INTRODUCTION — The acute phase response, in the broad sense, refers to the large number of behavioral, physiologic, biochemical, and nutritional changes that occur during inflammatory states [1]. Awareness of this phenomenon followed the discovery of C-reactive protein (CRP) in the serum of patients during the acute phase of pneumococcal pneumonia [2,3].
In the acute phase response, there are changes in the concentration of a number of plasma proteins, called acute phase reactants (APR); these changes are thought to contribute to host defense and adaptive capabilities [4]. While this array of changes is sometimes referred to as systemic inflammation, we avoided this term because of confusion with the systemic inflammatory response syndrome (SIRS) that is associated with sepsis and the potential suggestion of widespread inflammation.
This topic presents 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) and CRP. 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 separately (see appropriate topic reviews of individual clinical disorders):
●(See "An overview of the innate immune system" and "The adaptive humoral immune response" and "The adaptive cellular immune response: T cells and cytokines" and "Laboratory evaluation of the immune system".)
●(See "The adaptive humoral immune response".)
●(See "The adaptive cellular immune response: T cells and cytokines".)
●(See "Laboratory evaluation of the immune system".)
THE ACUTE PHASE RESPONSE
Definition and regulation — Despite its name, the acute phase response accompanies chronic as well as acute inflammatory states and is associated with a wide variety of disorders, including infection, trauma, tissue infarction, inflammatory arthritides, other systemic autoimmune and inflammatory diseases, and various neoplasms. Less marked changes may occur in response to metabolic stresses [5].
Acute phase proteins are arbitrarily defined as those proteins whose plasma 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 [6]. (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 6 (IL-6) is the major inducer of most APR [7]. Some of the other major cytokines impacting the acute phase response are 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 [8]. Combinations of cytokines can have additive, inhibitory, or synergistic effects, and patterns of cytokine production differ under various inflammatory conditions [9-11]. (See "Interleukin 6 inhibitors: Biology, principles of use, and adverse effects" and "The adaptive cellular immune response: T cells and cytokines" and "Pathogenesis of rheumatoid arthritis" and "Epidemiology and pathogenesis of systemic lupus erythematosus" and "Pathogenesis of systemic sclerosis (scleroderma)".)
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 [9,12,13]. Negative APR include albumin, transferrin, and transthyretin [14].
Molecules other than proteins may also exhibit acute phase behavior. Thus, during the acute phase response, concentrations of zinc and iron decrease, while concentrations of copper rise. The concentrations of a variety of vitamins also manifest acute phase behavior [15]. This has been problematic for clinicians since the acute phase behavior of these molecules tends to be overlooked. As an example, it may be concluded erroneously that an individual is iron deficient when low serum iron levels are found, but that may be because iron is merely behaving as a negative APR. Serum iron levels fall because the liver-produced APR hepcidin reduces intestinal iron absorption and impairs the release of iron from macrophages [12].
Similarly, vitamin D, as measured by serum 25-hydroxyvitamin D (25[OH]D or calcidiol) levels, is a negative APR. Numerous metabolic stresses have been associated with low 25(OH)D levels, and inflammatory insults such as surgery have been shown to lower levels acutely [15-22]. This may in part explain why vitamin D supplementation has been a focus of numerous nutraceutical trials for coronavirus disease 2019 (COVID-19) [23], as well as cancer and cardiovascular disease [24].
It has become clear that 25(OH)D is a negative APR because less than 1 percent of circulating 25(OH)D exists in unbound form; the majority is tightly bound to vitamin D binding protein, while 10 to 15 percent is bound to albumin. Both vitamin D binding protein and albumin are negative acute-phase proteins [25]. As the serum concentrations of these proteins decrease, so does that of 25(OH)D. Similarly, the positive acute-phase behavior of copper is explained by the fact that it is bound to ceruloplasmin, a positive acute-phase protein [26].
Function — The assumption that the changes induced by the acute phase response are largely beneficial is based on the known functions of the individual proteins and 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 the waxing and the waning of inflammation at different points in time [27]. (See 'Roles of CRP' below and 'Roles of other proteins' below.)
In addition to changes in plasma proteins, a number of physiologic, biochemical, behavioral, and nutritional changes are induced during the acute phase response by inflammation-associated cytokines. In addition to fever [28,29] and the development of anemia of chronic disease (also termed anemia of chronic inflammation) [30], the response can be associated with behavioral changes, such as anorexia, somnolence, and lethargy [31,32]; neuroendocrine effects, such as increased production of corticotropin-releasing hormone [33]; muscle wasting [34-36]; cachexia; impaired growth in children; altered serum concentrations of various cations, including iron, copper, and zinc. As a consequence of the acute phase response, secondary (AA or reactive) amyloidosis may develop. Marked cytokine overproduction and imbalance can be fatal, as in the systemic inflammatory response syndromee (SIRS) [37] or in macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH) [38]. (See "Anemia of chronic disease/anemia of inflammation" and "Pathophysiology of sepsis".)
