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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 7  |  Issue : 1  |  Page : 12-18

Utility of acute-phase reactants testing in clinical practice


Department of Pathology, AIIMS, Bibinagar, Telangana, India

Date of Submission22-Jul-2020
Date of Decision21-Aug-2020
Date of Acceptance14-May-2021
Date of Web Publication29-Jun-2021

Correspondence Address:
Dr. Shailaja Prabhala
Department of Pathology, All India Institute of Medical Sciences, Bibinagar, Rangapur, Bhuvangiri, Yadadri Bhuvanagiri - 508 126, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJCFM.IJCFM_82_20

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  Abstract 


Acute-phase proteins (APPs) or acute phase reactants (APRs) are diverse biochemical proteins which are seen as a response in inflammatory processes due to varied etiologies. Some of these proteins increase and some decrease due to various mechanisms during inflammation. The secretion, time to attain peak concentrations, half-life, and degradation are different for different APPs. Some of the markers can be easily tested with minimum equipment whereas, others require sophisticated instruments. They are not pathognomonic for any one particular disease but their elevation may point toward a bacterial, viral, or noninfectious inflammatory process. Testing for APPs and interpreting the result in correlation with results of other tests and clinical details can help in arriving at a diagnosis, in ordering further appropriate tests and in taking treatment decisions. We attempted to look at the present published literature and summarize the different APRs in inflammation. A MEDLINE search for articles published in the English language, with acute-phase proteins [MeSH Terms] OR acute phase reactants [Text Word] was done for the years between 1985 and 2019. In addition, other cross-referenced articles were also searched for relevant data.

Keywords: Acute phase reactants, C-reactive protein, erythrocyte sedimentation rate, procalcitonin


How to cite this article:
Prabhala S, Sivakoti S, Sahoo B. Utility of acute-phase reactants testing in clinical practice. Indian J Community Fam Med 2021;7:12-8

How to cite this URL:
Prabhala S, Sivakoti S, Sahoo B. Utility of acute-phase reactants testing in clinical practice. Indian J Community Fam Med [serial online] 2021 [cited 2021 Nov 29];7:12-8. Available from: https://www.ijcfm.org/text.asp?2021/7/1/12/319963


  Introduction Top


Acute-phase proteins (APPs) comprise about 30 proteins that are biochemically and functionally unrelated to each other but come into play during inflammatory processes. A few of these proteins show marked elevations in the plasma and have been extensively studied. While others may not show marked variations in serum levels, they are affected by numerous confounding factors, their assays are difficult to perform, or due to various other reasons, they have been less extensively studied.

Broadly, the APP are divided as positive APPs and negative APPs. The positive APPs increase in the plasma during any inflammatory process, whereas, the negative APPs decrease in the plasma during inflammation. The response elicited to inflammation is called as “Acute-phase reaction” where the patient typically manifests fever along with leukocytosis with or without shift to left in the neutrophil counts. APPs and acute-phase reactants (APRs) are often used interchangeably.[1] Whenever there is a focus of inflammation, cytokines are liberated into the bloodstream by neutrophils and macrophages. Tumor necrosis factor-alpha (TNF-α), Interleukin (IL) 1, and IL 6 are the most prominent of all cytokines. They stimulate the hepatocytes to synthesize positive APPs and to reduce the production of negative APPs.[2]

Positive APPs are a part of the innate immune system. The immune system, complement system, and coagulation system are interrelated with each other and help in maintaining the internal milieu. Some of these proteins provide positive and negative feedback to the inflammatory process. Examples of positive APPs are C-reactive protein (CRP), Procalcitonin, erythrocyte sedimentation rate (ESR), Mannose-binding protein, Complement factors (C3 and C4), ferritin, ceruloplasmin, serum amyloid A and haptoglobin, fibrinogen, alpha 1 antitrypsin, and alpha 1 acid glycoprotein [Table 1].[3]
Table 1: Commonly tested acute-phase reactants[3]

