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Acute Phase Reactants in Infections: Evidence-Based Review and a Guide for Clinicians

Acute Phase Reactants in Infections: Evidence-Based Review and a Guide for Clinicians REVIEW ARTICLE Acute Phase Reactants in Infections: Evidence- Based Review and a Guide for Clinicians 1,2,3 Anurag Markanday 1 2 Division of Infectious Diseases, Fraser Health Authority, Department of Medicine, Abbotsford Regional Hospital and Cancer Center, Abbotsford, British Columbia, and Clinical Assistant Professor, University of British Columbia, Canada Acute-phase reactants such as erythrocyte sedimentation rate and C-reactive protein have traditionally been used as markers for inflammation and as a measure of “sickness index” in infectious and noninfectious condi- tions. In the last decade, more data have become available on the wider and more specific role for these markers in the management of complex infections. This includes the potential role in early diagnosis, in differentiating infectious from noninfectious causes, as a prognostic marker, and in antibiotic guidance strategies. A better defined role for biological markers as a supplement to clinical assessment may lead to more judicious antibiotic prescriptions, and it has the potential for a long-term favorable impact on antimicrobial stewardship and an- tibiotic resistance. Procalcitonin as a biological marker has been of particular interest in this regard. This review examines the current published evidence and summarizes the role of various acute-phase markers in infections. A MEDLINE search of English-language articles on acute-phase reactants and infections published between 1986 and March 2015 was conducted. Additional articles were also identified through a search of references from the retrieved articles, published guidelines, systematic reviews, and meta-analyses. Keywords. acute phase reactants; antibiotic guidance; C-reactive protein; endocarditis; ESR; infections; menin- gitis; osteomyelitis; pneumonia; procalcitonin; prosthetic joint infections; sepsis. Infections are a major cause of morbidity and mortality interleukin (IL)-6, IL-1, tumor necrosis factor-alpha, and worldwide. There has been increasing focus on the use interferon gamma. These cytokines, which are produced of acute-phase reactants (APRs) in the management of by macrophages, monocytes, and other cells participating infections because the presence of these markers in the in the inflammatory response, then stimulate production serum signifies inflammation and injury. Acute-phase of APRs by the liver. Most APRs are mainly produced by reactants are a heterogeneous group of plasma proteins the liver, although other cell types such as macrophages, that increase or decrease in response to inflammatory endothelial cells, fibroblasts, and adipocytes have been im- stimuli such as infections, trauma, acute arthritis, systemic plicated in the synthesis [2]. C-reactive protein (CRP) was autoimmune disorders, and neoplasms [1]. The response first discovered in 1930 in the serum of patients with acute is proportional to the severity of the inflammatory stimu- pneumococcal pneumonia. The “C” in CRP stands for the lus and is mediated by proinflammatory cytokines such as C polysaccharide of Streptococcus pneumoniae [3]. Important APRs include erythrocyte sedimentation rate (ESR), CRP, procalcitonin (PCT), serum amyloid A (SAA) protein, fibrinogen, ferritin, alpha-1 antitryp- Received 13 April 2015; accepted 26 June 2015. sin, haptoglobin, alpha-1 acid glycoprotein, ceruloplas- Correspondence: Anurag Markanday, MB, BS, FRCPC, ABIM, Abbotsford Regional Hospital and Cancer Centre, 32900 Marshall Road, Abbotsford, BC V2S 0C2 (anurag. min, and complement proteins C3 and C4. The level of markanday@fraserhealth.ca). response may vary among different APRs. C-reactive Open Forum Infectious Diseases protein and SAA protein can increase a few thousand- © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Societyof America. This is an Open Access article distributed under the terms fold in response. Ceruloplasmin and complement pro- of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http:// teins rise by approximately 25% to 50%, and fibrinogen creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work levels usually increase a few fold. Albumin, transferrin, is not altered or transformed in any way, and that the work is properly cited. For transthyretin, and retinol binding proteins decrease commercial re-use, please contact journals.permissions@oup.com. DOI: 10.1093/ofid/ofv098 in response to inflammation and are called negative Acute Phase Reactants in Infections OFID 1 � � APRs [2]. Erythrocyte sedimentation rate is a nonprotein APR of circulating CRP concentration is the synthesis rate, which in- that changes in response to plasma fibrinogen levels and plasma creases proportionally with the intensity of the inflammatory viscosity and hence is an “indirect” APR [4]. process stimulating CRP production, and vice-versa [8]. In The ESR and CRP are currently the most commonly used healthy individuals, the CRP level is generally below 2 mg/L acute-phase markers in clinical practice. Procalcitonin as a but can be up to 10 mg/L. There may be slight variation with marker in bacterial infections has generated a lot of interest in age, sex, and race [8]. It has a half-life of approximately 19 the last decade, and there is increasing evidence to support its hours, begins to rise after 12–24 hours, and peaks within 2–3 usefulness in specific infections. Other acute-phase markers are days. With mild to moderate stimulus, such as uncomplicated not used regularly in clinical practice for many reasons such skin infection, cystitis, or bronchitis, it can rise to 50–100 mg/L as difficulty in measuring levels, lack of standardization and within 6 hours [8]. Low levels of elevated CRP, with values be- uniformity in reporting, and paucity of clinical data. Serum tween 2 mg/L and 10 mg/L, may be seen with “metabolic in- amyloid A proteins comprise a family of apolipoproteins flammatory” states such as smoking, uremia, cardiac ischemia, synthesized in response to cytokines released by activated and other low level noninfectious inflammatory conditions. The monocytes and macrophages. It is as sensitive a marker for only difference between high-sensitivity CRP (hsCRP) and the inflammation as CRP, and it may have a role in vascular in- standard CRP is that hsCRP assay is designed to measure jury, atherogenesis, and allograft rejection, but it is not used very low levels of CRP [9]. Extremely high CRP elevation of routinely [5]. more than 500 mg/L, in 1 study, was associated with more than 80% likelihood of bacterial infections [10]. Erythrocyte Sedimentation Rate The ESR measures the distance that a vertical column of anti- Procalcitonin coagulated blood has fallen in one hour. Although there have Procalcitonin is the peptide prehormone of calcitonin that, been abundant publications on the clinical use of ESR in the under normal conditions, is secreted by the C-cells of the last several decades, its value and specificity in diagnosis of in- thyroid gland in response to hypercalcemia or as a result of fections remains unclear. Any condition that affects red blood medullary carcinoma of thyroid. In systemic inflammatory con- cells or fibrinogen