Roles of CRP — CRP and many other APR can influence multiple stages of inflammation, and CRP has been shown to have both proinflammatory and antiinflammatory actions, although the primary effect may be antiinflammatory [39,40]. CRP can promote the recognition and elimination of pathogens and enhance the clearance of necrotic and apoptotic cells [41-47]. CRP 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 [48]. CRP and related proteins with this structure are termed pentraxins, constituting 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 [4,49,50]. (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 as well as phospholipid constituents of damaged cells [41]. 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 [40]. 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 [51].
Proinflammatory effects of CRP include activation of the complement system and the induction in monocytes of inflammatory cytokines and tissue factor [52,53] and shedding of the IL-6 receptor [54]. As a result, the CRP response to tissue injury may worsen tissue damage in some settings [55].
Roles of other proteins — Like CRP, other APR have a wide variety of functional effects, including initiating or sustaining inflammation, antiinflammatory effects, and effects on 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 [56,57]. SAA may increase the adhesion and chemotaxis of phagocytic cells and lymphocytes [58,59]. 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 [60,61].
●Alpha-1 antitrypsin, which inhibits superoxide anion generation, and alpha-1-antichymotrypsin both antagonize proteolytic enzyme activity [62].
●Hepcidin, an acute phase protein made by the liver, causes a decrease in serum iron by reducing intestinal iron absorption and impairing the release of iron from macrophages [12]. (See "Anemia of chronic disease/anemia of inflammation", section on 'Hepcidin (primary regulator of iron homeostasis)'.)
●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 [63].
●Ferritin is an iron storage protein whose release is stimulated by IL-6 and TNF-alpha. High levels are an important mechanism for host defense as the toxicity of iron for bacteria results in inhibition of bacterial growth [64].
●Procalcitonin is a precursor to calcitonin produced by two alternate mechanisms during bacterial infections. Lipopolysaccharide or other microbial toxic metabolites stimulate production as well as various inflammatory mediators (eg, IL-6, TNF-alpha). This alternative pathway does not produce high serum calcitonin levels nor decreased calcium like the typical endocrine pathway does [65]. It is unclear why procalcitonin increases during bacterial infections.
LABORATORY EVALUATION
Clinical utility — 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 differentiate infection from other causes of acute and chronic inflammation. The most widely employed 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 and 'Discrepancies between acute phase reactant levels' below.)
In certain circumstances, the results of ESR and CRP determinations may be discrepant, sometimes strikingly so. At times, this occurs because CRP levels change rapidly while ESR is a relative laggard. This can also occur due to factors related to the inflammatory process, including differences between APR in their sensitivity to change due to differences in the specific inducing cytokines or their modulators in different diseases. 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 acute phase reactant levels' below and 'Erythrocyte sedimentation rate' below.)
Erythrocyte sedimentation rate — The ESR, defined as the rate (expressed in mm/hour) at which erythrocytes suspended in plasma fall when placed in a vertical tube, is an indirect measure of the acute phase response and of levels of APR, particularly fibrinogen [6]. It can be influenced by other constituents of the blood, such as immunoglobulins and monoclonal proteins 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 — Normally, erythrocytes suspended in plasma settle slowly. Several plasma proteins, mainly fibrinogen, promote the formation of red cell clusters called rouleaux. Such aggregation makes them heavier and more likely to fall rapidly.
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
●Monoclonal proteins
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 kidney disease responsible for 17 percent each and a variety of inflammatory disorders responsible for 14 percent [66]. Of interest, in a study of patients with ESR values over 100 mm/hour, a definitive diagnosis could not be established in 18 percent of patients [67].
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 [68] 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 [69].
●Anemia – It has long been known that anemia increases the sedimentation rate [70]. 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. Macrocytosis may also increase ESR [71].
●Pregnancy – The pregnant state includes hemodilution because of increase in plasma volume; corrected for this anemia, ESR increases with gestational age of the pregnancy [72].
●Kidney disease – The ESR is elevated (greater than 25 mm/hour by the Westergren method) in almost all patients with end-stage kidney disease (ESKD) or the nephrotic syndrome, and is unaffected by hemodialysis [73-75]. Nearly 60 percent of patients with ESKD 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 kidney disease, without other systemic signs or symptoms, does not necessarily indicate the presence of infection, disease activity, or an underlying malignancy (see "Membranous nephropathy: Pathogenesis and etiology"). Compared with hemodialysis patients, patients utilizing peritoneal dialysis have a higher ESR [76].
