Open Journal of Veterinary Medicine, 2013, 3, 58-66 Published Online March 2013 (
Factors Influencing Serum Amyloid
Type A (SAA) Concentrations in Horses
Katy Satué1*, Antonio Calvo2, Juan Carlos Gardón2
1Department of Animal Medicine and Surgery, Faculty of Veterinary,
CEU Cardenal Herrera University, Valencia, Spain
2Department of Experimental Sciences and Mathematics, Faculty of Veterinary,
Catholic University of Valencia, Valencia, Spain
Email: *
Received January 18, 2013; revised February 18, 2013; accepted March 8, 2013
The acute phase response (APR) is the reaction that occurs in animals in response to disturbances in hemostasis follow-
ing tissue damage. In horses, the APR is manifested in a variety of pathological processes of various origins, such as
infections caused by bacteria, viruses, parasites, arthritis, burns, chemicals, trauma surgery and stress. Acute phase pro-
teins (APPs) are considered those proteins that modify its plasma concentration at least 25% in inflammatory and infec-
tious processes. In adult horses, various respiratory inflammatory processes, gastrointestinal tract, reproductive organs
and musculoskeletal system are accompanied by increased levels of a specific APP, so-called serum amyloid type A
(SAA). SAA is the most important major APP in the horse. This paper provides a review of physiological factors af-
fecting SAA levels and their role in horses in defense of natural mechanisms, the pathways involved and their material
Keywords: Acute Phase Response; Serum Amyloid A; Equine
1. Introduction
The acute phase response (APR) is the reaction that oc-
curs in animals in response to disturbances in hemostasis
following tissue damage [1,2]. The main functions of this
systemic response are to provide energy and substrates
for the fight against invading pathogens, preventing the
transfer of metabolites necessary to pathogens, limiting
the damage caused by pathogens and/or remove damaged
or infected tissue and restore it. During the development
of APR release pro-inflammatory cytokines interleukin-1
(IL-1), interleukin-6 (IL-6) and tumor necrosis factor
(TNF-α) that act through different receptors on the mem-
brane of hepatocytes, certain proteins synthesized in the
so-called acute phase proteins (APPs), including: C-re-
active protein, serum amyloid A (SAA), haptoglobin, fi-
brinogen, C-reactive protein, ceruloplasmin and
glycoprotein [1-4].
SAA is the major protein in horses and presents the
following characteristics: they are present at very low or
undetectable levels in the serum of healthy animals but
increase rapidly from 10 to 1000 times during the APR.
This level of response is related to the size of the damag-
ed tissue and can be expressed in a wide dynamic range
and decrease rapidly in response to treatment, although
not totally reduced in the absence of recovery. The peri-
ods of relapse or the presence of secondary complica-
tions lead to new elevation of SAA, and are brought
about by non-inflammatory processes, nutritional status,
exercise, manipulation or other forms of stress, such as
transport [5] that should not affect the normal values. On
the other hand, endurance horses with SAA levels higher
than 1000 ng/mL may not complete the distance. Thus,
high SAA concentration may indicate a poor condition of
a horse, resulting in elimination during a competition
[6,7]. Also, Kent [8] noted that the baseline should re-
main unchanged with age, sex or genetics of animals.
These properties are the most interesting from a clinical
perspective of the horse, and are represented by the SAA.
Also, the SAA is involved in the defense of the animal in
its adaptation or the body’s defense against pathogens
[9-11]. Thus, the SAA is the protein that responds quick-
ly to stimuli in the horse. Serum concentration of reactant,
ie SAA, increases a few hours after the onset of the sti-
mulus, reaches a peak at 24 - 48 h, and then normalizes
2. Serum Amyloid Type A
*Corresponding author. The SAA belongs to the family of apolipoproteins,
opyright © 2013 SciRes. OJVM
whose molecular weight is estimated at around 9 and 11
kDa [14,15]. The complete sequence of equine SAA was
published by Sletten et al. [16]. Three isoforms were
identified by their isoelectric point electrophoresis and
amino acid sequence [17,18]. SAA3 isoform has been
isolated both in hepatocytes during the APR and in vari-
ous cell types that are checked for extra hepatic synthesis
in the digestive tract, airways, mammary gland, synovial
tissue and articular cartilage chondrocytes [18-20]. Thus,
the protein levels rise substantially in inflammatory ar-
thritis and mastitis [13,18,21,22].
