Acute Phase Reactants

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Acute phase reactants
Author: Irving Kushner, MD

Section Editor: Daniel E Furst, MD
Deputy Editor: Paul L Romain, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2018. | This topic last updated: Jul 12, 2017.
INTRODUCTION — An increase in the concentration of serum proteins that are referred to as acute phase
reactants (APR) accompanies inflammation and tissue injury [1,2]. Focus on the acute phase phenomenon,
termed the acute phase response, first occurred with the discovery of C-reactive protein (CRP) in the serum
of patients during the acute phase of pneumococcal pneumonia [3,4]. During the acute phase response, the
usual levels of various proteins maintained by homeostatic mechanisms can change substantially. These
changes are thought to contribute to host defense and other adaptive capabilities.
A discussion of the biology of the acute phase response; the general clinical utility and interpretation of
measurement of APR, such as CRP; and the clinical utility of indirect measures of the acute phase response,
such as the erythrocyte sedimentation rate (ESR), are presented here. Detailed reviews of disorders
associated with variations in APR and the utility of APR measurements in specific conditions, the innate
immune response, and the role of cytokines in immunity and inflammation are described separ ately (see
appropriate topic reviews of individual clinical disorders). (See "An overview of the innate immune system"
and "Role of cytokines in the immune system".)
THE ACUTE PHASE RESPONSE
Definition and regulation — Despite its name, the acute phase response accompanies both acute and
chronic inflammatory states and is associated with a wide variety of disorders, including infection, trauma,
infarction, inflammatory arthritides and other systemic autoimmune and inflammatory diseases, and various
neoplasms. Acute phase proteins are defined as those proteins whose serum concentrations increase or
decrease by at least 25 percent during inflammatory states [1]. Such proteins are termed either positive or
negative acute phase reactants (APR), respectively. The erythrocyte sedimentation rate (ESR), an indirect
APR, reflects plasma viscosity and the presence of acute phase proteins, especially fibrinogen, as well as
other influences, some of which are as yet unidentified [5]. (See 'Erythrocyte sedimentation rate' below.)
Changes in the levels of APR largely reflect altered production by hepatocytes, resulting primarily from the
effects of cytokines produced during the inflammatory process by macrophages, monocytes, and a variety of
other cells. Interleukin (IL)-6 is the major inducer of most APR [6]. Some of the other major cytokines relevant
to the acute phase response are IL-6, IL-1 beta, tumor necrosis factor (TNF)-alpha, and interferon gamma.
These cytokines also suppress the synthesis of albumin, which is termed a "negative APR" because its levels
decrease with inflammation [7]. Combinations of cytokines can have additive, inhibitory, or synergistic effects,
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and patterns of cytokine production differ under various inflammatory conditions [8-10]. (See "Role of
cytokines in rheumatic diseases".)
Increases in APR can vary from approximately 50 percent for ceruloplasmin and several components of the
complement cascade to 1000-fold or more for C-reactive protein (CRP) and serum amyloid A (SAA).
Additional positive APR include fibrinogen, levels of which have substantial effects on the ESR; alpha-1
antitrypsin; haptoglobin; IL-1 receptor antagonist; hepcidin; ferritin; procalcitonin; and others [8,11,12].
Negative APR include albumin, transferrin, and transthyretin.
Function — The assumption that APR are largely beneficial is based upon the known functions of the
individual proteins, but is also influenced by speculation as to how they may serve useful purposes in
inflammation, healing, or adaptation to noxious stimuli. Inflammation is a complex, highly orchestrated
process that involves many cell types and molecules which may initiate, amplify, sustain, attenuate, or abolish
inflammation. A number of the participating molecules are also multifunctional, contributing to both th e
waxing and the waning of inflammation at different points in time [13]. (See 'Roles of CRP' below and 'Roles
of other proteins' below.)
The acute phase response is not uniformly beneficial, and a number of behavioral, physiologic, biochemical,
and nutritional changes are induced during the response by inflammation-associated cytokines. In addition to
fever [14,15] and the development of anemia of chronic disease (also termed anemia of chronic
inflammation) [16], the response can be associated with behavioral changes, such as anorexia, somnolence,
and lethargy [17,18]; neuroendocrine effects, such as increased production of corticotropin-releasing
hormone [19]; muscle wasting [20-22]; cachexia; impaired growth in children; altered serum concentrations of
various cations, including iron, copper, and zinc; and secondary (AA or reactive) amyloidosis. Cytokine
overproduction and imbalance can be fatal, as in septic shock [23]. (See "Anemia of chronic
disease/inflammation" and "Pathophysiology of sepsis".)
Roles of CRP — CRP and many other APR can influence multiple stages of inflammation, and CRP has
both proinflammatory and antiinflammatory actions, although the primary effect may be antiinflammatory
[24,25]. CRP can promote the recognition and elimination of pathogens and enhance the clearance of
necrotic and apoptotic cells [26-32]. The protein consists of five identical, non-covalently associated subunits,
each with a molecular weight of approximately 23 kD, which are arranged symmetrically around a central