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 [77]. The precise mechanism by which this occurs is not known, although an underlying inflammatory kidney disease process may cause both an elevated ESR and result in proteinuria.
●Obesity – Both ESR and CRP can be elevated in obesity [78]; this is due at least in part to interleukin 6 (IL-6) secretion by adipose tissue [79] and skeletal muscle [80]. In fact, metabolic syndrome is associated with an increase in ESR [81].
●Other lifestyle characteristics – Smoking has been associated with elevated ESR [81].
●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 [82,83]. These include:
●Abnormalities of erythrocytes – The ESR may be reduced by changes in red cell shape or number (eg, sickle cell disease, anisocytosis, spherocytosis, and acanthocytosis) as well as by microcytosis and polycythemia. This can be confusing, for example, in patients with sickle cell disease, who may have a spuriously low ESR [84,85].
●Extremely high serum bile salt levels [83]
●Heart failure [86,87]
●Hypofibrinogenemia [88]
●Medications that suppress the inflammatory response, such as high-dose glucocorticoids, high-dose salicylate therapy, IL-6 inhibitors (eg, tocilizumab, sarilumab) [89], and, in biopsy-proven giant cell arteritis, statins and nonsteroidal antiinflammatory drugs (NSAIDs) [90]
●Other lifestyle characteristics – Moderate and high regular physical activity has been associated with decreased ESR, as has light alcohol consumption (ie, one to four drinks weekly) compared with non-consumers [81]
●Technical factors, including:
•Clotting of the blood sample or delay in testing of greater than two hours
•Low room temperature
•Short ESR tube
Because low levels of fibrinogen are part of the macrophage activation syndrome (also known as acquired hemophagocytic lymphohistiocytosis), a patient with "cytokine storm" may have a declining ESR. This is thought to be due to the consumptive coagulopathy and decreased synthesis of fibrinogen, a main driver of the ESR [91].
Because numerous chronic factors can affect ESR, it is important to consider all the elements that influence ESR. It may be beneficial for clinicians to think of these confounders which may give a "false positive" (or "false negative") value when considering and investigating a more acute condition (table 1).
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. Modest increases 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 — It is important to be aware 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 a high-sensitivity CRP (hs-CRP), are routinely reported in units of mg/L. 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 people identifying as African American (table 2) [92]. A very rough correction of the CRP for age has been proposed using the following formulas: the upper limit of the reference range (mg/dL) equals (age in years)/50 for males and (age in years/50) + 0.6 for females [93,94].
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) reported 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; minor CRP elevation) indicate what is commonly referred to as low-grade inflammation [95].
Low-grade inflammation is not accompanied by the classic signs of inflammation and may result from an immense number of metabolic stresses and metabolic syndromes [4,96-99]. Some of these stresses are clinically apparent; examples include atherosclerosis, obesity, obstructive sleep apnea, insulin resistance, hypertension, and type 2 diabetes. Low-grade inflammation, as reflected by minor CRP elevations, is 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. This realization has led to a redefinition of inflammation as the innate immune response to harmful stimuli such as pathogens, injury, and metabolic stress [5].
Although CRP levels do not correlate with gestational age in pregnancy, median CRP levels are marginally higher during pregnancy than in nonpregnant persons [100,101]. Also, CRP levels increase during labor [101]. In addition to the usual metabolic stressors, this low level of subclinical inflammation has been associated with preeclampsia and gestational diabetes [102-104].
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) [105,106]. Levels of CRP may also be elevated in patients with viral infections, although usually not to the degree seen in patients with bacterial infection [107,108]. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults", section on 'Serum biomarkers'.)
High-sensitivity CRP and low-grade inflammation — Some confusion has arisen because of widespread use of the term "high-sensitivity CRP" [109]. 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 a highly sensitive assay designed to quantitate very low levels of CRP. The CRP that is measured is "plain old" CRP itself, not anything new or different [110]. CRP and hs-CRP assays both answer the same question: how much CRP is in the serum?
Minor CRP elevation (concentrations between 3 and 10 mg/L) is regarded as indicating low-grade inflammation. Inflammation, one of the first responses of the activated innate immune system, has long been defined as the response to infection and tissue injury. Its presence was classically recognized by the presence of heat, swelling, redness, and pain. In the 21st century, our understanding of what can elicit inflammation has expanded considerably. We have learned that the innate immune system responds to metabolic stress with chronic low-grade inflammation ("metaflammation") without the classic signs of acute inflammation. 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 (see 'C-reactive protein' above). This low-grade inflammatory state differs in several important ways from the acute inflammation that occurs in response to infection or tissue injury [109,111]. 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 [5,112].
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) [111]. The latter are sometimes referred to as alarmins [113]. 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 [114]. Just beginning to be investigated are other harmful metabolic stimuli that can trigger inflammatory responses ("metaflammation") via metabolism-associated molecular patterns (MAMPs) [115].