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Examples of negative APPs are albumin, transferrin, transthyretin, retinol-binding protein, antithrombin, transcortin, etc., It is thought that these proteins decrease to conserve amino acids and to divert them for the production of positive APPs.[4]

C3 is a complement factor and its level in plasma often decreases as it is consumed and hence, it is recognized as a negative APR [Figure 1].[5]
Figure 1: Acute phase reactants in moderate inflammation.[5] Several patterns of response are seen. Major acute phase reactant increase 100-fold (C-reactive protein, seum amyloid A), moderate acute phase reactant increase two to four-fold (fibrinogen, haptoglobin), minor acute phase reactant increase 50%–100% (C3) and negative acute-phase reactant show decrease in levels (Albumin and transferrin)

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  Methodology Top


A MEDLINE search for articles published in the English language, with keywords as APRs and APPs was done for the years between 1985 and 2019. In addition, other cross-referenced articles were also searched for relevant data.


  Clinical Significance of Testing Top


There are various causes for inflammation. Main stimuli that elicit an inflammatory response are infections due to various etiologies, namely, viral, bacterial, fungal, parasitic, helminthic, etc., significant trauma leading to tissue ischemia or necrosis, systemic autoimmune diseases, solid organ malignancies or hematopoietic malignancies, etc., Greater the stimulus, higher is the inflammatory response.[6] The measurement of APPs in plasma gives an estimate about the magnitude of the injury and follow-up measurements reflect the upward or downward trend of the disease. Serial measurements guide in taking treatment decisions and are helpful for prognostication as well.[9]

In present clinical practice, the ESR, CRP, Procalcitonin, are used extensively [Table 1] and [Table 2]. ESR is a nonprotein APR and is influenced by the amount of fibrinogen in plasma and also by plasma viscosity and is viewed as “indirect” APR.[10]
Table 2: Other acute-phase reactants[9]

Click here to view



  Erythrocyte Sedimentation Rate Top


The ESR measures RBC sedimentation rate when the blood sample is held in a vertical column for one hour. It is affected by various factors like fibrinogen, the shape of RBC, blood viscosity, presence of paraproteins, etc. It is elevated in noninflammatory conditions such as pregnancy, anemia, obesity, aging, chronic renal insufficiency, nephrotic syndrome.[11] It is low or normal in polycythemia as blood is viscous, sickle cell anemia, hereditary spherocytosis where the shape of the RBCs does not allow to form proper rouleaux, in conditions with low fibrinogen, and in severe liver disease. Whenever an inflammatory process begins, ESR starts rising within 24–48 h and with the cessation of the inflammation, it gradually comes back to normal values.

In health, the relative contributions of plasma proteins to this phenomenon are fibrinogen 55%, alpha 2-macroglobulin 27%, the immunoglobulins 11%, and albumin 7%.[12]

ESR is more useful, particularly in chronic inflammations. As ESR is mainly dependent on the elevation of fibrinogen, which has a half-life of approximately one week, the elevated level of ESR in a given patient may persist for a longer time even though the inflammatory stimuli have ceased. ESR value more than 100 mm/hour should be investigated for hidden pathologies and markedly elevated ESR provides a reliable “sickness index.”[13]


  C-Reactive Protein Top


This APP has a rapid response time and short half-life of about 19 h. The type of inflammation does not have any bearing on catabolism. It has a wide reference range of 68–8000 microgm/L.[14] In mild inflammations and in some viral infections, the CRP rises to concentrations of 10–40 mg/L.[15] Elevation up to 40–200 mg/L are encountered in acute inflammation and bacterial infections whereas, higher elevation of more than 300 mg/L are likely in severe trauma and serious bacterial infections.[16]