pore [33]. CRP and related proteins with this structure are termed pentraxins, which are a family of pattern
recognition molecules involved in the innate immune response; others include serum amyloid P and a
number of pattern recognition molecules referred to as long pentraxins [34]. (See "An overview of the innate
immune system", section on 'Pentraxins'.)
A major function of CRP is its ability to bind phosphocholine, thereby permitting recognition both of foreign
pathogens that display this moiety and phospholipid constituents of damaged cells [26]. CRP can also
activate the complement system and bind to phagocytic cells via Fc receptors, suggesting that it can initiate
elimination of pathogens and targeted cells by interaction with both humoral and cellular effector systems of
inflammation [25]. These functions of CRP may have negative effects in some settings. As an example, CRP
levels are increased in patients with immune thrombocytopenia (ITP), where CRP may amplify antibody -
mediated platelet destruction upon binding to phosphocholine that is exposed after oxidation triggered by
antiplatelet antibodies [35].
Proinflammatory effects of CRP include activation of the complement system and the induction in monocytes
of inflammatory cytokines and tissue factor [36,37] and shedding of the IL-6 receptor [38]. As a result, the
CRP response to tissue injury may worsen tissue damage in some settings [39].
Roles of other proteins — Like CRP, other APR have a wide variety of functional effects, including
initiating or sustaining inflammation, antiinflammatory effects, and effects upon wound healing, as well as
other functional consequences. As examples:
● The SAA proteins, a major human acute phase protein family, are apolipoproteins that are rapidly
associated with high-density lipoprotein following their synthesis and secretion and can influence
cholesterol metabolism during inflammatory states [40,41]. SAA may increase the adhesion and
chemotaxis of phagocytic cells and lymphocytes [42,43]. However, in some patients with chronic
inflammation, the net effect of increased SAA production is deleterious, because of the tissue deposition
of SAA fragments and development of systemic amyloidosis. (See "Pathogenesis of AA amyloidosis".)
● Complement components serve proinflammatory roles, including chemotaxis, plasma protein exudation
at sites of inflammation, and opsonization of infectious agents and damaged cells. (See "Overview and
clinical assessment of the complement system".)
● Haptoglobin and hemopexin are antioxidants that protect against reactive oxygen species by removing
iron-containing cell-free hemoglobin and heme, respectively, from the circulation [44,45].
● Alpha-1 antitrypsin, which inhibits superoxide anion generation, and alpha-1-antichymotrypsin both
antagonize proteolytic enzyme activity [46].
● Hepcidin, a protein made by the liver, can contribute to decreases in serum iron by reducing intestinal
iron absorption and impairing the release of iron from macrophages [11]. (See "Anemia of chronic
disease/inflammation", section on 'Hepcidin'.)
● Fibrinogen and haptoglobin influence wound healing. Fibrinogen causes endothelial cell adhesion,
spreading, and proliferation, which are critical to tissue repair; and haptoglobin aids in wound repair by
stimulating angiogenesis [47].
CLINICAL USE — The measurement of serum acute phase reactant (APR) levels is useful because
abnormalities generally reflect the presence and intensity of an inflammatory process. However, APR
measurements in clinical use are not specific to any particular disease, nor can they distinguish infection from
other causes of acute and chronic inflammation. The most widely used indicators of the acute phase
response are the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels (see 'Erythrocyte
sedimentation rate' below and 'C-reactive protein' below). Other markers, such as procalcitonin, may prove to
have a greater capacity than other APR to distinguish infection from malignant neoplasia or noninfectious
inflammation. (See 'Discrepancies between APR levels' below.)
In certain circumstances the results of ESR and CRP determinations may be discrepant, sometimes strikingly
so. This can occur due to factors related to the inflammatory process, including differences between APR in
their sensitivity to change due to the composition of elements involved in a particular inflammatory and
immune response. However, discrepancies between the ESR and another APR can also result from factors
that may increase or reduce the ESR but are unrelated to acute or chronic inflammation. (See 'Discrepancies
between APR levels' below and 'Erythrocyte sedimentation rate' below.)
Serum amyloid A (SAA) concentrations usually parallel those of CRP. Although some studies suggest that
SAA is a more sensitive marker of inflammatory disease, assays for SAA are not widely available for use in
routine clinical practice [48].
Erythrocyte sedimentation rate — The ESR, defined as the rate (expressed in mm/hour) at which
erythrocytes suspended in plasma settle when placed in a vertical tube, is an indirect measure of the acute
phase response and of levels of APR, particularly fibrinogen [5]. It can be influenced by other constituents of
the blood, such as immunoglobulins, as well. The ESR can also be affected by changes that may be
unrelated to inflammation, including changes in erythrocyte size, shape, and number; and by other technical
factors. (See 'Increased ESR' below and 'Decreased ESR' below.)
Increased ESR — The ESR, like other APR, is increased in patients with active inflammation from most
causes. These include:
● Systemic and localized inflammatory and infectious diseases