Normal plasma concentrations of SAA in horses range
from 0.5 to 20 mg/L [15,23-27], although in most situa-
tions they exceed 7 mg/L [23]. It is noteworthy that the
cytokine responsible for hepatic synthesis of SAA are
released from inflamed tissues, regardless of the cause of
the injury. For this reason, the SAA is a nonspecific
marker of inflammation and therefore cannot be used for
etiologic diagnosis. In fact, Hultén et al. [28] identified
levels of SAA above 7 mg/L in both viral and bacterial
infections, showing the non-specific nature of this pro-
tein. In response to tissue damage after inflammation or
infection, these values increase rapidly and reach concen-
trations ranging between 100 - 200 and 1000 mg/L [13,
23]. This type of response develops after 6 - 8 hours of
the onset of the stimulus, and reaches peak values within
36 - 48 hours and then decrease to baseline levels within
1 to 2 weeks in the absence of new stimuli [28]. The
plasma clearance of SAA is very fast and is degraded in
the liver between 30 minutes and 2 hours after synthesis.
Thus, the levels decrease rapidly when the cause of tissue
damage ceases [13]. These features make the SAA a suit-
able marker of real-time inflammatory activity and there-
fore a good indicator of the current health status of the
horse [13,29].
Some studies have suggested that SAA is even more
sensitive than classical markers of inflammation, such as
white blood cell count and Fb [30,31], as stated previ-
ously. Various factors such as fear, excitement and infec-
tions, among others, mainly induce increased cortisol and
neutrophilic leukocytosis type levels. Neutrophils have a
very limited kinetics and, therefore, are not considered to
be markers of the intensity of the trauma [32]. For this
reason, to monitor certainly inflammatory or infectious
process, the serum profiles of SAA reflect better the
course of the inflammation, since they are correlated by
the severity of the process. In contrast, fever and changes
in the number of leukocytes, are generally considered as
markers of inflammation and infection, and are not useful
parameters for monitoring post-operatively, due to its
non-specificity [29,31].
Until a few years ago and even today, the most widely
used APP in equine clinics has been the Fb. Because re-
search in recent years has shown that the APP of choice
is the SAA, as it responds more actively to inflammation
and/or infection. Among the numerous advantages of the
SAA to Fb cited, it is quicker responsiveness, the Fb
peak occurs within 7 - 10 days, while the SAA occurs in
24 - 48 h, and evolves in parallel with the degree of in-
jury and recovery and broader responsiveness. While the
Fb reaches values between 1000 - 4000 and 11,500 mg/L,
the SAA is significantly lower (0.5 - 20 mg/L), the Fb
can be estimated at 1000 mg/L, which allows the degree
of injury to be determined. In addition, Fb does not serve
to monitor the effective of the treatment as the response
and plasma clearance occur over time. By contrast, the
levels of SAA after injury are independent of the values
before the onset of the disease [32] and its half-life in
blood is very short.
The Fb is present in high amounts in healthy horses,
and decrease in situations of increased vascular perme-
ability or excessive consumption and coagulation disor-
ders which may mask the inflammatory or infectious
process [13,31,32]. Finally, the standard method of meas-
urement of Fb is insensitive to small changes, so it only
detects changes above 100 mg/dL [33]. Furthermore, the
levels of SAA rise when the inflammatory process is
active, and fall after the cessation of the stimulus. Thus,
relapse or exacerbation of inflammation must be accom-
panied by further increases, indicating the extent of tissue
injury. Therefore, repeated measurements provide an ob-
jective assessment of the health status, and help to moni-
tor the treatment, the degree of recovery and to decide
when the patient is fit to return to perform their normal
daily activity [13,34,35].
3. Factors Related to the Variations of
Serum Amyloid Type A Concentration in
3.1. Influence of Age and Sex
Several investigations have examined the effect of age
and sex on concentrations of SAA in horses, showing
conflicting results. Thus, while gender does not seem to
affect basal levels of this protein, age exerts a significant
influence on the protein profiles. In neonates, a signifi-
cant increase occurred at 72 hours after delivery. This
increase was related to the combined effect of tissue
trauma induced by the passage of the fetus through the
birth canal, as well as the release of cytokines from the
maternal circulation which reflects on the inflammatory
nature of the physical phenomenon of labor [15,36,37].