It is thought that a serum CRP concentration of >60 mg/L is strongly indicative of infection while a serum CRP concentration <30 mg/L suggests that the presence of severe infection is unlikely. Generally, in good health, the CRP level is below 2 mg/L but can be up to 10 mg/L. The CRP rises after 12–24 h, and attains peaks in 2–3 days. In case of mild to moderate infections, uncomplicated skin infections, cystitis, or bronchitis, or other infections, it can rise to 50–100 mg/L within 6 h.[17] Values between 2 and 10 mg/L, may be seen with “metabolic inflammatory” states such as chronic smokers, renal disease, cardiac ischemia, arteriosclerosis, diabetes mellitus, and other low level noninfectious inflammatory conditions. High-sensitivity CRP (hsCRP) which is available nowadays can detect extremely low levels of CRP and is used as a marker for cardiac disease.[18] Bacterial infections as the cause for inflammation usually give very high CRP levels, usually more than 500 mg/L, as was observed in one study.[19] Interferon-alpha has an inhibitory effect on CRP production from hepatocytes and hence, in viral infections, a relatively low levels of CRP are encountered.[20] Serial estimation of CRP values can be helpful to determine the progress of the disease or the effectiveness of treatments. In the laboratory, different methods can be used to test for CRP. They are ELISA, immunoturbidimetry, nephelometry, rapid immunodiffusion, and visual agglutination. The sensitivity of these methods varies. The simpler visual agglutination methods can be used by health care workers in primary health care settings.

hsCRP is available nowadays and is used as a marker for cardiac disease.[18] This test can be done using laser nephelometry. It is a rapid test and takes 25 min only. It has a high sensitivity of 0.04 mg/L. Based on hsCRP, according to the American Heart Association, the risk of developing cardiovascular disease is quantified as:

Low risk: hs-CRP level under 1.0 mg/L, Average risk: between 1.0 and 3.0 mg/L and High risk: above 3.0 mg/L.

As compared to ESR, CRP is a better marker of acute-phase response as it is more sensitive and accurate. However, in acute inflammatory processes, in the very early stages, the ESR may be normal while CRP is elevated. Similarly, CRP returns to normal more quickly than ESR in response to therapy due to the shorter half-life of CRP as compared to fibrinogen. Hence, during the resolution phase, the CRP may be normal but the ESR may be elevated. Hence, the clinical correlation of these tests is very important.


  Procalcitonin Top


Many cytokines like IL-1, IL-6, and TNF-α stimulate the secretion of the proximal convoluted tubule (PCT). In viral infections, due to the increased production of interferon-gamma, PCT levels decrease.[21] Procalcitonin has a few advantages over CRP and ESR as a test modality. It can be detected within 3–4 h and attains peak value within 6–24 h, i.e. much earlier than CRP and ESR. The normal serum concentration of PCT is < 0.05 ng/mL. Unlike CRP and ESR, the elevation of PCT is not encountered in other noninfectious inflammatory conditions like autoimmune diseases. However, temporary elevation can be seen in massive trauma such as extensive burns or major surgery. It can also rise in any therapy that stimulates cytokines such as T-cell antibody therapy, granulocyte transfusion, or graft-versus-host disease. It can also increase in medullary carcinoma of the thyroid. PCT is a better marker than CRP for differentiating bacterial from noninfectious causes of inflammation as it is more sensitive and specific.[22] De Jager et al. in their study on patients with legionella pneumonia observed that early high values of PCT indicated a more severe disease, and constantly higher levels portended a worse prognosis for these patients.[23]

Procalcitonin testing is considered to be more specific for bacterial infections and is used for patients in primary care, emergency department, and intensive care units. It helps in the diagnosis of sepsis and guides antibiotic therapy. PCT helps in earlier diagnosis and better monitoring of patients than CRP testing because its rise as well as return to normalcy is quicker than CRP.[24]

Magrini et al. in their study analyzed patients with infection in the emergency department and recommended that its better to use a multi-diagnostic tools approach comprising of total white blood cell count, Procalcitonin and CRP to guide for antibiotic decision to arrive at a correct and quick diagnosis of infection and sepsis.[25]

Sridharan and Chamberlain[26] in their study observed that the diagnostic value of serum PCT concentrations for discriminating among systemic inflammatory response (SIRS), sepsis, severe sepsis, and septic shock remains to be established. Although higher PCT concentrations suggest a systemic bacterial infection as opposed to a viral, fungal, or inflammatory etiology of sepsis, serum PCT concentrations do not correlate with the severity of sepsis or with mortality. PCT concentrations are used to guide the escalation and de-escalation of antimicrobial therapy in sepsis.