levels alters the value of the ESR. Noninflam- ditions and, in particular, bacterial infections, PCT secretion is matory conditions such as age, anemia, pregnancy, drugs, and stimulated by various cytokines such as IL-1, IL-6, and tumor obesity can cause elevation in ESR. It may be elevated up to 60 necrosis factor-alpha. In viral infections, the PCT production mm/hour in patients with chronic renal insufficiency and ne- is downgraded, likely from increased interferon gamma produc- phroticsyndrome[6]. Causes for decreased ESR level include tion [11]. Procalcitonin has several advantages over CRP and polycythemia, disorders of erythrocytes such as sickle cell dis- ESR as a biological marker. Serum concentrations of PCT are ease or hereditary spherocytosis, low fibrinogen levels, and se- normally <0.05 ng/mL. Procalcitonin levels become detectable vere liver disease. Normal ESR value is generally calculated in within 3–4 hours and peak within 6–24 hours, which is earlier men as age divided by 2 and in women as age +10 divided by than both CRP and ESR. Elevated PCT levels are not seen in 2. The ESR rises within 24–48 hours of the onset of inflamma- other noninfectious inflammatory conditions such as polymyal- tion and falls back slowly with resolution of inflammation [6]. gia, inflammatory bowel disease, polyarteritis nodosa, systemic Erythrocyte sedimentation rate levels of more than 100 mm/ lupus erythematosus, gout, and temporal arteritis. However, hour should prompt a search for underlying etiology. In a levels of PCT can transiently rise in massive trauma such as se- large retrospective study of 1006 patients, an ESR of 100 mm/ vere burns or major surgery. Any therapy that stimulates cyto- hour or more had low sensitivity of 0.36 among patients with kines such as T-cell antibody therapy, granulocyte transfusion, infection, 0.25 among those with malignant neoplasms, and or graft-versus-host disease can raise PCT levels. It has also been 0.21 among patients with noninfectious inflammatory disor- reported to be high in addisonian crisis, malaria and severe fun- ders. However, specificity was high: 0.96 for malignant neo- gal infections, and medullary carcinoma of thyroid. Many plasms,0.97for infections,and 0.99 as a “sickness” index. assays (BRAHMS) have been developed to measure PCT, in- The positive predictive value (PPV) for an identifiable cause cluding a rapid, semiquantitative point-of-care test that pro- of marked ESR elevation was 90% [7]. vides result in 30 minutes or less [11, 12]. In a systematic review comparing PCT and CRP as markers C-Reactive Protein for bacterial infections, the authors reported that PCT level C-reactive protein has some advantages over ESR because was more sensitive, 0.88 (95% confidence interval [CI], it seems to be a better measure of an acute-phase response 0.80–0.93) vs 0.75 (95% CI, 0.62–0.84), and more specific, and is also more sensitive than ESR to subtle changes in the 0.81 (95% CI, 0.67–0.90) vs 0.67 (95% CI, 0.56–0.77), than acute-phase response [1]. It is primarily produced by the liver CRP for differentiating bacterial from noninfectious causes in response to cytokines, mainly IL-6. The sole determinant of inflammation. The Q value for PCT markers was higher 2 OFID Markanday � � (0.82 vs 0.73) compared with CRP. A Q value is an adjusted P Necrotizing Skin and Soft Tissue Infections value that provides quantitative information about the prob- It is often clinically challenging to differentiate between early ability of clinical significance. The sensitivity for differentiat- necrotizing fasciitis versus more superficial skin and soft tissue ing bacterial from viral infections was also higher for PCT involvement. The Laboratory Risk Indicator for Necrotizing with a higher Q value (0.89 vs 0.83). This review concluded Fasciitis (LRINEC) is a laboratory-based scoring method that, that the diagnostic accuracy of PCT markers was higher in its original validation study, reported a PPV of 92% and a than that of CRP markers among patients hospitalized for negative predictive of 96% for necrotizing skin and soft tissue suspected bacterial infections [12]. Another study reported infection for a LRINEC score of equal to or more than 6 [16]. that initial high levels of PCT were indicative of a more severe A CRP level of more than 150 mg/L was assigned a score of 4 in disease, and persistently increased levels of PCT were indica- this scoring system. Some subsequent reports on attempts at tive of an unfavorable outcome in patients with legionella validating LRINEC score have failed to show reliable sensitivity pneumonia [13] (Table 1). [17]. Another study reported that a PCT ratio of 1.14 or more between the postoperative day 1 and day 2 after surgery for nec- Cellulitis rotizing fasciitis indicated successful surgical treatment with a In skin and soft tissue infections, ESR and CPR levels on admis- sensitivity of 0.83 and a specificity of 0.71. The PPV was sion may predict the severity of the infection and the duration of 75.8%, and the negative predictive value (NPV) was 80.0% [18]. hospitalization. In a retrospective study at a tertiary hospital, pa- tients who required longer hospitalization had significantly Osteoarticular Infections higher levels of ESR and CRP on admission but similar white The likelihood of diabetic foot osteomyelitis increases with ESR blood cell (WBC) counts. The mean CRP and ESR values for value of more than 70 mm/h [19]. In another prospective study, the group with more severe disease requiring longer hospitali- the sensitivity and specificity of CRP for the diagnosis of oste- zation was 100 mg/L and 70 mm/hour compared with a mean omyelitis at a level of more than 14 mg/L was 0.85 and 0.83; the CRP and ESR of 40 mg/L and 50 mm/hour for the group with sensitivity and specificity of ESR at a level more than 67 mm/ less severe disease requiring shorter hospitalization [14]. hour was 0.84 and 0.75; and the sensitivity and specificity of Another retrospective study reported a statistically significant PCT at a level more than 0.30 ng/mL was 0.81 and 0.71. All val- association between longer hospitalization and a high ESR on ues declined after initiation of treatment with antibiotics. The admission. The cutoff for ESR in this study was 50 mm/hour, CRP and PCT values returned to near-normal levels by day 7, and the mean CRP level was 78 mg/L [15]. whereas the values of ESR remained high for up to 3 months only in patients with osteomyelitis. The authors recommended that ESR be used for the follow-up of patients with osteomyelitis Table 1. Acute Phase Reactants [20]. A meta-analysis on the diagnostic value of PCT in osteo- articular infections indicated that PCT may be more suitable as ESR Extremely elevated ESR (>100 mm/hour)-high specificity a marker for rule-in diagnosis rather than for exclusion of septic for infection, malignancy, or arteritis. arthritis or osteomyelitis, and that use of a lower cutoff value at Rises within 24–48 hours of the onset of inflammation and falls back slowly with resolution. 