● Malignant neoplasms
● Tissue injury/ischemia
● Trauma
Marked elevations in the ESR are more often due to infection than other causes, but noninfectious disorders
are also a common etiology. In a retrospective study of 1006 consecutive outpatients, ESR values of over
100 mm/hour were most commonly due to infection (33 percent), with malignant neoplasms and renal
disease responsible for 17 percent each and inflammatory disorders responsible for 14 percent [49].
Conditions or factors unrelated to acute or chronic inflammation that may also increase the ESR include:
● Increased age and female sex – ESR values increase markedly with age [50] and are slightly higher
among women than men. As a result, any single set of normal values will not be valid for the population
at large. One can roughly correct ESR for age by using the following formulas: the upper limit of the
reference range equals (age in years)/2 for men and (age in years + 10)/2 for women [51].
● Anemia – It has long been known that anemia increases the sedimentation rate [52]. The sedimentation
of red blood cells is presumably impeded by other red blood cells; sedimentation is thus more rapid in
anemia, in which this retardation is lessened, thus increasing the ESR.
● Renal disease – The ESR is elevated (greater than 25 mm/hour by the Westergren method) in almost all
patients with end-stage renal disease (ESRD) or the nephrotic syndrome and is unaffected by
hemodialysis [53-55]. Nearly 60 percent of patients with ESRD have an ESR above 60 mm/hour, while
20 percent have extreme elevations above 100 mm/hour. Thus, an isolated ESR elevation in a patient
with renal disease, without other systemic signs or symptoms, does not necessarily indicate the
presence of infection, disease activity, or an underlying malignancy. (See "Causes and diagnosis of
membranous nephropathy".)
In one study of patients with glomerular disease, a positive correlation between the degree of proteinuria
and the ESR was observed, with the ESR being found to be about 10 times the daily rate of protein
excretion in patients who had not been treated with immunosuppressive agents [56]. The precise
mechanism by which this occurs is not known, although an underlying inflammatory renal disease
process may cause both an elevated ESR and result in proteinuria.
● Obesity – Both ESR and CRP can be elevated in obesity [57]; this is due at least in part to interleukin
(IL)-6 secretion by adipose tissue [58].
● Technical factors – Tilting of the ESR tube or high room temperature may increase the ESR.
Decreased ESR — A number of factors may spuriously result in a very low ESR or ESR that is less than
the expected level in a patient with acute or chronic inflammation [59,60]. These include:
● Abnormalities of erythrocytes – Changes in red cell shape or number may reduce the ESR, including
sickle cell disease, anisocytosis, spherocytosis, and acanthocytosis, as well as microcytosis and
polycythemia
● Extreme leukocytosis
● Extremely high serum bile salt levels [60]
● Heart failure
● Hypofibrinogenemia
● Cachexia
● Technical factors, including:
• Clotting of the blood sample or delay in testing of greater than two hours
• Low room temperature
• Short ESR tube
C-reactive protein — Elevations of CRP occur in association with acute and chronic inflammation due to a
range of causes, including infectious diseases and noninfectious inflammatory disorders. Very small changes
in CRP levels, detected with highly-sensitive assays, may also occur in association with metabolic stresses in
the absence of acute or chronic inflammatory states as they have traditionally been viewed.
'Normal' CRP levels — The level of CRP that is truly normal or clinically innocuous is not known. Data
from a study conducted by the National Health and Nutrition Evaluation Survey of over 21,000 people in the
United States revealed that CRP levels vary with age, sex, and race, with slightly higher levels seen with
increased age, with female sex, and in African Americans (table 1) [61]. A rough correction of the CRP for
age can be made by using the following formulas: the upper limit of the reference range (mg/dL) equals (age
in years)/50 for men and (age in years/50) + 0.6 for women [62,63].
It is very important to note that there is no uniformity in the units that are used to report CRP levels. Some
laboratories report CRP concentrations as mg/dL while others employ mg/L. Standard CRP determinations