CRP and procalcitonin have short half-life of 19 h and 22–35 h and hence fall quickly after the cessation of the inflammatory stimuli.[7],[8]


  Hepcidin Top


Hepcidin is an APR that plays a critical role in inflammation and iron homeostasis. It has an important role in anemia; there is a known relationship between iron metabolism and innate immunity. Synthesis of hepcidin is up-regulated by lipopolysaccharide and IL-6. Serum hepcidin test can be used in conjunction with blood culture and other tests to diagnose late-onset neonatal sepsis.[27]

At present, very few studies have looked at the use of circulating cytokine profiles as a strategy to predict disease severity and outcome in different diseases. Cytokines have been mostly studied to get insight into the immunopathogenesis of disease processes. These tests are not widely available for patient care services per SE.[28]


  Mannose-Binding Lectin Top


Mannose-binding lectin (MBL) is an APP synthesized by hepatocytes and activates the Complement system via the lectin pathway. It facilitates the phagocytosis of miroorganisms. MBL has high affinity for mannose and other sugar residues on the cell wall of bacteria, viruses, and parasites. A study suggested that low MBL concentrations predispose to sepsis associated with Gram-positive infections but not Gram-negative bacteria.[29]


  Cytokines Top


Certain cytokines like IL-6, IL-8, or TNF-α increase in the serum and precede the increase of CRP and stimulate the hepatocytes to produce CRP. It is unclear whether they are more sensitive than measurements of the APP response or whether they can provide any differential diagnostic information.

Even though immunoassay kits for IL-6, IL-l, and TNF are available, they are very expensive and not feasible in low-resource settings.


  Specific Pathologies and Acute Phase Reactants Top


Sepsis and septic shock

Wacker et al.[30] in their meta-analysis involving 30 studies, concluded that procalcitonin is a good biomarker for early diagnosis of sepsis in critically ill patients with median values being 1.1 ng/ml.

A recent study from Korea that evaluated the activities of presepsin, PCT, IL-6, and hs-CRP for their utility in the diagnosis of sepsis has revealed that among the biomarkers tested presepsin activities significantly differed in infectious (1403.47 pg/mL) and noninfectious (239.00 pg/mL) group highlighting the importance of presepsisn in the diagnosis and prognosis of sepsis.[31] Vodnik et al.[32] in their recent study evaluated the performance of presepsin preoperative diagnosis of abdominal sepsis and found that presepsin was significantly higher in severe sepsis (1508.3 ± 866.6 pg/mL) group when compared to healthy individuals (258.7 ± 92.53) and SIRS patients (430.0 ± 141.33 pg/m).

Liu et al.[33] evaluated the diagnostic value of CRP test in detecting neonatal septicemia in their meta-analysis study of 1819 neonates. They observed a positive likelihood ratio (LR), sensitivity, negative LR, and specificity of the CRP test for neonatal septicemia as 5.63 (95% confidence interval [CI] =2.86–11.09), 0.70 (95% CI = 0.66–0.75), 0.36 (95% CI = 0.21–0.60), and 0.89 (95% CI = 0.87–0.91), respectively.

For skin and soft-tissue infections

Studies have shown that CRP values of more than 70 mg/L and an ESR of more than 50 mm/1 h predict a longer hospital stay and thereby indicate the severity of infection.[34],[35] CRP more than 150 mg/L is indicative of the possibility of Necrotizing skin and soft tissue infection.

