Procalcitonin (PCT)

Number: 0771

Policy

Aetna considers the measurement of procalcitonin (PCT) medically necessary for initiating and discontinuing antibiotic therapy in persons in the intensive care unit and for persons with respiratory tract infections in the inpatient hospital setting to reduce antibiotic prescription rates and duration of use. 

Aetna considers the measurement of procalcitonin (PCT) experimental and investigational for the following indications because of insufficient evidence of its effectiveness (not an all-inclusive list): 

• As a biomarker of neonatal bacterial infection
• Diagnosis and monitoring of surgical infections (e.g., intra-abdominal infection after elective colorectal surgery, and peri-prosthetic joint infection)
• Diagnosis and prognosis of bacterial infections in persons with rheumatoid arthritis or severe acute malnutrition
• Diagnosis of acute pyelonephritis
• Diagnosis of appendicitis
• Diagnosis of chronic renal insufficiency
• Diagnosis of early-onset neonatal sepsis
• Diagnosis of hypersensitivity pneumonitis
• Diagnosis of infective endocarditis
• Diagnosis of medullary thyroid carcinoma
• Diagnosis of non-alcoholic fatty liver disease
• Diagnosis of parapneumonic pleural effusions
• Diagnosis of pancreatic necrosis
• Diagnosis of spontaneous bacterial peritonitis
• Diagnosis of ventilator-associated pneumonia
• Differentiation of infection from other inflammatory complications following hematopoietic stem cell transplantation
• Evaluation of fever of uncertain source in infants
• Evaluation of individuals with suspected lower respiratory tract infection or sepsis in the ambulatory care/emergency department setting
• Evaluation of community-acquired pneumonia
• Guidance of antibiotic use in individuals with acute exacerbations of chronic obstructive pulmonary disease or diabetic foot ulcers
• Management of immunocompromised individuals
• Prediction and prevention of stroke
• Prediction of neurological deficits following carotid endarterectomy
• Prediction of pneumonia in persons with acute cough
• Prognostication in persons with acute coronary syndrome.

Background

Sepsis and septic shock are the leading causes of death in intensive care units (ICUs) despite advances in critical care medicine.  Sepsis is the systemic inflammatory response to infection frequently associated with hypo-perfusion followed by tissue injury and organ failure.  The activation of neutrophils and monocytes/macrophages, with the consecutive release of pro-inflammatory mediators and activation of the coagulation cascade, seems to play a key role in the pathogenesis of sepsis.  Removal of the septic source, anti-microbial therapy and supportive treatment are the basis of sepsis therapy.

Procalcitonin (PCT), a propeptide synthesized in the C cells of the thyroid, is a precursor of calcitonin.  Procalcitonin is not found in the serum of healthy individuals; however, in response to bacterial infections, a rapid rise in serum PCT levels occurs.  Procalcitonin has been identified as a promising biomarker that may assist in distinguishing bacterial infection from other causes of fever or sepsis (e.g., viral infections) that do not lead to an increase in serum PCT levels.  The level of PCT in the serum is reportedly a reflection of the severity of bacterial infection, ranging from slightly elevated in infections with minor systemic inflammatory response to very high values in cases of severe sepsis and septic shock.  Once an infection is under control, PCT levels decrease. 

