneumonia q
Immune-mediated hemolytic anemia q Proximal respiratory tract disease q
Disseminated intravascular coagulationq Shock q
Pyometra q
Pyoderma Q Thromboembolism Q
Intervertebral disk disease Q Diabetes mellitus Q
Feline asthma Q
Lung contusion Q
Prevalence of disease categories in animals with toxic neutrophils, compared with controls
Neoplasia q Metabolic q
Infectious bacterial q Infectious bacterial q
Developmental Q Infectious viral q
Degenerative Q Idiopathic Q
Allergic Q
Nutritional Q

q, Higher prevalence; Q, lower prevalence; LDH, lactate dehydrogenase; ALP, alkaline phosphatase; ALT, alanine transaminase; c-GT,
c-glutamyltransferase.
*
Included are categories with prevalence ratio $2 and P # .06.

Although cats with toxic neutrophils had a signifi-
cantly higher prevalence of neutrophilia and neutrope-
nia, compared with controls, 53 and 47% of these cats
presented with normal leukocyte and neutrophil counts,
respectively. A combination of normal neutrophil and
WBC counts and no left shift was present in 43% of cats
with toxic neutrophils, whereas in 45% of those cats,
leukocytosis, left shift, or neutrophilia and left shift were
absent. Furthermore, difference was not found in mean
band neutrophil count between cats with toxic neutro-
phils and controls. These findings indicate that presence
of toxic neutrophils may not necessarily correlate with
abnormalities in the absolute numbers of leukocytes,
neutrophils, and band cells. Thus, in certain cases,
 Feline Toxic Neutrophils
presence of toxic neutrophils may serve as the only
hematologic marker of inflammation and infection. This
finding emphasizes the benefit of assessing neutrophil
morphology.
Cats with toxic neutrophils also were found to be
significantly more anemic, compared with controls,
similar to what was reported in dogs.20 Unfortunately,
reticulocyte counts, bone marrow cytologic examination
findings, and quantitative analysis of polychromasia
were not available for the cats of this retrospective
study. Thus, it is impossible to provide a definitive
explanation for the higher prevalence of anemia in cats
with toxic neutrophils. In contrast to dogs with toxic
neutrophils, in which immune-mediated hemolytic ane-
mia was more prevalent, compared with that in controls,
we found no significant difference in the prevalence of
hemolysis between the two groups of cats. Inflammation
and blood loss are 2 possible mechanisms that might
have led to a higher prevalence of anemia in cats with
toxic neutrophils. Although anemia of inflammation is
normocytic in most cases,25 some cats with toxic
neutrophils might have experienced other kinds of
anemia, because macrocytosis, a possible marker of
erythroid regeneration, was significantly (P 5 .0002)
more prevalent in cats with toxic neutrophils, compared
with controls (6.71% versus 1.3%, respectively), al-
though no significant (P 5 .09) difference in mean
MCV was found between groups.
There were 4 of 23 significant mean serum bio-
chemical variable differences between cat groups
(Table 4). When the prevalence of deviations from the
reference interval for 5 variables was compared between
groups, it was statistically significant (Table 7). Hypo-
calcemia and mean lower total calcium concentration in
cats with toxic neutrophils probably was of little clinical
relevance, because differences in mean ionized calcium
concentration between groups were not observed. We
have no reasonable explanation for the observed higher
mean serum ALP activity in the control cats, but there
was no difference in the prevalence of increased serum
ALP activity between groups.
Data of disease categories in both groups (Table 6)
indicate that cats with toxic neutrophils had a
significantly higher prevalence of bacterial and viral
infections. Possibly, the presence of viruses alone did
not lead to toxic neutrophil formation, but rather,
secondary bacterial infections complicated some of
these viral diseases (eg, panleukopenia, upper respirato-
ry tract infection), and played a major role in such
changes.
Compared with controls, cats with toxic neutrophils
had a significantly higher prevalence of metabolic
disorders (Table 6), as was also reported in dogs
(Table 7).20 This probably was a result of a cumulative
effect of the higher, although nonsignificant, prevalence
of acute renal failure, diabetic ketoacidosis, hepatic
lipidosis, and other metabolic conditions, more com-
monly observed in cats with toxic neutrophils (Table 5).
Idiopathic conditions were more prevalent in the control
group because of the higher prevalence of FLUTD
(obstructive and nonobstructive). The significantly
29
higher prevalence of feline asthma in the controls
probably accounted for the higher prevalence of allergic
conditions in this group. Differences in the prevalence of
toxicologic conditions between cat groups were not
found, similar to what was reported for dogs,20 although
these conditions were previously linked with presence of
toxic neutrophils.2,9,17,26 This inconsistency could result
from differences in the type and nature of toxicoses
between the present study and previous reports.