0.2–0.3 ng/mL may improve its diagnostic performance [21]. CRP Begins to rise after 12–24 hours and peaks within 2–3days. In spondylodiscitis, ESR is elevated in over 90% of cases, with Low levels of CRP elevation with values between 2 and 10 mean values ranging from 43 mm/hour to 87 mm/hour [22]. In mg/L measured by a “high sensitivity CRP” assay seen in noninfectious “metabolic inflammatory” states such as the same review, no correlation in the value of ESR was found to cardiac ischemia, uremia, or smoking. the severity of infection or patient’s age. The authors also noted PCT Detectable within 3–4 hours and peaks within 6–24 hours. that a fall in ESR to more than 25% of its presenting value was a Elevated levels not seen in other noninfectious inflammatory conditions such as polymyalgia, good prognostic marker, but an unchanged or rising ESR was inflammatory bowel disease, polyarteritis nodosa, more difficult to interpret. C-reactive protein has a good sensi- systemic lupus erythematosus, gout, and temporal arteritis. tivity and was noted to be elevated in patients with acute spon- More sensitive and specific than CRP for distinguishing dylodiscitis in a number of studies. In these patients, CRP bacterial from noninfectious causes of inflammation returned to normal within 3 months after the successful treat- Others Apolipoproteins: SAA proteins Coagulation Pathway: Fibrinogen, Protein S, Plasminogen ment of infection [22, 23]. Complement System: C3, C4, C9, Factor B, C1 inhibitor In septic arthritis, both CRP and ESR have a high sensitivity Antiproteases: Alpha-1 antitrypsin, Alpha-1 acid glycoprotein at a cutoff value of 20 mg/L and 15 mm/hour, respectively [24]. Proteins: Haptoglobin, Hemopexin, Hepcidin, Ferritin, Measurement of CRP in the synovial fluid does not offer a bet- Ceruloplasmin ter diagnostic advantage [25]. Procalcitonin can be useful in the Cytokines: IL-1, IL-6, tumor necrosis factor-alpha diagnosis of bacterial joint infections in patients with inflamma- Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IL, interleukin; PCT, procalcitonin; SAA, serum amyloid A. tory rheumatic diseases [26]. Acute Phase Reactants in Infections OFID 3 � � Prosthetic Joint Infections canbeusefulinearly identification of bacterial pneumonia, In a meta-analysis involving more than 30 studies and 300 pa- guide antibiotic management, and help stratify patients with a tients, the authors concluded that the diagnostic accuracy for higher risk of developing complications. In a randomized trial prosthetic joint infection was best for serum IL-6 level, followed involving 302 consecutive patients, PCT guidance substantially by serum CRP level and ESR [27]. The pooled sensitivity and reduced antibiotic use in lower respiratory tract infections with- specificity were noted to be 0.97 and 0.91 for IL-6, 0.88 and out compromising outcomes from withholding antibiotics. In 0.74 for CRP, and 0.75 and 0.70 for ESR, respectively. C-reactive the PCT group, antibiotic treatment was based on serum PCT protein may remain elevated for up to 6 weeks and ESR may concentrations as follows: strongly discouraged, <0.1 µg/L; dis- remain elevated up to 26 weeks after prosthetic joint surgery. couraged, <0.25 µg/L; encouraged, >0.25 µg/L; strongly encour- Another study on the diagnosis of early prosthetic joint infec- aged, >0.5 µg/L [36]. A Cochrane database review of more than tion reported a high sensitivity of CRP, with optimal cutoff 14 trials also concluded that the use of PCT to guide initiation value of 93 mg/L, and high specificity of synovial WBC count, and duration of antibiotic treatment in patients with pneumo- with optimal cutoff value of 12 800 cells/mL. The combination nia was not associated with higher mortality rates or treatment of a normal ESR and CRP level is reliable for predicting the failure [37]. Two other studies reported on the usefulness of a absence of prosthetic joint infection [28]. higher PCT level as a measure of severity in patients with bac- teremia or a higher Pneumonia Severity Index score [38, 39]. Sepsis and Septic Shock The serum PCT levels do not correlate well with culture-proven In a meta-analysis involving 30 studies and 3244 critically ill pa- empyema with a sensitivity and specificity of 0.76 and 0.81 at a tients, the authors concluded that PCT is a helpful biomarker cutoff value of 0.19 µg/L [11]. Two systematic reviews on the for early diagnosis of sepsis in critically ill patients. The cutoff usefulness of CRP in the diagnosis and management of lower for PCT concentrations differed between 0.5 ng/mL and 2.0 ng/ respiratory tract infections did not report any significant benefit mL, with a median of 1.1 ng/mL. The pooled sensitivity and in its role as a diagnostic or management modality [40]. Anoth- specificity of serum PCT levels in the early diagnosis of sepsis er study reported extremely high CRP levels (mean levels >166 was noted to be 0.77 (95% CI, 0.72–0.81) and 0.79 (95% CI, mg/L) in patients with pneumococcal and legionella pneumo- 0.74–0.84), respectively [29]. In another systematic review, the nia [41]. There is good quality evidence to suggest that PCT authors concluded that PCT levels in early stages of sepsis are guidance to discontinue antibiotic therapy in pneumonia re- significantly lower among the survivors compared with nonsur- duces antibiotic usage in intensive care units (ICUs) and reduc- vivors of sepsis. A maximum PCT level of 1–5 ng/mL correlated es duration of antibiotic use and prescription rates with a with a 90-day mortality of 11%; a maximum PCT level of reduction in total antibiotic exposure in ambulatory care or in- 51–100 ng/mL correlated with a 90-day mortality of 42% [29, patient setting in patients with pneumonia. There is also at least 30]. In a meta-analysis comparing PCT with CRP as a diagnos- moderate evidence that PCT guidance to discontinue antibiotic tic test for sepsis after surgery or trauma, the authors concluded therapy does not increase morbidity, as indicated by ICU length that PCT was superior to CRP [31]. Another meta-analysis of stay, and that PCT guidance does not increase mortality, hos- examining patients with bacteremia concluded that low PCT pital length of stay, or ICU admission rates in patients diag- levels can be used to rule out the presence of bacteremia [32]. nosed with pneumonia in an inpatient or ambulatory care Procalcitonin level elevations of 0.5 ng/mL occur very early dur- setting [42] (Table 2). ing sepsis with levels increasing from systemic inflammatory re- sponse syndrome (0.6 −2.0 ng/mL) to severe sepsis (2–10 ng/mL) Neurological Infections and septic shock (10 ng/mL). Most importantly, viral infections, Serum and cerebrospinal fluid (CSF) levels of both CRP and recent surgery, and chronic inflammatory states are not associated PCT have been evaluated in the diagnosis of bacterial meningi- with an increment in PCT levels [33]. tis. A meta-analysis involving both adult and pediatric studies A meta-analysis of 16 studies examining serum PCT as a diag- reported that the serum concentrations of CRP had a sensitivity nostic marker in neonatal sepsis reported a pooled sensitivity and that ranged from 0.69 to 0.99 and a specificity that ranged from specificity of 0.81 and 0.91, respectively [34]. The diagnostic ac- 0.28 to 0.99. The authors concluded that CRP may have a good curacy of PCT seemed higher for neonates with late-onset sepsis NPV, but the overall usefulness in diagnosing meningitis re- (>72 hours of life) than for those with early onset sepsis. A per- mained uncertain [43]. Serum and CSF PCT level can be sistently negative CRP or a CRP that decreases to < 10 mg/L in more