The U.S. Food and Drug Administration (FDA) has cleared for marketing through the 510(k) process the BRAHMS PCT sensitive KRYPTOR  (Brahms USA, Inc., Annapolis, MD), the VIDAS  BRAHMS PCT (bioMerieux, Inc., Hazelwood, MO), and the BRAHMS PCT LIA (BRAHMS Diagnostica, LLC, Tracys Landing, MD) quantitative assays to determine the concentration of PCT in serum and plasma.  These devices utilize different technologies and instruments to obtain results but have a similar indication for use, which is to aid in the assessment of risk progression to severe sepsis and septic shock in critically ill patients on the first day of admission to ICU.  The devices are intended to be used in conjunction with other laboratory findings and clinical assessments to determine whether an infection is bacterial or viral, thus, potentially avoiding unnecessary use of antibiotics.  According to the BRAHMS website, PCT levels greater than 2.0 ng/ml on the first day of ICU admission represent a high risk for progression to severe sepsis and/or septic shock, while levels less than 0.5 ng/ml represent a low risk, and levels less than 0.3 ng/ml are below the detection limit of the test and represent a healthy icondition.  BRAHMS website states that, "PCT levels below 0.5 ng/ml do not exclude an infection, because localized infections (without systemic signs) may also be associated with such low levels.  As various non-infectious conditions are known to induce PCT as well, PCT levels between 0.5 ng/ml and 2.0 ng/ml should be reviewed carefully to take into account the specific clinical background and conditions(s) of the individual patient.  PCT should always be interpreted in the clinical context of the patient.  Therefore, clinicians should use the PCT results in conjunction with other laboratory findings and clinical signs of the patient."  The first hours of sepsis can not be detected with the BRAHMS PCT LIA assay; however, the BRAHMS PCT Kryptor test is more sensitive and can provide information in less than an hour after a blood sample is drawn.  The FDA has determined through the 510(k) process that the BRAHMS PCT KRYPTOR test system is substantially equivalent to other inflammatory response markers; thus, the manufacturer was not required to provide the evidence of effectiveness that is necessary to support a premarket approval application.

An assessment of procalcitonin prepared for the Agency for Healthcare Research and Quality (AHRQ) (Soni et al, 2012) concluded that PCT guidance reduces antibiotic use when used to discontinue antibiotics in adult intensive care unit patients and to initiate or discontinue antibiotics in patients with respiratory tract infections. The authors of the AHRQ assessment identified 18 randomized, controlled trials that addressed 5 patient populations.  The report found high quality evidence that PCT guidance reduced antibiotic use when used to discontinue antibiotics in adult intensive care unit patients and to initiate or discontinue antibiotics in patients with respiratory tract infections, moderate evidence that this can be accomplished without increasing morbidity and and low quality evidence that this can be accomplished without increasing mortality.  The report found, by contrast, moderate evidence that PCT-guided intensification of antibiotics in adult intensive care unit patients increases morbidity.  The report also found moderate evidence from a single good quality study that PCT guidance reduces antibiotic use for suspected early neonatal sepsis, but found insufficient evidence on morbidity and mortality outcomes.  The report found insufficient evidence to draw conclusions on outcomes of PCT guidance for:

1. fever of unknown source in children 1 to 36 months of age; and
2. preemptive antibiotics after surgery. 

The authors noted that immunocompromised hosts and other special populations were generally excluded from PCT guidance studies.  The authors stated, therefore, that findings from this review should not be extrapolated to patients with the following conditions: pregnancy; absolute neutropenia; immunocompromised states; chronic infections, and infections for which prolonged antibiotic therapy is standard of care (e.g., infective endocarditis).  The authors stated that populations for future research should include immunocompromised patients, patients with other conditions (e.g., pregnancy, cystic fibrosis), and pediatric patients.  The report stated that future research should compare PCTguidance with antibiotic stewardship programs and to implementation of guidelines.  The report noted that outcomes of high interest for future research are the consequences of reduction in antibiotic use for antibiotic resistance and for adverse events of antibiotic therapy.

In preterm infants, PCT appears to be reasonably specific, but lacks sensitivity as a marker of sepsis.  Turner et al (2006) evaluated the role of PCT in detecting nosocomial sepsis in preterm infants, after the onset of clinical symptoms in 100 preterm infants.  Procalcitonin and C-reactive protein (CRP) levels were measured within 3 days of sepsis work-up events.  Blood samples were drawn from 36 infants during 85 episodes of sepsis performed between 4 and 66 days of life.  Of these episodes, 51 (60 %) were not a result of documented sepsis and thereby served as the negative comparison group.  Median PCT levels were higher in the septic group compared with the non-septic group at the time of the sepsis work-up (2.7 versus 0.5 ng/ml, p = 0.003), at 1 to 24 hours after the sepsis work-up (4.6 versus 0.6 ng/ml, p = 0.003), and at 25 to 48 hours (6.9 versus 2.0 ng/ml, p = 0.016).  Using high cut-off levels, both PCT (2.3 ng/ml) and CRP (30 mg/l) had high specificity and positive-predictive value (97 %, 91 % and 96 %, 87 %, respectively) but low sensitivity (48 % and 41 %, respectively) for detection of sepsis. 