Also, Stoneham et al. [24] and Paltrinieri et al. [38] re-
lated this increase to the ingestion of immunoglobulins
from the colostrum. These levels remain elevated until 2
weeks of age [15,36].
In several species, SAA3 isoform has been isolated
from colostrum and milk [21,37,39]. Colostral levels of
Copyright © 2013 SciRes. OJVM
this protein are closely related to serum levels in healthy
foals at 48 hours after birth, suggesting that the protein
can be absorbed intact through the intestine and alter the
circulating levels. By contrast, other researchers have
shown undetectable levels of this protein in healthy foals
during this same time period [24,33,40]. These contro-
versial results suggest that fluctuations in the levels of
age-dependent SAA are so insignificant that no clinical
significance in the horse. In fact, a recent study by Jacob-
sen et al. [32] showed no variations in this age-associated
However, SAA concentrations have been reported in
foals less than 12 months of age and older than 18
months of 21.23 ± 12.20 and 14.93 ± 9.07 µg/mL, re-
spectively, according to Satoh et al. [36] and 19.37 ±
9.41 and 21.53 ± 9.81 µg/mL, respectively, according to
Nunokawa et al. [15]. In addition, both studies showed
significantly lower levels in foals and horses aged 18
months to over 21 years. This evolution experienced by
the SAA with age confirmed previous results from re-
search in human [41]. The higher incidence of diseases
of diverse origin with advancing age seems to be the
source of the increase of this protein in older animals,
although not all researchers agree with this theory [33].
3.2. Reproductive Status
These proteins are diagnostically useful tools to study
several diseases, such as endometritis, in mares [42,43]
and bitches [44] and mammary tumor disorders [45],
among others. Specifically in the mare, in the authors’
knowledge, the scientific literatures is very scarce and
fragmentary, and have focused primarily on the peripar-
tum period [15,36], estrous cycle [25] and pregnancy [26,
27]. The studies of Nunokawa et al. [15] and Satoh et al.
[36] showed that during the last four months of gestation
the levels of SAA remained within the physiological
range of reference, ranging from 16.6 to 23.6 mg/L. Se-
rum concentrations were increased 2 days before partum
(23.81 µg/mL), reaching levels of 56.74 ± 136.78 pg/mL
[15] and 101.29 ± 98.82 µg/mL [36] three days after de-
livery. This dynamic suggests that birth is an inflamma-
tory event in horse breeding, which could be due to tissue
damage induced by the passage of the fetus through the
birth canal. However, this increase is modest and the
levels of SAA return to normal one month after delivery
Satué and Calvo [25] and Satué et al. [26,27] showed
that SAA could not be used to diagnose heat or preg-
nancy in mares. On the contrary, an increase in SAA in
early pregnancy has been related with early embryonic
death [46].
Later, Duggan [47] found no significant differences in
concentrations of SAA between mares and pregnant
women. These same researchers showed significantly
higher levels of the SAA3 isoform in colostrum and milk
in the serum of pregnant mares in peripartum period.
SAA3 levels of colostrum have been associated such
features as protection, growth, development and matura-
tion of intestinal cells, immune system and other tissues
in the neonate [48-50]. Although it is not precisely known,
perhaps the endocrine pattern present in the mare during
this period could be responsible for the elevated levels of
this protein, since prolactin levels increase rapidly in the
last week of gestation [51] and therefore, the production
of colostrum, as previously shown in women [52,53].
3.3. Inflammatory Processes
As mentioned previously, the concentrations of SAA be-
come very evident in horses with clinical signs of inflam-
mation. Thus, in horses with experimentally induced in-
flammation, Nunokawa et al. [15] and Satoh et al. [36]
showed that concentrations of SAA increased in 2 days
after induction, reaching values of 4 to 40 times higher
than pretreatment values. Subsequently, these values
returned to baseline levels in 10 days to 4 weeks, which
coincided with to the disappearance of clinical signs. To
monitor the responsiveness of SAA aseptic arthritis in
Standardbred horses, serial blood samples were taken by
Hultén et al. [30] using the following protocol: before
induction (0 h), at 8, 16, 24, 36 and 48 hours and then at
3, 4, 5 and 15 days post-induction. SAA concentrations
increased at 16 hours, reached a peak at 36 - 48 h (227
times higher than the baseline), and remained elevated
for two weeks. In complicated septic arthritis situations,
SAA remains elevated both in serum and synovial fluid,
so it can be used to monitor treatment effect, and that
decreases simultaneously with the action of the treatment
Henriksen et al. [55] and Labelle et al. [56] monitored
the levels of SAA in the eye and in the local and sys-
temic inflammatory processes accompanying uveitis and
corneal ulcers in adult horses and foals with hypopyon.