may be reported either in units of mg/dL or in units of mg/L, while determinations using a highly sensitive
assay, generally referred to as "high-sensitivity CRP" (hs-CRP), are routinely reported in units of mg/L. (See
'High-sensitivity CRP and low-grade inflammation' below.)
Population studies reveal a skewed, rather than Gaussian, distribution of plasma CRP concentrations. About
70 to 90 percent of samples from reference populations have CRP concentrations under 0.3 mg/dL (3 mg/L),
but some individuals have minor elevations up to 1 mg/dL (10 mg/L). What we commonly call normal ranges
(properly called reference ranges) for CRP vary greatly from one laboratory to another, to a degree that
cannot be explained on a biologic or technical basis. What is thus regarded as "elevated" is often misleading.
It would be best to regard CRP concentrations >1 mg/dL (10 mg/L) as indicating clinically significant
inflammation while concentrations between 0.3 and 1 mg/dL (3 and 10 mg/L) indicate what is co mmonly
referred to as low-grade inflammation [64].
Low-grade inflammation is not accompanied by the classic signs of inflammation and may result from an
immense number of metabolic stresses [65-68]. Some of these stresses are clinically apparent; examples
include atherosclerosis, obesity, obstructive sleep apnea, insulin resistance, hypertension, and type 2
diabetes. Low-grade inflammation is, however, also associated with an astounding number of conditions and
lifestyles known to be associated with poor health, including low levels of physical activity, prehypertension, a
large variety of unhealthy diets, social isolation, and even being unmarried [69].
Moderate to marked elevation of CRP — In most inflammatory conditions, the CRP, like the ESR,
becomes elevated as part of the acute phase response. Markedly elevated levels of CRP are strongly
associated with infection. Infections, most often bacterial, were found in approximately 80 percent of patients
with values in excess of 10 mg/dL (100 mg/L) and in 88 to 94 percent of patients with values over 50 mg/dL
(500 mg/L) [70,71]. Levels of CRP may also be elevated in patients with viral infections, although usually not
to the degree seen in patients with bacterial infection [72,73]. (See "Diagnostic approach to community-
acquired pneumonia in adults", section on 'Procalcitonin and CRP'.)
ESR and CRP levels may be discrepant due to differences in kinetics, with the CRP both rising and
decreasing more rapidly; or related to characteristics of the inflammatory or and immune-disease related
mechanisms, as in systemic lupus, where significant CRP elevations are typically not as common or to as
great a degree as are increases in the ESR. (See 'Discrepancies between APR levels' below.)
High-sensitivity CRP and low-grade inflammation — Some confusion has arisen because of
widespread use of the terms "high-sensitivity CRP" and "low-grade inflammation" [74]. One common
misunderstanding has been the incorrect belief that hs-CRP is different in some way from the CRP that has
been measured for many years. It is not. "High-sensitivity" only means that the concentration of CRP was
determined using an assay designed to measure and distinguish very low levels of CRP. The CRP that is
measured has no new or unique properties [75].
Minor CRP elevation (concentrations between 3 and 10 mg/L) has been generally regarded as a marker of
what has been called low-grade inflammation. However, this poorly defined state, sometimes referred to as
mini-inflammation or subclinical inflammation, occurs in many conditions in which there are minor degrees of
metabolic dysfunction, such as obesity and insulin resistance, unlike inflammation as it has traditionally been
understood (see 'C-reactive protein' above). Moreover, the low-grade inflammatory state differs in several
important ways from the acute inflammation that occurs in response to infection or tissue injury [74,76]. The
acute inflammatory state is associated with the classic signs of inflammation (swelling, erythema, warmth,
and pain), while low-grade inflammation is not. Acute inflammation generally shows a marked CRP response
while low-grade inflammation shows only minor CRP elevation. The inflammatory response to infection and
tissue injury supports host defense, clearance of necrotic tissue, adaptation, and repair, while the purpose of
low-grade inflammation appears to be restoration of metabolic homeostasis [77].
The factors that trigger the acute inflammatory response and low-grade inflammation differ as well. Acute