Studies and systematic reviews are in disagreement over the utility of PCT in distinguishing infection from other causes of systemic inflammatory response syndrome in older individuals (Suprin et al, 2000; Gattas et al, 2003; Uzzan et al, 2006; Tang et al, 2007).

Nobre et al (2008) reported on a study suggesting that monitoring plasma PCT levels could allow discontinuation of antibiotic therapy safely earlier than is currently done using clinical criteria alone.  In this study, 79 patients were enrolled among 282 patients who were assessed.  A total of 40 patients were randomized to a control group, consisting of treatment according to standard practice, and 39 patients were randomized to the PCT group, in which a recommendation was given to continue or stop antibiotic therapy based on a 90 % or greater reduction in PCT level after 3 days (for patients with baseline PCT levels less than 1 µg/L) or 5 days (for patients with baseline levels 1 µg/L or more) of antibiotic therapy.  Only 37 control-group and 31 PCT-group patients reached the 3- or 5-day mark and were evaluable per protocol.  Excluding 6 patients for whom the algorithm was over-ruled (i.e., the treating physician refused to stop the antibiotics, despite the investigators’ encouragement to do so), PCT-group participants had a shorter median duration of antibiotic therapy than did controls (6.0 versus 12.5 days; p = 0.0002).  Clinical cure and 28-day mortality rates were similar between groups, but the median ICU stay was shorter for PCT-group patients (3.0 versus 5.0 days; p = 0.03).  Ampel (2008) noted that this study was plagued by the initial exclusion of many patients, the need to analyze by per protocol rather than by intent-to-treat, and algorithm over-ruling.

In a systematic review to assess the diagnostic accuracy of PCT in sepsis diagnosis in critically ill patients, Tang et al (2007) examined 18 studies.  The authors reported that the diagnostic performance of PCT is poor, with mean values of both sensitivity and specificity being 71 % (95 % confidence interval [CI]: 67 to 76).  The authors concluded that PCT can not reliably differentiate sepsis from other non-infectious causes of systemic inflammatory response syndrome in critically ill adult patients and that these findings do not support the wide-spread use of PCT testing in critical care settings.

Measurement of PCT is a promising biomarker for the assessment of risk progression to severe sepsis and septic shock in critically ill individuals on their first day of ICU admission.  However, there is insufficient evidence of its clinical utility.

Jensen et al (2008) noted that for the first time ever, a mortality-endpoint, large scale randomized, controlled trial with a biomarker-guided strategy compared to the best standard of care, is conducted in an ICU setting.  Results will, with a high statistical power answer the question: Can the survival of critically ill patients be improved by actively using biomarker PCT in the treatment of infections?

Manzano and associates (2009) compared PCT measurements between semi-quantitative and quantitative assays.  Procalcitonin was measured with the PCT-Q and the Kryptor assays in a pediatric emergency department.  Among the 359 pairs of results, 103 had discordant results.  The linear weighted kappa was 0.44 (95 % CI: 0.36 to 0.51).  The concordant/discordant results distribution varied depending on the laboratory technician (p = 0.018).  The authors concluded that agreement between PCT measured semi-quantitatively and quantitatively was moderate.  This is probably due to a subjective interpretation of the assay result.

Rowther and colleagues (2009) compared the results of polymerase chain reaction (PCR) and PCT with blood culture for ICU patients suspected of having septicemia.  A total of 90 patients (60 patients meeting the criteria for sepsis and 30 patients not meeting the criteria for sepsis) were evaluated.  Compared with blood culture as the gold standard, the sensitivity, specificity, and positive- and negative-predictive values for PCR were 100 %, 43.33 %, 46.87 %, and 100 %, respectively, and for PCT were 100 %, 61.66 %, 56.6 %, and 100 %, respectively.  The average times required to produce a final result were as follows: PCR, 10 hrs; blood culture, 33 hrs; PCT, 45 mins.  Both PCR and PCT may be useful as rapid tests for detecting septicemia but compared with blood cultures lacked specificity.