The results of this study indicated that the presence of
toxic neutrophils in cats is associated with a higher pre-
valence of systemic and more severe diseases, compared
with that in controls. This was reflected by marked
clinical signs of disease and hematologic abnormalities,
as well as a significantly longer hospitalization period
and higher treatment cost in cats with toxic neutrophils.
The hospitalization period was consistently longer when
cats with toxic neutrophils were compared with controls
that had the same diseases (Fig 4). Thus, for a given
disease, when toxic neutrophils are present, a longer
hospitalization period should be expected.
There are some differences between cats and dogs
with toxic neutrophils, compared with their respective
control, but some similarities can be pointed out
(Table 7).20 The prevalence of many of the clinical signs
of disease was higher in dogs and cats with toxic
neutrophils, compared with that for their respective
controls, indicating that, in both species, presence of
toxic neutrophils was associated with more severe
illness. In contrast, dogs with toxic neutrophils had
considerably more serum biochemical and hematologic
abnormalities (13 and 12, respectively) and mean serum
biochemical and hematologic variable differences (13
and 12, respectively) than did controls. However, in this
study, cats with toxic neutrophils had significantly fewer
serum biochemical and hematologic abnormalities (5
and 6, respectively), and fewer mean serum biochemical
and hematologic variable differences (4 and 6, re-
spectively) than did their controls.20 Thus, in cats, toxic
neutrophils possibly may appear in milder disorders or
earlier in the disease course, and may be a more sensitive
indicator of illness in them, compared with dogs.
Nevertheless, certain diseases were found to be signifi-
cantly more prevalent in dogs and cats with toxic
neutrophils, compared with their respective controls (eg,
sepsis, peritonitis, canine parvovirus, panleukopenia). In
both species, the infectious bacterial disease category
was the most prevalent category in animals with toxic
neutrophils. In dogs and in cats, presence of toxic
neutrophils was associated with longer hospitalization
duration (3.9 and 2.7 times longer, respectively) and
higher treatment cost (2.0 and 1.4-fold, respectively),
compared with their respective controls. However, only
in dogs, was it also associated with significantly higher
mortality. These differences further support the sugges-
tion that presence of toxic neutrophils in cats is
associated with milder diseases, compared with those
in dogs.
The comparison between dogs and cats has its
limitations because of the different disease prevalence
and bone marrow characteristics between species, and
30 Segev, Klement, and Aroch
differences in the number of cases between studies (248
dogs versus 150 cats). Possibly, some variables that had
only a tendency for higher prevalence in cats with toxic
neutrophils, compared with controls, could potentially
have become significant if a higher number of feline
cases had been included in the study.
This study has a limitation that relates mainly to the
problem of multiple comparisons. We performed over
100 comparisons throughout the study. Thus, it is
probable that some of the associations were erroneously
found to be statistically significant. However, as out-
lined in a recent similar study conducted in dogs,20
correction of this problem involves a major reduction in
the statistical power of the study.27 Thus, we preferred
to maintain the P 5 .05 value as the statistical
significance cut-off, with the risk of rejecting some
spurious null hypotheses. Additional research is
warranted to strengthen the associations found in this
study, and to assess the sensitivity and specificity of
such changes for diagnosis of various diseases and
conditions.
In conclusion, evaluation of blood smears for
neutrophil toxic changes is an inexpensive, quick,
simple, and readily available process that was found to
be a marker of infectious and metabolic disease
processes in cats. In some cats, such changes were
present when abnormal results of other tests, such as
CBC and serum biochemical analysis, were minimal or
absent, and along with the clinical signs, were the only
indicators of disease. The presence of toxic neutrophils
also was associated with longer hospitalization and
higher treatment cost. Observation of toxic neutrophils
was found to be an important diagnostic finding, as well
as an aid in assessment of the patient, disease course,
hospitalization duration, and therapeutic planning. In
cats, unlike that in dogs, toxic neutrophils were not
associated with higher mortality; therefore, they may not
necessarily indicate the same severity of illness as they do
in dogs. Additional research is warranted to strengthen
the associations found in this study, to shed light on the
mechanisms that induce toxic neutrophil production,
and to assess the sensitivity and specificity of such
changes for diagnosis of various diseases and conditions.
Footnotes
a
Minos, ST-Vet, Montpellier, France
b
Abacus, Diatron, Vienna, Austria
c
Kone Progress Selective Chemistry Analyzer, Kone Corporation
Instrument Group, Espoo, Finland
d
Nova 8, Nova Biomedical, Waltham, MA
e
SPSS 10.0 for Windows, SPSS Inc, Chicago, IL
f
PEPI 4.0, Abramson JH, Gahlinger PM. Computer programs for
epidemiologists: PEPI version 4.0. 2001. Salt Lake City, UT;
Sagebrush press
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