The observed values of SAA in serum and vitreous were
significantly higher in foals than in adult animals. Al-
though it was found that this protein does not cross the
blood ocular barrier in uveitis and corneal ulcers, the
local levels increased significantly in the process of hy-
popyon. Finally, these same researchers showed that
uveitis does not seem to cause an acute phase response.
3.4. Surgery
Generically, surgery induces a marked APR, character-
ized by a biphasic pattern of SAA [23,31,33]. In particu-
lar, after castration, SAA levels have been identified
above 7 mg/L, with a peak at 2 - 3 days followed by a
second rise 4 or 5 days after surgery [23]. This pattern
had also previously been shown in mares experimentally
Copyright © 2013 SciRes. OJVM
infected with equine herpesvirus type 1 (EHV-1), al-
though in this case, a second rise occurred later, i.e., at
10 - 12 days from the onset of the process, an expected
phenomenon during the inflammatory process [34]. In
both cases, the second increase was not accompanied by
a worsening of clinical signs and the values returned to
the normal reference ranges for 7 - 15 days after surgery
In response to surgical stimulus, Satoh et al. [36] and
Pollock et al. [33] showed a narrow range for this protein
(from 0.0 to 0.1 µg/mL), which increased rapidly (from
16.1 to 27.29 µg/mL) compared with other markers of
inflammation, such as HP or Fb, suggesting that the SAA
is useful in the diagnosis and monitoring of disease with
surgical intervention in horses.
In three types of surgery, arthroscopic surgery, correc-
tion of the recurrent laryngeal nerve neuropathy, and
laparoscopic ovariectomy, Jacobsen et al. [32] affirmed
the induction of the APR, and an increase of SAA. The
concentrations of IL-6 were higher in the postoperative
period after conventional open surgery, which is a mini-
mally invasive process.
Therefore, this cytokine seems to be a sensitive indi-
cator of the intensity of surgical trauma, since it is the
main inducer of the hepatic synthesis of APPs. Jacobsen
et al. [32] also described the nature of the surgical trauma
that could affect the inflammatory response after surgery.
Both the length of the surgical incision, as the degree of
tissue disruption and the type of tissue, may influence the
magnitude of the inflammatory response. In fact, levels
of IL-6 after abdominal and thoracic surgery are superior
to those of a skeletal muscle. Moreover, peritoneal cells
produce different types of cytokines, including IL-6, so
that laparotomy may result in an increase of these cyto-
kines in the peritoneal fluid, which affect the APR post-
operative process [57]. By contrast, the type of anesthetic
and the time of exposure to it seem to influence the levels
of APPs [32].
The postsurgical inflammatory and infectious compli-
cations are also accompanied by significantly higher
values of SAA [31], that correlate with the severity of
symptoms. Thus, monitoring the SAA allows making
quick decisions about the treatment to apply, and thus
decrease the discomfort and postoperative complications
3.5. Bacterial and Viral Infections
Serum levels of SAA were significantly elevated within
hours of the establishment of infection, thus behaving as
an immediate indicator of the disease. This type of re-
sponse occurs with infections caused by bacteria [24,28,
34,38] and viruses [23,28,34]. Specifically, in adult
horses with bacterial infections, SAA levels have been
reported levels above 2000 mg/L [13], but there was a
more moderate increase associated with viral infections.
Thus, the degree of response will help to differentiate the
type of microorganisms involved. Hultén et al. [28]
showed that although an increase in SAA is not a specific
indicator of influenza or other viral infection is it an im-
portant diagnostic tool for the control, management and
monitoring of viral infections in horses. The SAA re-
sponse against the influenza virus occurs within 48 hours,
and returns to baseline levels after 11 - 22 days, in the
absence of complications. Therefore, persistent eleva-
tions of SAA beyond the 11 - 22 days could be related to
severe infections, infectious complications or tissue
damage secondary to another source that goes unnoticed.