Mommertz and co-workers (2009) stated that outcome of carotid endarterectomy (CEA) is defined by mortality rate and the neurological outcome due to cerebral ischemia.  These investigators assessed the role of the acute phase protein PCT as a predictor for neurological deficits following carotid endarterectomy.  A total of 55 patients with high grade stenosis of the internal carotid artery and inter-disciplinary consensus for endarterectomy were followed.  Neurological examination was performed before and after the procedure to analyze peri-operative neurological deficits.  Blood samples were obtained before and after CEA and PCT was analyzed in 55 consecutive patients (65.5 % symptomatic/34.5 % asymptomatic).  No peri-operative or in-hospital death was observed.  Major complications did not occur, 2 patients suffered from bleeding requiring surgical intervention and 1 patient had a temporary peripheral facial nerve lesion.  Post-operative neurological examination revealed no new deficit, there was no significant change of PCT (level pre- and post-CEA (the mean pre-operative PCT was 0.25 ng/ml [SD 0.78, min = 0.1, max = 4.3]; the mean post-operative PCT was 0.11 ng/ml [SD 0.06, min = 0.1, max = 0.5]).  There was no association found between peri-operative neurological deficit and PCT.  The authors concluded that these findings demonstrates that there is still insufficient evidence to recommend PCT measurement as a predictor for peri-operative neurological deficit during CEA.

In a review on the use of PCT in the diagnosis and monitoring of surgical infections, Zielińska-Borkowska et al (2009) stated that further research is needed to ascertain the accurate diagnostic value and the clinical application of the PCT level as a marker of surgical infections.

Sand et al (2009) examined if PCT levels in the serum of patients with acute appendicitis have any diagnostic value.  This prospective study included 103 patients who received an appendectomy, based on the clinical diagnosis of acute appendicitis.  White blood cell count (WBC), CRP and PCT values were determined pre-operatively.  All appendectomy specimens were sent for routine histopathological evaluation.  Based on this information, the patients were assigned to 1 of 5 groups that reflected the severity of the appendicitis.  Of the 103 patients who were included in the study, 98 had appendicitis.  Fourteen (14.3 %) showed an increase in PCT values.  Of those 14, 4 had a serum PCT greater than 0.5 ng/ml, 9 had a PCT value greater than 2 to 10 ng/ml and 1 had a PCT value greater than 10 ng/ml.  The sensitivity of PCT was calculated to be 0.14.  The mean WBC value was 13.0/nl (+/- 5.2, range of 3.4 to 31), and for CRP it was 8.8 mg/dl (+/- 13, range of 0 to 60.2).  The values of CRP, WBC and PCT increased with the severity of the appendicitis.  The authors concluded that PCT is potentially increased in rare cases of severe inflammation and, in particular, after appendiceal perforation or gangrenous appendicitis.  However, its remarkably low sensitivity prohibits its routine use for the diagnosis of appendicitis.

In a case-control study, Oruc and co-workers (2009) examined the diagnostic and discriminative role of serum PCT and CRP in non-alcoholic fatty liver disease (NAFLD).  A total of 50 NAFLD cases and 50 healthy controls were included to the study.  Liver function tests were measured, body mass index was calculated, and insulin resistance was determined by using a homeostasis model assessment (HOMA-IR).  Ultrasound evaluation was performed for each subject.  Serum CRP was measured with nephalometric method; and serum PCT was measured with Kryptor based system.  Serum PCT levels were similar in steatohepatitis (n = 20) and simple steatosis (n = 27) patients, and were not different than the control group (0.06 +/- 0.01, 0.04 +/- 0.01 versus 0.06 +/- 0.01 ng/ml, respectively).  Serum CRP levels were significantly higher in simple steatosis, and steatohepatitis groups compared to healthy controls (7.5 +/- 1.6 and 5.2 +/- 2.5 versus 2.9 +/- 0.5 mg/dl, respectively p < 0.01).  C-reactive protein could not differentiate steatohepatitis from simple steatosis.  Beside, 3 patients with focal fatty liver disease had normal serum CRP levels.  The authors concluded that serum PCT was within normal ranges in patients with simple steatosis or steatohepatitis and has no diagnostic value.  Serum CRP level was increased in NAFLD compared to controls; CRP can be used as an additional marker for diagnosis of NAFLD but it has no value in discrimination of steatohepatitis from simple steatosis.