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 some increase in CRP levels [111,114].
Discrepancies between acute phase reactant 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 [14]. 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. Potential reasons may include the following:
●The acuity of the acute phase response – CRP levels measure a single molecule, and one will note acute and rapid rise following an insult and fall with improvement. By contrast, because ESR is the reflection of numerous factors and the interaction of these elements (ie, long half-life of some plasma proteins), ESR levels do not rapidly rise at the beginning of an inflammatory insult; similarly, normalization is slower. This difference between ESR and CRP may help clinicians distinguish between acute processes and a more chronic process (for example, high CRP and normal ESR may suggest an acute paronychia; by contrast, elevated CRP and ESR may suggest osteomyelitis).
●Disease-related mechanisms – ESR and CRP may sometimes be discrepant due the underlying disease mechanism. As an example, in systemic lupus erythematosus (SLE), substantial CRP elevations are typically not as common as elevations in the ESR, and the CRP level generally does not rise, in relative terms, to as great a degree with increased disease activity as does the ESR [116]. This is discussed in more detail elsewhere. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Laboratory evaluation'.)
An elevated ESR observed together with a normal CRP may 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 clinical practice to order serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) in such instances, unless there is a markedly elevated globulin level and/or a clinical presentation that suggests that multiple myeloma, Waldenström macroglobulinemia, or primary amyloidosis may be present.
Since there are undoubtedly a number of 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 [117]. The results must be interpreted in light of the clinical context and the considerations previously indicated.
Other acute phase reactants
●Procalcitonin – Several studies have suggested that elevations of the acute phase protein procalcitonin are highly specific for infection [118-120]; thus, procalcitonin may prove useful in differentiating infections from other inflammatory stimuli in autoimmune disease patients [121-123]. 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) [124]. Thus, procalcitonin determination was inadequate to exclude infection. Procalcitonin was found to have a greater predictive value than serum ferritin, CRP, or any other biomarkers [125]. However, others have found no advantage of procalcitonin over CRP [126]. The median ferritin to procalcitonin ratio was found to be significantly higher in patients with COVID-19 than in patients with bacterial pneumonia [127]. Further study is required to define their clinical utility. (See "Acute bronchitis in adults", section on 'Procalcitonin' and "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults", section on 'Serum biomarkers'.)
Rarely tumors, trauma, burns, and liver failure may cause an elevation in procalcitonin [128].
●Serum amyloid A – 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 [129].
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 the 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, although a significant number of patients do not have elevated values [117]. (See "Biologic markers in the assessment of rheumatoid arthritis", section on 'Erythrocyte sedimentation rate' and "Biologic markers in the assessment of rheumatoid arthritis", section on 'C-reactive protein'.)
●Polymyalgia rheumatica and giant-cell arteritis – Both the ESR and CRP are useful in diagnosing polymyalgia rheumatica and giant-cell arteritis and usually correlate well with disease activity. However, therapies used to treat these conditions can also affect the results of APR. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica", section on 'Laboratory testing' and "Clinical manifestations of giant cell arteritis", section on 'Erythrocyte sedimentation rate and C-reactive protein' and "Treatment of polymyalgia rheumatica".)
●Systemic lupus erythematosus – Comparison of the ESR and CRP may be useful in patients with systemic lupus erythematosus, particularly when infection is suspected. Discrepancies between the two APR are related to the particular nature of the immune response in these patients [116]. (See 'Discrepancies between acute phase reactant levels' above and "Systemic lupus erythematosus in adults: Overview of the management and prognosis", 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. In addition, measurement of procalcitonin may prove useful in suspected bacterial infections and sepsis [118-120]. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis".)
●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 [130]. 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 [109,131].
SUMMARY AND RECOMMENDATIONS
●Definitions – 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.)
●Regulation – Changes in levels of APR result largely from the effects of cytokines, particularly interleukin 6 (IL-6), as well as IL-1 beta, tumor necrosis factor (TNF)-alpha, and interferon gamma. These proteins influence acute phase protein production in hepatocytes. (See 'Definition and regulation' above.)
●Functions – 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 seems to have 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.)
●ESR – The erythrocyte sedimentation rate (ESR), defined as the rate (mm/hour) at which erythrocytes suspended in plasma fall 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.)
●CRP – The level of CRP that is truly normal or clinically innocuous is not known. The serum concentration in most people is under 3 mg/L. 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.)
●Low-level CRP elevations – 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 (10 mg/L) are felt to reflect clinically significant inflammation. (See 'C-reactive protein' above and 'High-sensitivity CRP and low-grade inflammation' above.)
●Discrepancies between ESR and CRP elevations – 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 acute phase reactant levels' above.)
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