Thus, the SAA can be used as a prognostic marker in
bacterial and viral respiratory diseases on a large scale in
herds, indicating the clinical severity and recovery status
of the animals [28,34].
Recurrent airway obstruction (RAO) is an inflamma-
tory, obstructive airway disease that becomes clinically
evident in middle-aged horses. The disease, also known
as heaves, is most prevalent in the northern hemisphere
where horses are stabled for large parts of their lives and
are fed hay. Attacks of airway obstruction are induced by
exposure of susceptible animals to organic dust (typically
hay dust). Following dust exposure, there is massive in-
flux of neutrophils into the airways. This is accompanied
by bronchospasm and mucus accumulation [58].
Systemic inflammation in horses with heaves is poorly
characterized. In a study done by Lavoie-Lamoureux et
al. [59], serum haptoglobin concentrations were signifi-
cantly higher in heaves-affected horses compared with
healthy controls. They were also significantly increased
by antigen challenge in both controls and horses with
heaves. Serum SAA was detected more frequently in
heaves-affected horses compared with healthy controls.
Thus concluded in heaves, haptoglobin is a marker of
both acute and chronic systemic inflammation, while
high concentrations of SAA indicate acute inflammation.
3.6. Neonatal Diseases
Generically, in newborn foals the manifestations of clini-
cal signs of disease usually are non-specific, so diagnosis
is often made with difficulty. For this reason, the accu-
racy and reliability of the measurement of SAA can pro-
vide positive results. In neonates, the SAA rises in the
presence of sepsis and infection [24,29,40]. Certain in-
vestigations on the evaluation of SAA in foals by non-
infectious causes, such as prematurity, failure of passive
transfer of immunity, neonatal maladjustment syndrome,
isoerythrolysis, meconium impaction, have given con-
flicting results. In some of these cases the levels of SAA
remain within the physiological range of reference [24,
29], while in other situations they are elevated [37,40].
Chronic infections in foals also lead to an increase of
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SAA, although at lower levels than in acute infections
High concentrations of SAA in foals often are indica-
tive of infection. It has also been suggested that values
above 100 mg/L could distinguish infectious from non-
infectious causes [24]. In fact, to distinguish these proc-
esses, the SAA is more accurate than traditional analytic
markers (Fb and leukocyte count) [29]. Neonatal sepsis is
a serious problem and a delay in starting treatment can be
fatal. Therefore, the SAA measurement can aid in the
diagnosis and most appropriate treatment setting in less
time [24]. Like in adult horses, localized infections, such
as abscesses in umbilical cord of foals, the SAA may
remain low or undetectable. This response is related to
the location of these abscesses and the removal of the
hepatic synthesis [24].
3.7. Respiratory Processes
Elevated levels of SAA have been detected in horses
infected with influenza [28] and pneumonic processes of
unknown etiology [15,34]. The SAA in horses with in-
fluenza is a more sensitive marker of acute infection de-
tected by nasal swabs. In addition, the SAA is positively
correlated with the severity of the clinical disease and
decreases or becomes undetectable in horses recovering
from viral infection [28]. High concentrations of SAA
were detected in foals infected by Rhodococcus equi
which decreased after initiating treatment [29]. However,
a study conducted in foals younger than 1 month showed
no variations in the concentrations of SAA among foals
with pneumonia caused by Rhodococcus equi at the time
of onset of clinical signs and clinically healthy foals.
Thus, SAA should not be used as a source of reliable
diagnosis, but as a tool to assist in the early detection of
respiratory tract infections [60].
SAA is also a useful tool to monitor the response to
treatment of respiratory tract infections. Secondary bac-
terial complications or severe influenza processes induce
persistent elevations in the levels of SAA [28]. For this
reason, the SAA can be used as a marker of the degree of
recovery and determine the appropriate convalescence
period, avoiding the detrimental effects of a return to
daily activity [61].
The responsiveness of SAA has been used to monitor
vaccinations against influenza, and tetanus. Generically,
vaccination causes a moderate increase of SAA, which
begins at 24 hours, persists for 96 hours and decreases in
3 - 4 days [62,63]. The A2 influenza virus produces a
type of local response which in some cases is systemic
and is due to the synthesis of IL-6 and TNF-α [64]. Simi-
larly, inoculation of endotoxins produced by Escherichia
coli induces a marked release of IL-1 [65].