Ataoglu and colleagues (2010) stated that PCT is implicated as an inflammatory marker in early atherosclerosis.  In order to investigate the clinical consequences of increased PCT levels in acute coronary syndrome, 77 patients (29 with non-ST-elevation myocardial infarction [MI], 34 with ST-elevation MI, and 14 with unstable angina pectoris) were included and followed-up for 6 months.  The PCT levels were determined at initial presentation and within 48 hrs of admission.  Five patients died during hospitalization and their PCT levels within 48 hrs of admission were significantly higher than survivors (n = 72) (0.588 +/- 0.56 versus 0.399 +/- 1.33 ng/ml, respectively).  The PCT levels within 48 hrs post-admission in the 9 patients who died within 6 months were also significantly higher compared with the survivors (0.451 +/- 0.44 versus 0.406 +/- 1.37 ng/ml, respectively).  The authors concluded that higher PCT levels within 48 hrs post-admission may reflect an inflammatory state that is associated with increased early and 6-month mortality.

Knudsen et al (2010) noted that diagnostic delay contributes to high morbidity and mortality in infective endocarditis.  A readily available diagnostic marker of infective endocarditis is desirable.  Serum PCT (S-PCT) has been proposed as a candidate, but data on its yield are conflicting.  These investigators tested its diagnostic value in a large population of patients seen in a tertiary center.  This prospective study included 759 consecutive patients referred for echocardiographic examination on clinical suspicion of infective endocarditis.  Transthoracic echocardiography was followed by immediate trans-esophageal examination, and a blood sample was obtained for PCT analysis.  Infective endocarditis was diagnosed by an inter-disciplinary team and confirmed according to the Duke criteria.  The team was unaware of the results of PCT analyses.  Infective endocarditis was present in 147 patients (19 %).  Procalcitonin was higher in these patients than in those in whom infective endocarditis was rejected (median of 0.21 ng/ml versus 0.13 ng/ml; p < 0.0005).  Multi-variate analysis identified significant independent determinants of high PCT: blood culture with endocarditis-typical microorganisms (odds ratio [OR], 2.81), temperature greater than or equal to 38^°C (OR, 2.61), symptoms less than or equal to 5 days (OR, 2.39), immunocompromised status (OR, 1.74), and male gender (OR, 1.61).  Tests at various PCT thresholds yielded an acceptable sensitivity of 95 % at 0.04 ng/ml, but specificity was only 14 %.  Only 12 % had PCT below this threshold, which might justify postponement of further examinations for infective endocarditis.  The authors concluded that PCT was significantly higher in patients with infective endocarditis than in patients without infective endocarditis and bacteremia with endocarditis-typical organisms was the strongest independent determinant of high procalcitonin.  The clinical importance of this is questionable, because a suitable PCT threshold for diagnosing or excluding infective endocarditis was not established.

Cincinnati Children's Hospital Medical Center's evidence-based care guideline for fever of uncertain source in infants 60 days of age or less (2010) noted that CRP and PCT have been studied in infants less than 90 days presenting with fever of uncertain source.  Inclusion in a diagnostic evaluation of fever of uncertain source does not improve the confidence in ruling out serious bacterial infections at this time.

The Pediatric Infectious Diseases Society and the Infectious Diseases Society of America's clinical practice guideline on "The management of community acquired pneumonia in infants and children older than 3 months of age"(Bradley et al, 2011) stated that acute-phase reactants (e.g., the erythrocyte sedimentation rate, CRP concentration, or serum PCT concentration) can not be used as the sole determinant to differentiate viral and bacterial causes of community acquired pneumonia.