inflammation is largely triggered by components of an invading pathogen, referred to as pathogen-associated
molecular patterns (PAMPs), and by products of damaged cells, damage- (or danger-) associated molecular
patterns (DAMPs) [76]. The latter are sometimes referred to as alarmins [78]. One molecular mechanism that
can trigger low-grade inflammation and CRP induction in response to metabolic stress that has been well-
studied is the unfolded protein response [79].
These differences between acute inflammation and low-grade inflammation are so great that two leading
researchers in the field have suggested distinct nomenclatures for the latter; both "para-inflammation" and
"metaflammation" (metabolically-triggered inflammation) have been proposed to emphasize the distinction
between metabolic perturbation and inflammation as it is traditionally viewed, both of which may result in
increases in CRP levels [76,79].
Discrepancies between APR levels — Although elevations in multiple components of APR commonly occur
together, not all happen uniformly in all patients. Discordance between concentrations of different APR is
common; some may be elevated while others are not. Differences in the production of specific cytokines or
their modulators in different diseases may account in large part for these variations [2]. Additionally, as a
patient’s condition worsens or improves, the ESR changes relatively slowly, while CRP concentrations can
change rapidly.
Discrepancies between ESR and CRP are found with some frequency. An elevated ESR observed together
with a normal CRP is often a misleading result that may, for example, reflect the effects of blood constituents,
such as monoclonal immunoglobulins, that are not related to inflammation but that can influence the ESR. It
should not be routine practice to order serum protein electrophoresis (SPEP) and urine protein
electrophoresis (UPEP) in such instances, unless the clinical presentation suggests that a plasma cell
dyscrasia may be present.
Systemic lupus erythematosus (SLE) represents an exception to the generalization that CRP concentrations
correlate with the extent and severity of inflammation in patients with rheumatic disorders [80]; the ESR may
be elevated, sometimes markedly, in patients with active SLE, while the CRP response is muted. The muted
CRP response in SLE appears to result from the ability of type I interferons, which are highly expressed in
most lupus patients, to inhibit CRP induction in hepatocytes [81]. While many patients with active SLE do not
have elevated CRP concentrations [82], CRP concentrations may be quite elevated in patients with active
lupus serositis [83] or with chronic synovitis [84]. In a febrile lupus patient, marked CRP elevation (greater
than 6 or 7 mg/dL) favors the diagnosis of bacterial infection [82]. In a landmark study, infection was present
in all patients with CRP levels over 6 mg/dL (60 mg/L) except for those with serositis, supporting the clinical
utility of regarding marked CRP elevation as strongly suggestive of infection [83]. (See "Diagnosis and
differential diagnosis of systemic lupus erythematosus in adults".)
In patients with active rheumatoid arthritis, the ESR and CRP generally tend to both be elevated or not in the
same patients. However, one study found that results for the two tests were discordant (ESR >28 mm/hr with
CRP ≤0.8 mg/dL or ESR ≤28 mm/hr with CRP >0.8 mg/dL) in about one-quarter of patients with active
rheumatoid arthritis in a large practice-based registry [85].
Several studies have suggested that elevations of the acute phase protein, procalcitonin, are highly specific
for infection [86-88]; thus, procalcitonin may prove useful in differentiating infections from other inflammatory
stimuli in autoimmune disease patients [89-91]. A 2012 systematic review and meta-analysis of nine
observational studies that evaluated procalcitonin as a marker of infection in patients with autoimmune
disease found that procalcitonin and CRP exhibited similar sensitivity for infection (75 versus 77 percent), but
that procalcitonin had significantly higher specificity (90 versus 56 percent) [92]. Thus, procalcitonin
determination was inadequate to exclude infection. Further study is required to define its clinical utility in
patients with systemic autoimmune disease. (See "Diagnostic approach to community-acquired pneumonia in
adults", section on 'Procalcitonin and CRP' and "Acute bronchitis in adults", section on 'Procalcitonin'.)