useful in the diagnosis of bacterial meningitis and in dis- 24 hours has a good NPV in neonatal bacterial sepsis [35]. tinguishing bacterial from viral meningitis. A prospective study of 105 adults and children with suspected meningitis reported Respiratory Infections that a serum PCT level of more than 0.2 ng/mL had a sensitivity There is increasing evidence on the usefulness of PCT as a bio- and specificity of up to 100% in the diagnosis of bacterial men- marker in lower respiratory tract infections. Procalcitonin levels ingitis [44]. Another recent prospective study of 105 patients 4 OFID Markanday � � Table 2. Procalcitonin Guidance in Respiratory Infections and Sepsis Acute respiratory tract infections including community PCT <0.10: Strongly discourage antibiotic acquired pneumonia [36–40, 42] (PCT-ng/mL) PCT <0.25: Discourage antibiotic PCT >0.25: Encourage antibiotic PCT >0.50: Strongly encourage antibiotic Good quality evidence suggests that PCT guidance reduces antibiotic duration of use and prescription rates. Moderate to good quality evidence suggests that PCT guidance did not increase mortality, hospital length of stay, or ICU admission rates. This guidance will need further validation in large multicenter trials. Sepsis and fever in a critically ill patients PCT >0.5 within 2–3 hours of onset of sepsis [29–34, 42] PCT levels (0.6–2.0): Systemic inflammatory response syndrome PCT levels (2–10): Sepsis PCT >10: Septic shock There is moderate quality evidence to suggest that PCT guidance in ICUs decreases overall antibiotic use and has no significant effect on morbidity (based on the length of stay). More research is needed to study the effect on PCT antibiotic guidance on the mortality in ICU patients. Abbreviations: ICU, intensive care unit; PCT, procalcitonin. reported that with a cutoff of ≥0.74 ng/mL, PCT achieved and 0.92 respective for serum PCT level of more than 0.15 ng/ 94.7% sensitivity, 100% specificity, an NPV of 93.9%, and a mL, CRP level of more than 25 mg/mL, and a WBC count of PPV of 100% to predict meningitis in emergency room patients more than 9500 per cubic mm [47]. [45]. In a prospective study of patients after neurosurgery, the authors reported that in contrast to conventional markers of in- Infective Endocarditis flammation, PCT levels did not increase during the postopera- In a prospective study involving 123 consecutive patients, the tive period after major neurosurgery and remained <0.2 ng/mL. authors reported that high CRP level after 1 week of treatment Thus, elevated serum PCT levels of >0.2 ng /mL could serve as a and a slow percentage decline in CRP level during the first week useful tool for the evaluation of fever of unknown origin after of treatment are indicators of poor clinical outcome. The nor- neurosurgery [46]. Another prospective study in neurosurgical malization of CRP is a good predictor of a favorable late out- patients reported a combined sensitivity and specificity of 0.85 come (surgery, death) of infective endocarditis (IE) [48]. Table 3. Acute Phase Reactants in Specific Infections Clinical Infection Acute-phase reactant (ESR-mm/hour, CRP-mg/L, PCT-ng/mL) Cellulitis and Erysipelas CRP >70 and ESR >50 have a higher predictive value for the duration of hospital stay, which is an indirect Necrotizing Skin and Soft Tissue index of severity [14, 15]. Infections CRP >150 may suggest a higher likelihood of NSSTI [16]. (NSSTIs) PCT ratio of more than 1.14 between postoperative day 1 and day 2 after surgical debridement associated with favorable clinical recovery [18]. Osteomyelitis CRP >32 and ESR >70 helpful in distinguishing osteomyelitis from cellulitis in diabetic foot infections [19, Spondylodiscitis 50]. CRP, PCT decrease rapidly with treatment. Fall in previously elevated ESR is a marker for response Prosthetic Joint to treatment [20, 50]. Infection Both ESR (median value 60) and CRP have high sensitivity for diagnosis of pyogenic spondylodiscitis. Decreasing values (25–50%) in the first 4 weeks of treatment suggest favorable prognosis [22, 23]. CRP may remain elevated for up to 6 weeks and ESR for up to 26 weeks after prosthetic joint surgery. Serum IL-6, CRP, and ESR have the best diagnostic value. Likelihood of infection very low if both ESR and CRP are normal. Procalcitonin has a low sensitivity [26, 27]. Meningitis Serum and cerebrospinal PCT levels likely have a high diagnostic accuracy in bacterial meningitis [44, 45]. Neurosurgical CSF lactate at a cutoff of 35 mg/dL has a high negative likelihood ratio for distinguishing bacterial from infections viral meningitis [51]. Serum PCT levels of >0.15 have a high diagnostic value for bacterial infections after neurosurgical procedures [46, 47]. Infective Endocarditis An initial value of PCT > 0.5 is predictor for poor outcome. High levels of CRP (>122) after first week of treatment and slow decline are indicators of poor outcome [48, 49]. Pyelonephritis in PCT level >0.5 is associated with high likelihood of pyelonephritis and renal scars in pediatric patients with children urinary tract infection [52]. Abbreviations: CRP, C-reactive protein; CSF, cerebrospinal fluid; ESR, erythrocyte sedimentation rate; IL, interleukin; PCT, procalcitonin. Acute Phase Reactants in Infections OFID 5 � � 9. Kushner I, Rzewnicki D, Samols D. What does minor elevation of Another study reported PCT to be better marker for IE than C-reactive protein signify? Am J Med 2006; 119:16–6.e17–28. CRP with sensitivity of 0.81, specificity of 0.85, and NPV of 92% 10. Vanderschueren S, Deeren D, Knockaert DC, et al. Extremely elevated and a PPV of 72% at a cutoff value of 2.3 ng/mL. An initial value C-reactive protein. Eur J Intern Med 2006; 17:430–3. of PCT of more than 0.5 ng/mL is a useful predictor of poor 11. Gilbert D. Procalcitonin as a biomarker in respiratory tract infection. Clin Infect Dis 2011; 52(Suppl 4):S346–50. outcome, ie, death or serious infectious complications [49]. 12. Simon L, Gauvin F, Amre DK, et al. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis 2004; 39:206–17. Conclusions 13. de Jager CP, de Wit NC, Weers-Pothoff G, et al. Procalcitonin kinetics There is increasing evidence to support the use of various APRs in Legionella pneumophila pneumonia. Clin Microbiol Infect 2009; in different patient populations and clinical settings. Procalcito- 15:1020–5. nin has an advantage over CRP and ESR due to its better spe- 14. Lazzarini L, Conti E, Tositti G, de Lalla F. Erysipelas and cellulitis: clin- ical and microbiological spectrum in an Italian tertiary care hospital. cificity. However, the future role of APRs will likely continue as J Infect 2005; 51:383–9. an important adjunct to comprehensive clinical assessment. 15. 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Association of procalcito- the diagnosis and assessment of severity of community-acquired pneu- nin with acute pyelonephritis and renal scars in pediatric UTI. Pediat- monia. Chest 2004; 125:1335–42. rics 2013; 131:870–9. Acute Phase Reactants in Infections OFID 7 � � http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Acute Phase Reactants in Infections: Evidence-Based Review and a Guide for Clinicians

Markanday, Anurag
Open Forum Infectious Diseases , Volume 2 (3) – Sep 1, 2015
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© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.