A better recovery for cases of surgical debridement is indicated when PCT ratio is more than 1.14 between day 1 and day 2 post debridement.[36]

For bone-related diseases

An elevated ESR level of more than 70 mm/hour with no other plausible explanation points towards the likelihood of bone involvement/osteomyelitis in a diabetic foot over that of cellulitis in a diabetic foot.[37] In another recent study, ESR remained high for 3 months only in patients with bone infection and was recommended to be used for the follow-up of patients with osteomyelitis.[38]

ESR (median value 60) and CRP have good sensitivity for pyogenic spondylodiscitis and if the values decrease within the first 4 weeks of treatment, it indicates a favorable prognosis.[39] In cases of prosthetic joint surgeries which are becoming common these days, postsurgery values of CRP and ESR may remain elevated for 6 and 26 weeks, respectively.[40]

Meningitis and neurosurgical infections

Serum Procalcitonin level more than 0.15 ng/ml has high likelihood of bacterial infection after the neurosurgical intervention.[41]

Infective endocarditis

Whenever the level of CRP remains high even after 1 week of treatment for infective endocarditis (>122 mg/L) and the initial value of procalcitonin is >0.5, it indicates a poor outcome.[42]

Pyelonephritis in children

Procalcitonin >0.5 ng/ml indicated a likelihood of pyelonephritis and renal scars in children with urinary tract infections.[43]

A study by Ko YH et al.[44] (n = 49) studied PCT as an early biomarker of septic shock in patients with acute pyelonephritis secondary to ureteral calculi. They concluded that elevated PCT was an early independent predictor of the development of septic shock in acute pyelonephritis associated with ureteral calculi.

As a guide for antibiotic use

Petel et al.[45] did a systematic review and meta-analysis to assess whether CRP testing can be done as a marker to guide antibiotic treatment duration in adults, children, and neonates. They found that in neonates, CRP-based algorithms shortened antibiotic treatment duration by −1.45 days (95% CI −2.61 to −0.28) in two randomized controlled trials (RCTs), and by −.15 days (95% CI −2.06 to −0.24) in two cohort studies, with no differences in mortality or infection relapse. In out-patient adults, they found five RCTs where, the risk difference for antibiotic treatment initiation in the CRP group was −7% (95% CI: −10% to −4%), with no difference in hospitalization rate. They concluded that the use of CRP-based algorithms reduces antibiotic treatment duration in neonates, and also decreases antibiotic treatment initiation in adult outpatients.

Wirz et al.[46] did a meta-analysis of randomized trials on the effect of procalcitonin-guided antibiotic treatment on clinical outcomes in intensive care unit patients with infection and sepsis. They observed that mortality in the 2252 procalcitonin-guided patients was significantly lower compared with the 2230 control group patients (21.1% vs. 23.7%; adjusted odds ratio 0.89, 95% CI 0.8–0.99; P = 0.03). Procalcitonin testing guided earlier discontinuation of antibiotics and reduced treatment duration (9.3 vs. 10.4 days; adjusted coefficient −1.19 days, 95% CI −1.73 to −0.66; P < 0.001).

Presepsin is a newer biomarker and is present in human blood and urine. Its normal serum concentration is 2–6 μg/ml in serum. It has similar diagnostic accuracy for sepsis when compared to procalcitonin and is still under investigation.[47]


  Summary Top


Measurement of APPs/reactants is an important step for patients in various settings within the hospital and in apparently healthy people having hidden underlying pathologies. Testing for any one single parameter is not that useful but instead, a multi-diagnostic approach would be more beneficial. The choice of tests depends on the clinical situation and suspected etiology. The time of sampling and the spacing interval of serial samplings are important. Usually, CRP and Procalcitonin are useful in suspected cases of acute bacterial infections whereas, ESR is useful to screen for the presence of any chronic diseases. Cytokine assays may become the norm in the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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Abstract
Introduction
Methodology
Clinical Signifi...
Erythrocyte Sedi...
C-Reactive Protein
Procalcitonin
Hepcidin
Mannose-Binding ...
Cytokines
Specific Patholo...
Summary
References
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