Since there are undoubtedly a number of other clinical situations in which similar discrepancies occur, there
probably is no single best laboratory test to reflect inflammation. The optimal use of acute phase protein
measurements may be to obtain several measurements, usually ESR and CRP, rather than a single test [85].
The results must be interpreted in light of the clinical context and the considerations previously indicated.
SPECIFIC APPLICATIONS — The assessment of acute phase reactants (APR) may be helpful in a range of
disorders, where such testing may be useful for diagnosis, monitoring of disease activity, or as a prognostic
marker, depending upon the condition. The appropriate use of APR testing is described separately in t he
topics on each condition or specific disorder. The following examples are conditions in which measurement of
APR may be particularly helpful:
● Rheumatoid arthritis – APR are helpful in monitoring disease activity in rheumatoid arthritis. Generally,
both the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) respond to changes in
disease activity and may be sensitive indicators. However, in one study, nearly 60 percent of patients
with active rheumatoid arthritis had both ESR <28 mm/h and CRP <0.8 mg/dL, thereby limiting the utility
of these acute phase reactants for monitoring disease activity [85]. (See "Biologic markers in the
diagnosis and assessment of rheumatoid arthritis", section on 'Erythrocyte sedimentation rate' and
"Biologic markers in the diagnosis and assessment of rheumatoid arthritis", section on 'C-reactive
protein'.)
A multi-biomarker disease activity (MBDA) assay has been developed that measures a diverse variety of
biomarkers, using these data to identify and estimate the level of disease activity in patients with
rheumatoid arthritis and to predict disease progression. Molecules whose concentrations are measured
include two acute phase proteins (CRP and serum amyloid A), as well as one or two each of the
following: adhesion molecules, growth factors, cytokine-related proteins, matrix metalloproteinases,
skeletal-related proteins, and hormones. (See "Biologic markers in the diagnosis and assessment of
rheumatoid arthritis", section on 'Multi-protein biomarker algorithms'.)
● Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) – Both the ESR and CRP are useful in
diagnosing PMR and GCA and usually correlate well with disease activity. (See "Treatment of
polymyalgia rheumatica" and "Clinical manifestations of giant cell arteritis" and "Diagnosis of giant cell
arteritis", section on 'Clinical suspicion' and "Clinical manifestations and diagnosis of polymyalgia
rheumatica", section on 'Diagnosis' and "Clinical manifestations and diagnosis of polymyalgia
rheumatica", section on 'Laboratory findings' and "Clinical manifestations and diagnosis of polymyalgia
rheumatica", section on 'Laboratory testing'.)
● Systemic lupus erythematosus (SLE) – Comparison of the ESR and CRP may be useful in patients with
SLE, particularly when infection is suspected. Discrepancies between the two APR are related to the
particular nature of the immune response in these patients. (See 'Discrepancies between APR levels'
above and "Diagnosis and differential diagnosis of systemic lupus erythematosus in adults", section on
'Laboratory testing' and "Overview of the management and prognosis of systemic lupus erythematosus
in adults", section on 'Laboratory evaluation'.)
● Cardiovascular disease – There is a continually expanding literature on the predictive value of CRP in
cardiovascular disease and on the possible role of serum CRP in screening for cardiovascular risk.
These issues are discussed in detail elsewhere. (See "C-reactive protein in cardiovascular disease".)
● Infection – Infections are an important cause of elevated APR. Serial measurement may be used to
assess response of chronic infections to treatment. As an example, the ESR and CRP fall when
osteomyelitis is effectively treated. (See "Hematogenous osteomyelitis in adults".)
● Malignancy – Measurements of APR may be helpful in assessing the prognosis in some patients with
malignancy, assessing the presence or absence of tumor recurrence, and distinguishing a clonal from a
reactive process. (See "Approach to the patient with thrombocytosis" and "Clinical features, laboratory
manifestations, and diagnosis of multiple myeloma" and "Overview of the treatment of classical Hodgkin