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Abstract

REVIEW ARTICLE Acute Phase Reactants in Infections: Evidence- Based Review and a Guide for Clinicians 1,2,3 Anurag Markanday 1 2 Division of Infectious Diseases, Fraser Health Authority, Department of Medicine, Abbotsford Regional Hospital and Cancer Center, Abbotsford, British Columbia, and Clinical Assistant Professor, University of British Columbia, Canada Acute-phase reactants such as erythrocyte sedimentation rate and C-reactive protein have traditionally been used as markers for inflammation and as a measure of “sickness index” in infectious and noninfectious condi- tions. In the last decade, more data have become available on the wider and more specific role for these markers in the management of complex infections. This includes the potential role in early diagnosis, in differentiating infectious from noninfectious causes, as a prognostic marker, and in antibiotic guidance strategies. A better defined role for biological markers as a supplement to clinical assessment may lead to more judicious antibiotic prescriptions, and it has the potential for a long-term favorable impact on antimicrobial stewardship and an- tibiotic resistance. Procalcitonin as a biological marker has been of particular interest in this regard. This review examines the current published evidence and summarizes the role of various acute-phase markers in infections. A MEDLINE search of English-language articles on acute-phase reactants and infections published between 1986 and March 2015 was conducted. Additional articles were also identified through a search of references from the retrieved articles, published guidelines, systematic reviews, and meta-analyses. Keywords. acute phase reactants; antibiotic guidance; C-reactive protein; endocarditis; ESR; infections; menin- gitis; osteomyelitis; pneumonia; procalcitonin; prosthetic joint infections; sepsis. Infections are a major cause of morbidity and mortality interleukin (IL)-6, IL-1, tumor necrosis factor-alpha, and worldwide. There has been increasing focus on the use interferon gamma. These cytokines, which are produced of acute-phase reactants (APRs) in the management of by macrophages, monocytes, and other cells participating infections because the presence of these markers in the in the inflammatory response, then stimulate production serum signifies inflammation and injury. Acute-phase of APRs by the liver. Most APRs are mainly produced by reactants are a heterogeneous group of plasma proteins the liver, although other cell types such as macrophages, that increase or decrease in response to inflammatory endothelial cells, fibroblasts, and adipocytes have been im- stimuli such as infections, trauma, acute arthritis, systemic plicated in the synthesis [2]. C-reactive protein (CRP) was autoimmune disorders, and neoplasms [1]. The response first discovered in 1930 in the serum of patients with acute is proportional to the severity of the inflammatory stimu- pneumococcal pneumonia. The “C” in CRP stands for the lus and is mediated by proinflammatory cytokines such as C polysaccharide of Streptococcus pneumoniae [3]. Important APRs include erythrocyte sedimentation rate (ESR), CRP, procalcitonin (PCT), serum amyloid A (SAA) protein, fibrinogen, ferritin, alpha-1 antitryp- Received 13 April 2015; accepted 26 June 2015. sin, haptoglobin, alpha-1 acid glycoprotein, ceruloplas- Correspondence: Anurag Markanday, MB, BS, FRCPC, ABIM, Abbotsford Regional Hospital and Cancer Centre, 32900 Marshall Road, Abbotsford, BC V2S 0C2 (anurag. min, and complement proteins C3 and C4. The level of markanday@fraserhealth.ca). response may vary among different APRs. C-reactive Open Forum Infectious Diseases protein and SAA protein can increase a few thousand- © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Societyof America. This is an Open Access article distributed under the terms fold in response. Ceruloplasmin and complement pro- of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http:// teins rise by approximately 25% to 50%, and fibrinogen creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work levels usually increase a few fold. Albumin, transferrin, is not altered or transformed in any way, and that the work is properly cited. For transthyretin, and retinol binding proteins decrease commercial re-use, please contact journals.permissions@oup.com. DOI: 10.1093/ofid/ofv098 in response to inflammation and are called negative Acute Phase Reactants in Infections OFID 1 � � APRs [2]. Erythrocyte sedimentation rate is a nonprotein APR of circulating CRP concentration is the synthesis rate, which in- that changes in response to plasma fibrinogen levels and plasma creases proportionally with the intensity of the inflammatory viscosity and hence is an “indirect” APR [4]. process stimulating CRP production, and vice-versa [8]. In The ESR and CRP are currently the most commonly used healthy individuals, the CRP level is generally below 2 mg/L acute-phase markers in clinical practice. Procalcitonin as a but can be up to 10 mg/L. There may be slight variation with marker in bacterial infections has generated a lot of interest in age, sex, and race [8]. It has a half-life of approximately 19 the last decade, and there is increasing evidence to support its hours, begins to rise after 12–24 hours, and peaks within 2–3 usefulness in specific infections. Other acute-phase markers are days. With mild to moderate stimulus, such as uncomplicated not used regularly in clinical practice for many reasons such skin infection, cystitis, or bronchitis, it can rise to 50–100 mg/L as difficulty in measuring levels, lack of standardization and within 6 hours [8]. Low levels of elevated CRP, with values be- uniformity in reporting, and paucity of clinical data. Serum tween 2 mg/L and 10 mg/L, may be seen with “metabolic in- amyloid A proteins comprise a family of apolipoproteins flammatory” states such as smoking, uremia, cardiac ischemia, synthesized in response to cytokines released by activated and other low level noninfectious inflammatory conditions. The monocytes and macrophages. It is as sensitive a marker for only difference between high-sensitivity CRP (hsCRP) and the inflammation as CRP, and it may have a role in vascular in- standard CRP is that hsCRP assay is designed to measure jury, atherogenesis, and allograft rejection, but it is not used very low levels of CRP [9]. Extremely high CRP elevation of routinely [5]. more than 500 mg/L, in 1 study, was associated with more than 80% likelihood of bacterial infections [10]. Erythrocyte Sedimentation Rate The ESR measures the distance that a vertical column of anti- Procalcitonin coagulated blood has fallen in one hour. Although there have Procalcitonin is the peptide prehormone of calcitonin that, been abundant publications on the clinical use of ESR in the under normal conditions, is secreted by the C-cells of the last several decades, its value and specificity in diagnosis of in- thyroid gland in response to hypercalcemia or as a result of fections remains unclear. Any condition that affects red blood medullary carcinoma of thyroid. In systemic inflammatory con- cells or fibrinogen levels alters the value of the ESR. Noninflam- ditions and, in particular, bacterial infections, PCT secretion is matory conditions such as age, anemia, pregnancy, drugs, and stimulated by various cytokines such as IL-1, IL-6, and tumor obesity can cause elevation in