In a pilot study, Shomali and colleagues (2012) examined the role of PCT in non-neutropenic febrile cancer patients (NNCPs).  Between July 2009 and July 2010, a total of 248 NNCPs with fever were studied.  Procalcitonin was measured in plasma within 24 hours of fever onset and 4 to 7 days thereafter, using a Kryptor system with a lower limit of quantitation of 0.075 ng/ml.  Patients' clinical, microbiological, and radiological data were reviewed to make the diagnosis and were correlated with PCT levels.  This study included 30 patients with blood-stream infection (BSI), 60 with localized bacterial infection, 141 with no documented infection, and 8 with tumor-related fever.  Most patients (98 %) were inpatients or admitted to the hospital during the study.  Patients with BSI had significantly higher PCT levels than did those with documented localized infections (p = 0.048) and no documented infection (p = 0.011).  Procacitonin levels were significantly higher in septic patients than in those without sepsis (p = 0.012).  Patients with stage IV disease or metastasis had significantly higher baseline PCT levels than did those with early stages of cancer (p < 0.05).  Procalcitonin levels dropped significantly in patients with bacterial infections in response to antibiotics (p < 0.0001).  The authors concluded that baseline PCT levels are predictive of BSI and sepsis in NNCPs.  They may be predictors of metastasis and advanced cancer.  Subsequent decrease in PCT levels in response to antibiotics is suggestive of bacterial infection.  They stated that larger trials are needed to confirm the results of this study.

Su and associates (2012) stated that spontaneous bacterial peritonitis (SBP) is a life-threatening disease that poses a great diagnostic challenge to clinicians.  These investigators systemically and quantitatively summarized the current evidence on the diagnostic value of the PCT test in identifying SBP.  They searched Embase, Medline, the Cochrane database and reference lists of relevant articles with no language restrictions through May 2012.  They selected original research that reported the diagnostic performance of PCT alone or compared with other biomarkers to diagnose SBP.  These researchers summarized test performance characteristics using forest plots, summary receiver operating characteristic curves and bivariate random effects models.  They found only 3 qualifying studies examining 181 episodes of suspected infection with 50 (27.6 %) confirmed SBP episodes from 3 countries.  Bivariate pooled sensitivity, specificity, positive likelihood ratios and negative likelihood ratios were 86 % (95 % CI: 73 % to 94 %), 80 % (95 % CI: 72 % to 87 %), 7.73 (95 % CI: 0.91 to 65.64) and 0.14 (95 % CI: 0.01 to 1.89), respectively.  The global measures of accuracy, area under the receiver operating curve (AUC) and diagnostic odds ratio (DOR), showed PCT has excellent discriminative capability and individual study showed serum PCT testing has better accuracy than ascitic PCT, serum CRP or IL-6 testing.  There was evidence of significant heterogeneity but no evidence of publication bias.  The authors conclude that the existing literature suggested moderate-to-high accuracy for PCT as a diagnostic aid for SBP.  However, they stated that larger, appropriately designed prospective studies are needed to conclusively address the value of serum PCT testing in SBP diagnosis.

Zou and colleagues (2012) performed a systematic review and meta-analysis of the diagnostic performance of pleural fluid PCT or CRP in differentiating parapneumonic effusion in patients with pleural effusion.  These investigators searched the Embase, Medline, and Cochrane database in December 2011.  Original studies that reported the diagnostic performance of PCT alone or compared with that of other biomarkers for differentiating the characteristics of pleural effusion were included.  These researchers found 6 qualifying studies including 780 patients with suspected parapneumonic effusion and 306 confirmed cases of parapneumonic effusion.  Six studies examined the diagnostic performance of pleural fluid PCT, 3 also tested for serum PCT, and another 3 tested for serum CRP.  The bivariate pooled sensitivity and specificity were as follows 0.67 (95 % CI: 0.54 to 0.78) and 0.70 (95 % CI: 0.63 to 0.76), respectively, for pleural fluid PCT; 0.65 (95 % CI: 0.55 to 0.74) and 0.68 (95 % CI: 0.62 to 0.74), respectively, for serum PCT; and 0.54 (95 % CI: 0.47 to 0.61) and 0.77 (95 % CI: 0.72 to 0.81), respectively, for serum CRP.  There was evidence of significant heterogeneity (I(2) = 55.0 %) for pleural fluid or serum PCT but not for CRP (I(2) = 0.0 %).  The authors concluded that the existing literature suggested that both pleural fluid and serum PCT tests have low sensitivity and specificity for differentiating parapneumonic effusion from other etiologies of pleural effusion.  Compared with PCT, serum CRP has higher specificity and a higher positive likelihood ratio, and thus, it has a higher rule-in value than PCT.