lymphoma in adults".)
● Other chronic conditions – Indicators of inflammation imply a poor prognosis in many other conditions,
including type II diabetes, peripheral vascular disease, uremia, and ischemic stroke. In older adults,
elevated levels of APR predict "failure to thrive" and even increased mortality [93]. This may be because
a minor acute phase response reflects the presence of some degree of ongoing metabolic perturbation
which itself may contribute to a poor outcome. Alternatively, these minimally elevated acute phase
protein levels may merely identify individuals who are biologically older and who have sustained a
greater load of minor body insults and damage, such as would result from the cumulative effect of
metabolic stress [74,94].
SUMMARY AND RECOMMENDATIONS
● A change in the concentration of acute phase reactants (APR), defined as those proteins whose serum
concentrations increase or decrease by at least 25 percent during inflammatory states, is a major
pathophysiologic phenomenon that accompanies acute and chronic inflammation and tissue injury.
Those proteins whose concentrations increase are commonly referred to as positive APR, while those
whose concentrations decrease are regarded as negative APR. These changes are presumed to
contribute to defensive or adaptive capabilities. (See 'Introduction' above and 'Definition and regulation'
above.)
● Changes in levels of APR result largely from the effects of cytokines, including interleukin (IL)-6, IL-1
beta, tumor necrosis factor (TNF)-alpha, and interferon gamma. These proteins influence acute phase
protein production in hepatocytes, with IL-6 being the major inducer of most APR. (See 'Definition and
regulation' above.)
● The assumption that APR are beneficial is based upon the known functions of the involved proteins and
speculation as to how they may serve useful purposes in inflammation, healing, or adaptation to noxious
stimuli. C-reactive protein (CRP) is a component of the innate immune response, and has both
proinflammatory and antiinflammatory actions. A number of other APR can initiate or sustain
inflammation, while some APR may be antiinflammatory. (See 'Function' above and 'Roles of CRP'
above and 'Roles of other proteins' above.)
● The erythrocyte sedimentation rate (ESR), defined as the rate (mm/hour) at which erythrocytes
suspended in plasma settle when placed in a vertical tube, reflects a variety of factors, most notably the
plasma concentration of fibrinogen. Other constituents of the blood, such as immunoglobulins, can
influence it as well. The ESR can also be affected by changes that may be unrelated to inflammation,
including changes in erythrocyte size, shape, and number; and by other technical factors. (See
'Erythrocyte sedimentation rate' above and 'Increased ESR' above and 'Decreased ESR' above.)
● The level of CRP that is truly normal or clinically innocuous is not known. CRP levels vary somewhat
with age, sex, and race. There is no uniformity in the units that are used to report CRP levels; some
laboratories report CRP concentrations as mg/dL while others employ mg/L. Markedly elevated levels
are strongly associated with infection. (See 'C-reactive protein' above.)
● Although CRP is a sensitive indicator of inflammation, it is not specific for our traditional concept of
inflammation (tumor, calor, rubor, and dolor), especially at relatively low levels. Values between 0.3 and 1
mg/dL may reflect minor degrees of inflammation, such as that seen in periodontitis, but may also reflect
low-grade inflammatory states in conditions in which there are minor degrees of metabolic dysfunction,
such as obesity and insulin resistance. Values greater than 1 mg/dL are considered to reflect clinically
significant inflammation. (See 'C-reactive protein' above and 'High-sensitivity CRP and low-grade
inflammation' above.)
● Although elevations in multiple components of the APR typically happen together, not all occur uniformly
in all patients. Discordance between concentrations of different APR is common; discrepancies between
ESR and CRP are found with some frequency. These variations may be partially explained by
differences in the production of specific cytokines or their modulators in different diseases. (See
'Discrepancies between APR levels' above.)
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Topic 7483 Version 21.0
GRAPHICS
C-reactive protein levels in adults
0 to 2 mg/L (0 to 2 to 3 mg/L (0.2 3 to 10 mg/L (0.3 >10 mg/L

