THE FEVER OF UNKNOWN ORIGIN CASE CHALLENGE
Fred Metzger DVM, MRCVS,DABVP
Metzger Animal Hospital
State College, PA
Evaluation of the leukocyte compartment (the leukon) of the peripheral blood should be included
in the laboratory evaluation of any patient and is critical in the evaluation of FUO (fever of unknown origin)
cases. Evaluation should not stop at recognition of quantitative abnormalities. There are many situations
where qualitative abnormalities related to leukocyte morphology provide valuable information regarding
underlying inflammatory conditions as well as potentially aiding in the identification of underlying
myeloproliferative or lymphoproliferative diseases.
BONE MARROW NEUTROPHIL KINETICS:
The normal bone marrow neutrophil compartment can be divided into several functional pools.
The most common division of the maturing neutrophil compartment is the separation into a Mitotic Pool
and a Maturation Pool. Regardless how one breaks the neutrophil series, it should be constantly
reminded that the process of neutrophil maturation is a gradual and continuous process in health
spanning approximately 5-7 days from the first recognizable neutrophil for, the myeloblast, to the mature
segmented neutrophil we commonly see in the peripheral blood.
Stem
Cells
Myelocytes
Promyelocytes
Myeloblasts
Segs
Bands
Metamyelocytes
When examining and interpreting neutrophil quantitative changes in the peripheral blood, one must also
be aware of the different distribution compartments in the peripheral blood. Typically, peripheral blood
neutrophils are placed into two different compartments that are in constant dynamic equilibrium. During
health this equilibrium is even, but under various pathologic situations, the equilibrium is upset, which
directly affects our interpretation. The two compartments in the peripheral blood are the “Circulating Pool”
and the “Marginal Pool” as are indicated below. The mature neutrophils from the bone marrow mature
neutrophil storage pool transverse the marrow into the peripheral blood into the “Circulating Pool”.
Eventually, the more aged neutrophils will collect into the “Marginal Pool” where they extend into the
surrounding tissues.
Marginal Neutrophil Pool
Circulating Neutrophil Pool
Neutrophilia: Neutrophilia beyond chronic granulocytic leukemia can be categorized into three major
causes, physiologic, glucocorticoid-induced and inflammation related.
Physiologic neutrophilia is related to an epinephrine effect and has no changes in the bone marrow
compartment, only a change in the peripheral blood pool compartments where there is a shift from the
marginal pool that is not sampled during routine blood collection to the circulating pool.
The neutrophilia seen with glucocorticoid-induced changes is a true increase in total numbers of
peripheral blood neutrophil numbers and they are multifactorial. The early phases of a glucocorticoidinduced leukogram are the more common entities we see in veterinary medicine and the typical complete
blood count change we see is mild neutrophilias that in the dog do not typically exceed 30,000 / l. With
glucocorticoid-induced neutrophilias, a left shift is not present since immature neutrophils are not released
from the bone marrow early. This left shift is reserved for increased demand beyond what the mature
neutrophil storage pool can keep up with when there is significant tissue pool needs for neutrophils,
namely, inflammation.
Normal
Epinephrine
Corticosteroid
No
Left Shift
Normal
Corticosteroid Response
No Left Shift
The neutrophilias that may be seen with inflammatory disease can be quite varied depending on the
severity of the process. Typically, the more localized the inflammatory process and the more long
standing the inflammatory process is, the greater the neutrophilia. Classic conditions that result in some
of the highest peripheral neutrophil counts include conditions like closed pyometra, localized peritonitis /
pancreatitis, and abscess formation. In addition, inflammatory conditions that are present within the
peripheral blood itself can result in rapid and very high neutrophil counts. A common condition where this
actually occurs is with hemolytic anemias such as immune mediated hemolytic anemia. The tissue being
destroyed and recruiting neutrophils is the red blood cell mass itself. Hemoglobin is a strong
chemoatractant to neutrophils. Only with the examination of serial complete blood count changes in
neutrophil numbers does one truly recognize the changes taking place.
Normal
Early Inflammation
Normal
Normal
Chronic Inflammation
Establishing Inflammation
As a dramatic example of how rapid these changes in phase can occur, a three-day series of
leukograms from a dog with acute pancreatitis is presented below. In a period of only three days, these
leukogram changes suggest transition between the various phases of inflammation described above.
The progression in this particular case is extremely impressive. These degrees of changes typically take
2- 4 times longer than is shown in this case.
Day
WBC (/l)
Metamyelocyte (/l)
Band (/l)
Neutrophil (/l)
Lymphocyte (/l)
Monocyte (/l)
Eosinophil (/l)
1
2
3
Ref Interval
7,200
360
792
3,672
792
1,584
0
28,600
0
4,290
22,308
858
1,144
0
51,900
0
0
45,672
3,114
2,595
519
6,000
0
03,000
1,500
150
1,00
-17,000
300
-12,000
-5,000
-1,350
-1,250
These two figures represent serial leukogram evaluations in a dog with a pancreatic abscess. Note the
significant leukocyte changes following the surgical removal of the abscess. Also note that changes in
the leukogram are noted significantly before obvious clinical improvement; serial CBC data in this
case proved more sensitive than the clinical signs.