ESR. It may be elevated up to 60 necrosis factor-alpha. In viral infections, the PCT production mm/hour in patients with chronic renal insufficiency and ne- is downgraded, likely from increased interferon gamma produc- phroticsyndrome[6]. Causes for decreased ESR level include tion [11]. Procalcitonin has several advantages over CRP and polycythemia, disorders of erythrocytes such as sickle cell dis- ESR as a biological marker. Serum concentrations of PCT are ease or hereditary spherocytosis, low fibrinogen levels, and se- normally <0.05 ng/mL. Procalcitonin levels become detectable vere liver disease. Normal ESR value is generally calculated in within 3–4 hours and peak within 6–24 hours, which is earlier men as age divided by 2 and in women as age +10 divided by than both CRP and ESR. Elevated PCT levels are not seen in 2. The ESR rises within 24–48 hours of the onset of inflamma- other noninfectious inflammatory conditions such as polymyal- tion and falls back slowly with resolution of inflammation [6]. gia, inflammatory bowel disease, polyarteritis nodosa, systemic Erythrocyte sedimentation rate levels of more than 100 mm/ lupus erythematosus, gout, and temporal arteritis. However, hour should prompt a search for underlying etiology. In a levels of PCT can transiently rise in massive trauma such as se- large retrospective study of 1006 patients, an ESR of 100 mm/ vere burns or major surgery. Any therapy that stimulates cyto- hour or more had low sensitivity of 0.36 among patients with kines such as T-cell antibody therapy, granulocyte transfusion, infection, 0.25 among those with malignant neoplasms, and or graft-versus-host disease can raise PCT levels. It has also been 0.21 among patients with noninfectious inflammatory disor- reported to be high in addisonian crisis, malaria and severe fun- ders. However, specificity was high: 0.96 for malignant neo- gal infections, and medullary carcinoma of thyroid. Many plasms,0.97for infections,and 0.99 as a “sickness” index. assays (BRAHMS) have been developed to measure PCT, in- The positive predictive value (PPV) for an identifiable cause cluding a rapid, semiquantitative point-of-care test that pro- of marked ESR elevation was 90% [7]. vides result in 30 minutes or less [11, 12]. In a systematic review comparing PCT and CRP as markers C-Reactive Protein for bacterial infections, the authors reported that PCT level C-reactive protein has some advantages over ESR because was more sensitive, 0.88 (95% confidence interval [CI], it seems to be a better measure of an acute-phase response 0.80–0.93) vs 0.75 (95% CI, 0.62–0.84), and more specific, and is also more sensitive than ESR to subtle changes in the 0.81 (95% CI, 0.67–0.90) vs 0.67 (95% CI, 0.56–0.77), than acute-phase response [1]. It is primarily produced by the liver CRP for differentiating bacterial from noninfectious causes in response to cytokines, mainly IL-6. The sole determinant of inflammation. The Q value for PCT markers was higher 2 OFID Markanday � � (0.82 vs 0.73) compared with CRP. A Q value is an adjusted P Necrotizing Skin and Soft Tissue Infections value that provides quantitative information about the prob- It is often clinically challenging to differentiate between early ability of clinical significance. The sensitivity for differentiat- necrotizing fasciitis versus more superficial skin and soft tissue ing bacterial from viral infections was also higher for PCT involvement. The Laboratory Risk Indicator for Necrotizing with a higher Q value (0.89 vs 0.83). This review concluded Fasciitis (LRINEC) is a laboratory-based scoring method that, that the diagnostic accuracy of PCT markers was higher in its original validation study, reported a PPV of 92% and a than that of CRP markers among patients hospitalized for negative predictive of 96% for necrotizing skin and soft tissue suspected bacterial infections [12]. Another study reported infection for a LRINEC score of equal to or more than 6 [16]. that initial high levels of PCT were indicative of a more severe A CRP level of more than 150 mg/L was assigned a score of 4 in disease, and persistently increased levels of PCT were indica- this scoring system. Some subsequent reports on attempts at tive of an unfavorable outcome in patients with legionella validating LRINEC score have failed to show reliable sensitivity pneumonia [13] (Table 1). [17]. Another study reported that a PCT ratio of 1.14 or more between the postoperative day 1 and day 2 after surgery for nec- Cellulitis rotizing fasciitis indicated successful surgical treatment with a In skin and soft tissue infections, ESR and CPR levels on admis- sensitivity of 0.83 and a specificity of 0.71. The PPV was sion may predict the severity of the infection and the duration of 75.8%, and the negative predictive value (NPV) was 80.0% [18]. hospitalization. In a retrospective study at a tertiary hospital, pa- tients who required longer hospitalization had significantly Osteoarticular Infections higher levels of ESR and CRP on admission but similar white The likelihood of diabetic foot osteomyelitis increases with ESR blood cell (WBC) counts. The mean CRP and ESR values for value of more than 70 mm/h [19]. In another prospective study, the group with more severe disease requiring longer hospitali- the sensitivity and specificity of CRP for the diagnosis of oste- zation was 100 mg/L and 70 mm/hour compared with a mean omyelitis at a level of more than 14 mg/L was 0.85 and 0.83; the CRP and ESR of 40 mg/L and 50 mm/hour for the group with sensitivity and specificity of ESR at a level more than 67 mm/ less severe disease requiring shorter hospitalization [14]. hour was 0.84 and 0.75; and the sensitivity and specificity of Another retrospective study reported a statistically significant PCT at a level more than 0.30 ng/mL was 0.81 and 0.71. All val- association between longer hospitalization and a high ESR on ues declined after initiation of treatment with antibiotics. The admission. The cutoff for ESR in this study was 50 mm/hour, CRP and PCT values returned to near-normal levels by day 7, and the mean CRP level was 78 mg/L [15]. whereas the values of ESR remained high for up to 3 months only in patients with osteomyelitis. The authors recommended that ESR be used for the follow-up of patients with osteomyelitis Table 1. Acute Phase Reactants [20]. A meta-analysis on the diagnostic value of PCT in osteo- articular infections indicated that PCT may be more suitable as ESR Extremely elevated ESR (>100 mm/hour)-high specificity a marker for rule-in diagnosis rather than for exclusion of septic for infection, malignancy, or arteritis. arthritis or osteomyelitis, and that use of a lower cutoff value at Rises within 24–48 hours of the onset of inflammation and falls back slowly with resolution. 