Lu and co-workers (2013) noted that the diagnostic value of PCT for patients with renal impairment is unclear.  These investigators searched multiple databases for studies published through December 2011 that evaluated the diagnostic performance of PCT among patients with renal impairment and suspected systemic bacterial infection.  They summarized test performance characteristics with the use of forest plots, hierarchical summary receiver operating characteristic (HSROC) curves, and bivariate random effects models.  These researchers identified 201 citations, of which 7 diagnostic studies evaluated 803 patients and 255 bacterial infection episodes.  Hierarchical summary receiver operating characteristic-bivariate pooled sensitivity estimates were 73 % [95 % CI: 54 % to 86 %] for PCT tests and 78 % (95 % CI: 52 % to 92 %) for CRP tests.  Pooled specificity estimates were higher for both PCT and CRP tests [PCT, 88 % (95 % CI: 79 5 to 93 %); CRP, 84 % (95 % CI: 52 5 to 96 %)].  The positive likelihood ratio for PCT [likelihood (LR)+ 6.02, 95 % CI: 3.16 to 11.47] was sufficiently high to be qualified as a rule-in diagnostic tool, while the negative likelihood ratio was not low enough to be used as a rule-out diagnostic tool (LR- 0.31, 95 % CI: 0.17 to 0.57).  There was no consistent evidence that PCT was more accurate than CRP test for the diagnosis of systemic infection among patients with renal impairment.  The authors concluded that both PCT and CRP tests have poor sensitivity but acceptable specificity in diagnosing bacterial infection among patients with renal impairment.  Moreover, they stated that given the poor negative likelihood ratio, its role as a rule-out test is questionable.

Lyu and associates (2013) conducted a systematic review and meta-analysis of the performance of the PCT diagnostic test for identifying infectious complications after hematopoietic stem cell transplantation (HSCT).  These investigators searched Embase, Medline, the Cochrane database, and reference lists of relevant articles, with no language restrictions, through December 2011.  They selected original articles that reported diagnostic performance of PCT alone or compared with other biomarkers for identifying serious infections in HSCT recipients.  They quantitatively evaluated test accuracy parameters with the use of forest plots, hierarchical summary receiver operating characteristic curves, and bivariate random effect models.  These researchers found 6 qualifying studies (studying 1,344 episodes of suspected infection with confirmed infectious episodes) from 3 countries.  These 6 studies examined both PCT and CRP test performance.  Bivariate pooled sensitivity, specificity, positive likelihood ratios, and negative likelihood ratios were 0.66 (95 % CI: 0.60 to 0.72), 0.72 (95 % CI: 0.65 to 0.79), 2.39 (95 % CI: 1.84 to 3.09), and 0.47 (95 % CI: 0.39 to 0.57) for PCT, and 0.80 (95 % CI: 0.54 to 0.93), 0.73 (95 % CI: 0.56 to 0.86), 3.00 (95 % CI: 1.86 to 4.84), and 0.27 (95 % CI: 0.11 to 0.65) for CRP.  In terms of AUC, CRP was superior to PCT in detecting infectious complications, with an AUC of 0.82 for CRP versus an AUC of 0.69 for PCT.  The authors concluded that the pooled accuracy estimates of 6 different studies indicated only a moderate rule-out diagnostic value of both PCT and CRP in discriminating infection from other inflammatory complications following allogeneic HSCT.