It has been hypothesized that the measurement of SAA
in horses with respiratory disease could distinguish be-
tween infectious and noninfectious type caused by aller-
gic reactions. This justification is based on extrapolating
from human situations in which immune-mediated dis-
eases, such as systemic lupus eritrematoso, polymyositis
and ulcerative colitis that are associated with a low re-
lease of SAA [66,67]. At present, it remains to be clari-
fied if allergic or immune-mediated processes develop
alterations in the levels of SAA in horses.
Tables 1 and 2 describe the pathological causes com-
monly associated with elevated levels of SAA in horses.
Table 1. Description of the pathological processes infectious bacterial, septic and aseptic joint inflammation and surgeries
that lead to elevated levels of SAA in horses.
Process Description References
Experimentally induced aseptic arthritis Hultén et al. [23] Hultén and Demmers [29] Jacobsen et al. [18,22]
Naturally induced infectious arthritis Pepys et al. [34] Jacobsen et al. [24]
Joint diseases
IM injection of turpentine oil Nunokawa et al. [15]
Laparotomy Nunokawa et al. [15]
Different procedures
(laryngoplasty, ventriculectomy, ovariectomy)
Hultén et al. [17] Pepys et al. [34]
Pollock et al. [33] Jacobsen et al. [32]
Castration Nunokawa et al. [15] Hultén et al. [23] Jacobsen et al. [24]
Arthroscopy Jacobsen et al. [32]
Sepsis in foals Chavatte et al. [40] Hultén et al. [17] Stoneham et al.
[24] Hultén and Demmers [29]
Rhodococcus equi pneumonia Chavatte et al. [40] Hultén and Demmers [29]
Focal (abscesses, septic arthritis in foals) Stoneham et al. [24]
Strangles (Streptococcus equi) Pepys et al. [34] Hultén et al. [17]
Endometritis by experimental infection of E. coli Chistoffersen et al. [42]
Pyaemia, abscesses, post-operative infections Jacobsen et al. [32]
Unknown etiology abortion Nunokawa et al. [15]
Table 2. Description of the virus-like disease processes, gastrointestinal, non-infectious, reproductive and metabolic disorder s,
leading to elevated levels of SAA in horses and describe the processes.
Process Description References
Herpes virus type 1 in foals
Pepys et al. [34]
Chavatte et al. [40]
Hultén and Demmers [29]
Herpesvirus type 1 in adults Pepys et al. [34]
Viral infections
Influenza virus Hultén et al. [23,28]
Diarrhea and enteritis in foals Nunokawa et al. [15]
Colic in adult horses Nunokawa et al. [15] Vandeplas et al. (2005)
Gastrointestinal diseases
Peritonitis Jacobsen et al. [32]
Weakness, prematurity, neonatal maladjusted syndrome,
birth trauma and meconium colic retention Chavatte et al. [40]
Neonatal non-infectious diseases
Hypoxic-ischemic encephalopathy Duggan [47]
Foaling induction Duggan et al. [37]
Paltrinieri et al. [38]
Reproductive diseases
Abortion of unknown etiology Nunokawa et al. [15]
Metabolic diseases Laminitis Hultén et al. [17]
Other diseases Hyperlipidemia, anemia, weight loss, idiopathic edema
of unknown origin and ciatostomiasis Jacobsen et al. [32]
3.8. Amyloidosis
Recurrent inflammatory processes with sustained eleva-
tions of SAA can lead to reactive amyloidosis. This term
covers a variety of diseases involving the deposit of SAA
in the muscle fibers of the liver, spleen and kidney. Sys-
temic amyloidosis can have fatal consequences, as veri-
fied in horses with repeated immunization for the pro-
duction of antiserum [17,68].
4. Conclusion
The APPs determination of the physiological factor which
modifies the APR offers a biological effect mechanism
appropriate to assess the health in equine patients. De-
spite the nonspecific nature of the APR, the estimation of
plasma levels of SAA can be useful as a diagnostic aid,
helping to differentiate inflammatory from non-inflam-
matory conditions. Levels of SAA can also be important
for management of patients, since they generally reflect
the extent and intensity of the inflammatory process and
the response to, and need for, therapeutic interventions
and prognostic value, that ensures the return to normal
healthy condition in the shortest amount of time.
5. Conflict of Interest Statements
None of the authors of this paper has a financial or per-
sonal relationship with other people or organizations that
could inappropriately influence or bias the content of the
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