0.2 mg/dL) to 0.3 mg/dL) to 1.0 mg/dL) (>1.0 mg/dL)
All 48% 14% 29% 10%

adults
Men 56% 14 % 24% 6%
Women 40% 13% 33% 13%
White 48% 14% 29% 9%
Black 44% 12% 29% 15%
Age 20 59% 12% 22% 7%

to 29
Age 36% 17% 34% 13%

>70
Data from: National Health and Nutrition Evaluation Survey, 2005.
Graphic 59376 Version 3.0
Contributor Disclosures
Irving Kushner, MD Nothing to disclose Daniel E Furst, MD Grant/Research/Clinical Trial Support: AbbVie
[RA, IBD, PMS, PsA (adalimumab)]; Actelion [SSc (bosentan, macitentan)]; Amgen [RA, IBP, AS, PsA
(etanercept)]; BMS [RA, SSc (abatacept)]; Corbus [SSc, SLE (anabasum)]; NIH; Novartis; Pfizer [SSc
(sildenafil)]; Roche/Genentech [RA, IBD, AS, SSc (rituximab, tocilizumab)]. Consultant/Advisory Boards:
AbbVie [RA, IBD, PMS, PsA (adalimumab)]; Actelion [SSc (bosentan, macitentan)]; Amgen [RA, IBP, AS,
PsA (etanercept)]; BMS [RA, SSc (abatacept)]; Cytori [lab test advisory]; Novartis; Pfizer [SSc (sildenafil)];
Roche/Genentech [RA, IBD, AS, SSc (rituximab, tocilizumab)]. Paul L Romain, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
Conflict of interest policy

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Author: Irving Kushner, MD

THE ACUTE PHASE RESPONSE

● Systemic and localized inflammatory and infectious diseases

● Extremely high serum bile salt levels [60]

● Technical factors, including:

• Low room temperature

• Short ESR tube

SUMMARY AND RECOMMENDATIONS

Topic 7483 Version 21.0

C-reactive protein levels in adults

0 to 2 mg/L (0 to 2 to 3 mg/L (0.2 3 to 10 mg/L (0.3 >10 mg/L

All 48% 14% 29% 10%

Men 56% 14 % 24% 6%

Women 40% 13% 33% 13%

White 48% 14% 29% 9%

Black 44% 12% 29% 15%

Age 20 59% 12% 22% 7%

Age 36% 17% 34% 13%

Data from: National Health and Nutrition Evaluation Survey, 2005.

Graphic 59376 Version 3.0

Conflict of interest policy

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