0.2–0.3 ng/mL may improve its diagnostic performance [21]. CRP Begins to rise after 12–24 hours and peaks within 2–3days. In spondylodiscitis, ESR is elevated in over 90% of cases, with Low levels of CRP elevation with values between 2 and 10 mean values ranging from 43 mm/hour to 87 mm/hour [22]. In mg/L measured by a “high sensitivity CRP” assay seen in noninfectious “metabolic inflammatory” states such as the same review, no correlation in the value of ESR was found to cardiac ischemia, uremia, or smoking. the severity of infection or patient’s age. The authors also noted PCT Detectable within 3–4 hours and peaks within 6–24 hours. that a fall in ESR to more than 25% of its presenting value was a Elevated levels not seen in other noninfectious inflammatory conditions such as polymyalgia, good prognostic marker, but an unchanged or rising ESR was inflammatory bowel disease, polyarteritis nodosa, more difficult to interpret. C-reactive protein has a good sensi- systemic lupus erythematosus, gout, and temporal arteritis. tivity and was noted to be elevated in patients with acute spon- More sensitive and specific than CRP for distinguishing dylodiscitis in a number of studies. In these patients, CRP bacterial from noninfectious causes of inflammation returned to normal within 3 months after the successful treat- Others Apolipoproteins: SAA proteins Coagulation Pathway: Fibrinogen, Protein S, Plasminogen ment of infection [22, 23]. Complement System: C3, C4, C9, Factor B, C1 inhibitor In septic arthritis, both CRP and ESR have a high sensitivity Antiproteases: Alpha-1 antitrypsin, Alpha-1 acid glycoprotein at a cutoff value of 20 mg/L and 15 mm/hour, respectively [24]. Proteins: Haptoglobin, Hemopexin, Hepcidin, Ferritin, Measurement of CRP in the synovial fluid does not offer a bet- Ceruloplasmin ter diagnostic advantage [25]. Procalcitonin can be useful in the Cytokines: IL-1, IL-6, tumor necrosis factor-alpha diagnosis of bacterial joint infections in patients with inflamma- Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IL, interleukin; PCT, procalcitonin; SAA, serum amyloid A. tory rheumatic diseases [26]. Acute Phase Reactants in Infections OFID 3 � � Prosthetic Joint Infections canbeusefulinearly identification of bacterial pneumonia, In a meta-analysis involving more than 30 studies and 300 pa- guide antibiotic management, and help stratify patients with a tients, the authors concluded that the diagnostic accuracy for higher risk of developing complications. In a randomized trial prosthetic joint infection was best for serum IL-6 level, followed involving 302 consecutive patients, PCT guidance substantially by serum CRP level and ESR [27]. The pooled sensitivity and reduced antibiotic use in lower respiratory tract infections with- specificity were noted to be 0.97 and 0.91 for IL-6, 0.88 and out compromising outcomes from withholding antibiotics. In 0.74 for CRP, and 0.75 and 0.70 for ESR, respectively. C-reactive the PCT group, antibiotic treatment was based on serum PCT protein may remain elevated for up to 6 weeks and ESR may concentrations as follows: strongly discouraged, <0.1 µg/L; dis- remain elevated up to 26 weeks after prosthetic joint surgery. couraged, <0.25 µg/L; encouraged, >0.25 µg/L; strongly encour- Another study on the diagnosis of early prosthetic joint infec- aged, >0.5 µg/L [36]. A Cochrane database review of more than tion reported a high sensitivity of CRP, with optimal cutoff 14 trials also concluded that the use of PCT to guide initiation value of 93 mg/L, and high specificity of synovial WBC count, and duration of antibiotic treatment in patients with pneumo- with optimal cutoff value of 12 800 cells/mL. The combination nia was not associated with higher mortality rates or treatment of a normal ESR and CRP level is reliable for predicting the failure [37]. Two other studies reported on the usefulness of a absence of prosthetic joint infection [28]. higher PCT level as a measure of severity in patients with bac- teremia or a higher Pneumonia Severity Index score [38, 39]. Sepsis and Septic Shock The serum PCT levels do not correlate well with culture-proven In a meta-analysis involving 30 studies and 3244 critically ill pa- empyema with a sensitivity and specificity of 0.76 and 0.81 at a tients, the authors concluded that PCT is a helpful biomarker cutoff value of 0.19 µg/L [11]. Two systematic reviews on the for early diagnosis of sepsis in critically ill patients. The cutoff usefulness of CRP in the diagnosis and management of lower for PCT concentrations differed between 0.5 ng/mL and 2.0 ng/ respiratory tract infections did not report any significant benefit mL, with a median of 1.1 ng/mL. The pooled sensitivity and in its role as a diagnostic or management modality [40]. Anoth- specificity of serum PCT levels in the early diagnosis of sepsis er study reported extremely high CRP levels (mean levels >166 was noted to be 0.77 (95% CI, 0.72–0.81) and 0.79 (95% CI, mg/L) in patients with pneumococcal and legionella pneumo- 0.74–0.84), respectively [29]. In another systematic review, the nia [41]. There is good quality evidence to suggest that PCT authors concluded that PCT levels in early stages of sepsis are guidance to discontinue antibiotic therapy in pneumonia re- significantly lower among the survivors compared with nonsur- duces antibiotic usage in intensive care units (ICUs) and reduc- vivors of sepsis. A maximum PCT level of 1–5 ng/mL correlated es duration of antibiotic use and prescription rates with a with a 90-day mortality of 11%; a maximum PCT level of reduction in total antibiotic exposure in ambulatory care or in- 51–100 ng/mL correlated with a 90-day mortality of 42% [29, patient setting in patients with pneumonia. There is also at least 30]. In a meta-analysis comparing PCT with CRP as a diagnos- moderate evidence that PCT guidance to discontinue antibiotic tic test for sepsis after surgery or trauma, the authors concluded therapy does not increase morbidity, as indicated by ICU length that PCT was superior to CRP [31]. Another meta-analysis of stay, and that PCT guidance does not increase mortality, hos- examining patients with bacteremia concluded that low PCT pital length of stay, or ICU admission rates in patients diag- levels can be used to rule out the presence of bacteremia [32]. nosed with pneumonia in an inpatient or ambulatory care Procalcitonin level elevations of 0.5 ng/mL occur very early dur- setting [42] (Table 2). ing sepsis with levels increasing from systemic inflammatory re- sponse syndrome (0.6 −2.0 ng/mL) to severe sepsis (2–10 ng/mL) Neurological Infections and septic shock (10 ng/mL). Most importantly, viral infections, Serum and cerebrospinal fluid (CSF) levels of both CRP and recent surgery, and chronic inflammatory states are not associated PCT have been evaluated in the diagnosis of bacterial meningi- with an increment in PCT levels [33]. tis. A meta-analysis involving both adult and pediatric studies A meta-analysis of 16 studies examining serum PCT as a diag- reported that the serum concentrations of CRP had a sensitivity nostic marker in neonatal sepsis reported a pooled sensitivity and that ranged from 0.69 to 0.99 and a specificity that ranged from specificity of 0.81 and 0.91, respectively [34]. The diagnostic ac- 0.28 to 0.99. The authors concluded that CRP may have a good curacy of PCT seemed higher for neonates with late-onset sepsis NPV, but the overall usefulness in diagnosing meningitis re- (>72 hours of life) than for those with early onset sepsis. A per- mained uncertain [43]. Serum and CSF PCT level can be sistently negative CRP or a CRP that decreases to < 10 mg/L in more useful in the diagnosis of bacterial meningitis and in dis- 24 hours has a good NPV in neonatal bacterial sepsis [35]. tinguishing bacterial from viral meningitis. A prospective study of 105 adults and children with suspected meningitis reported Respiratory Infections that a serum PCT level of more than 0.2 ng/mL had a sensitivity There is increasing evidence on the usefulness of PCT as a bio- and specificity of up to 100% in the diagnosis of bacterial men- marker in lower respiratory tract infections. Procalcitonin levels ingitis [44]. Another recent prospective study of 105 patients 4 OFID Markanday � � Table 2. Procalcitonin Guidance in Respiratory Infections and Sepsis Acute respiratory tract infections including community PCT <0.10: Strongly discourage antibiotic acquired pneumonia [36–40, 42] (PCT-ng/mL) PCT <0.25: Discourage antibiotic PCT >0.25: Encourage antibiotic PCT >0.50: Strongly encourage antibiotic Good quality evidence suggests that PCT guidance reduces antibiotic duration of use and prescription rates. Moderate to good quality evidence suggests that PCT guidance did not increase mortality, hospital length of stay, or ICU admission rates. This guidance will need further validation in large multicenter trials. Sepsis and fever in a critically ill patients PCT >0.5 within 2–3 hours of onset of sepsis [29–34, 42] PCT levels (0.6–2.0): Systemic inflammatory response syndrome PCT levels (2–10): Sepsis PCT >10: Septic shock There is moderate quality evidence to suggest that PCT guidance in ICUs decreases overall antibiotic use and has no significant effect on morbidity (based on the length of stay). More research is needed to study the effect on PCT antibiotic guidance on the mortality in ICU patients. Abbreviations: ICU, intensive care unit; PCT, procalcitonin. reported that with a cutoff of ≥0.74 ng/mL, PCT achieved and 0.92 respective for serum PCT level of more than 0.15 ng/ 94.7% sensitivity, 100% specificity, an NPV of 93.9%, and a mL, CRP level of more than 25 mg/mL, and a WBC count of PPV of 100% to predict meningitis in emergency room patients more than 9500 per cubic mm [47]. [45]. In a prospective study of patients after neurosurgery, the authors reported that in contrast to conventional markers of in- Infective Endocarditis flammation, PCT levels did not increase during the postopera- In a prospective study involving 123 consecutive patients, the tive period after major neurosurgery and remained <0.2 ng/mL. authors reported that high CRP level after 1 week of treatment Thus, elevated serum PCT levels of >0.2 ng /mL could serve as a and a slow percentage decline in CRP level during the first week useful tool for the evaluation of fever of unknown origin after of treatment are indicators of poor clinical outcome. The nor- neurosurgery [46]. Another prospective study in neurosurgical malization of CRP is a good predictor of a favorable late out- patients reported a combined sensitivity and specificity of 0.85 come (surgery, death) of infective endocarditis (IE) [48]. Table 3. Acute Phase Reactants in Specific Infections Clinical Infection Acute-phase reactant (ESR-mm/hour, CRP-mg/L, PCT-ng/mL) Cellulitis and Erysipelas CRP >70 and ESR >50 have a higher predictive value for the duration of hospital stay, which is an indirect Necrotizing Skin and Soft Tissue index of severity [14, 15]. Infections CRP >150 may suggest a higher likelihood of NSSTI [16]. (NSSTIs) PCT ratio of more than 1.14 between postoperative day 1 and day 2 after surgical debridement associated with favorable clinical recovery [18]. Osteomyelitis CRP >32 and ESR >70 helpful in distinguishing osteomyelitis from cellulitis in diabetic foot infections [19, Spondylodiscitis 50]. CRP, PCT decrease rapidly with treatment. Fall in previously elevated ESR is a marker for response Prosthetic Joint to treatment [20, 50]. Infection Both ESR (median value 60) and CRP have high sensitivity for diagnosis of pyogenic spondylodiscitis. Decreasing values (25–50%) in the first 4 weeks of treatment suggest favorable prognosis [22, 23]. CRP may remain elevated for up to 6 weeks and ESR for up to 26 weeks after prosthetic joint surgery. Serum IL-6, CRP, and ESR have the best diagnostic value. Likelihood of infection very low if both ESR and CRP are normal. Procalcitonin has a low sensitivity [26, 27]. Meningitis Serum and cerebrospinal PCT levels likely have a high diagnostic accuracy in bacterial meningitis [44, 45]. Neurosurgical CSF lactate at a cutoff of 35 mg/dL has a high negative likelihood ratio for distinguishing bacterial from infections viral meningitis [51]. Serum PCT levels of >0.15 have a high diagnostic value for bacterial infections after neurosurgical procedures [46, 47]. Infective Endocarditis An initial value of PCT > 0.5 is predictor for poor outcome. High levels of CRP (>122) after first week of treatment and slow decline are indicators of poor outcome [48, 49]. Pyelonephritis in PCT level >0.5 is associated with high likelihood of pyelonephritis and renal scars in pediatric patients with children urinary tract infection [52]. Abbreviations: CRP, C-reactive protein; CSF, cerebrospinal fluid; ESR, erythrocyte sedimentation rate; IL, interleukin; PCT, procalcitonin. Acute Phase Reactants in Infections OFID 5 � � 9. Kushner I, Rzewnicki D, Samols D. What does minor elevation of Another study reported PCT to be better marker for IE than C-reactive protein signify? Am J Med 2006; 119:16–6.e17–28. CRP with sensitivity of 0.81, specificity of 0.85, and NPV of 92% 10. Vanderschueren S, Deeren D, Knockaert DC, et al. Extremely elevated and a PPV of 72% at a cutoff value of 2.3 ng/mL. An initial value C-reactive protein. Eur J Intern Med 2006; 17:430–3. of PCT of more than 0.5 ng/mL is a useful predictor of poor 11. Gilbert D. Procalcitonin as a biomarker in respiratory tract infection. Clin Infect Dis 2011; 52(Suppl 4):S346–50. outcome, ie, death or serious infectious complications [49]. 12. Simon L, Gauvin F, Amre DK, et al. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis 2004; 39:206–17. Conclusions 13. de Jager CP, de Wit NC, Weers-Pothoff G, et al. Procalcitonin kinetics There is increasing evidence to support the use of various APRs in Legionella pneumophila pneumonia. Clin Microbiol Infect 2009; in different patient populations and clinical settings. Procalcito- 15:1020–5. nin has an advantage over CRP and ESR due to its better spe- 14. Lazzarini L, Conti E, Tositti G, de Lalla F. Erysipelas and cellulitis: clin- ical and microbiological spectrum in an Italian tertiary care hospital. cificity. However, the future role of APRs will likely continue as J Infect 2005; 51:383–9. an important adjunct to comprehensive clinical assessment. 15. 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Procalcitonin ratio as a pre- There is good quality evidence to suggest that using PCT dictor of successful surgical treatment of severe necrotizing soft tissue guidance strategies decrease antibiotic usage in ICUs and out- infections. Am J Surg 2013; 206:368–73. 19. Markanday A. Diagnosing diabetic foot osteomyelitis: narrative review patient settings, but more research involving heterogeneous pa- and a suggested 2-step score-based diagnostic pathway for clinicians. tient groups in multicenter trials is needed to assess its effect on Open Forum Infect Dis 2014:1:ofu060. patient morbidity, mortality, antimicrobial stewardship, and 20. Michail M, Jude E, Liaskos C, et al. The performance of serum inflam- matory markers for the diagnosis and follow-up of patients with osteo- drug resistance. Clinical reassessment is important in patients myelitis. Int J Low Extrem Wounds 2013; 12:94–9. when the antibiotics have been withheld due to low serum 21. Shen CJ, Wu MS, Lin KH, et al. 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Open Forum Infectious Diseases – Oxford University Press

Published: Sep 1, 2015

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