Yu and colleagues (2013) systemically summarized the current evidence on the diagnostic value of PCT in identifying infective endocarditis (IE).  These investigators searched Embase, Medline, Cochrane database, and reference lists of relevant articles with no language restrictions through September 2012 and selected studies that reported the diagnostic performance of PCT alone or compare with other biomarkers to diagnose IE.  They summarized test performance characteristics with the use of forest plots, hierarchical summary receiver operating characteristic curves, and bivariate random effects models.  These researchers found 6 qualifying studies that included 1,006 episodes of suspected infection with 216 (21.5 %) confirmed IE episodes from 5 countries.  Bivariate pooled sensitivity, specificity, positive likelihood ratios, and negative likelihood ratios were 64 % (95 % CI: 52 % to 74 %), 73 % (95 % CI: 58 % to 84 %), 2.35 (95 % CI: 1.40 to 3.95), and 0.50 (95 % CI: 0.35 to 0.70), respectively.  Of the 5 studies examining CRP, the pooled sensitivity, specificity, positive likelihood ratios, and negative likelihood ratios were 75 % (95 % CI: 62 % to 85 %), 73 % (95 % CI: 61 % to 82 %), 2.81 (95 % CI: 1.70 to 4.65), and 0.34 (95 % CI: 0.19 to 0.60), respectively.  The global measures of accuracy, area under the receiver operating characteristic curve (AUC) and DOR, showed CRP (AUC 0.80, DOR 8.55) may have higher accuracy than PCT (AUC 0.71, DOR 4.67) in diagnosing IE.  The authors concluded that current evidence does not support the routine use of serum PCT or CRP to rule in or rule out IE in patients suspected to have IE.

van Vugt and colleagues (2013) quantified the diagnostic accuracy of selected inflammatory markers in addition to symptoms and signs for predicting pneumonia and derived a diagnostic tool.  Diagnostic study performed between 2007 and 2010.  Participants had their history taken, underwent physical examination and measurement of CRP and PCT in venous blood on the day they first consulted, and underwent chest radiography within 7 days.  Main outcome measure was pneumonia as determined by radiologists, who were blind to all other information when they judged chest radiographs.  Of 3,106 eligible patients, 286 were excluded because of missing or inadequate chest radiographs, leaving 2,820 patients (mean age of 50, 40 % men) of whom 140 (5 %) had pneumonia.  Re-assessment of a subset of 1,675 chest radiographs showed agreement in 94 % (κ 0.45, 95 % CI: 0.36 to 0.54).  Six published "symptoms and signs models" varied in their discrimination (ROC ranged from 0.55 (95 % CI: 0.50 to 0.61) to 0.71 (0.66 to 0.76)).  The optimal combination of clinical prediction items derived from the patients included absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever, with an ROC area of 0.70 (0.65 to 0.75).  Addition of CRP at the optimal cut-off of greater than 30 mg/L increased the ROC area to 0.77 (0.73 to 0.81) and improved the diagnostic classification (net re-classification improvement 28 %).  In the 1,556 patients classified according to symptoms, signs, and CRP greater than 30 mg/L as "low risk" (less than 2.5 %) for pneumonia, the prevalence of pneumonia was 2 %.  In the 132 patients classified as "high risk" (greater than 20 %), the prevalence of pneumonia was 31 %.  The positive likelihood ratio of low, intermediate, and high risk for pneumonia was 0.4, 1.2, and 8.6, respectively.  Measurement of PCT added no relevant additional diagnostic information.  A simplified diagnostic score based on symptoms, signs, and CRP greater than 30 mg/L resulted in proportions of pneumonia of 0.7 %, 3.8 %, and 18.2 % in the low, intermediate, and high risk group, respectively.  The authors concluded that the clinical rule based on symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough performed best in patients with mild or severe clinical presentation.  Moreover, they stated that addition of CRP concentration at the optimal cut-off of greater than 30 mg/L improved diagnostic information, but measurement of PCT concentration did not add clinically relevant information in this group.

Smith et al (2013) noted that although prior randomized trials have demonstrated that PCT-guided antibiotic therapy effectively reduces antibiotic use in patients with community-acquired pneumonia (CAP), uncertainties remain regarding use of PCT protocols in practice.  These investigators estimated the cost-effectiveness of PCT protocols in CAP.  Main measures were costs and cost per quality adjusted life year gained.  When no differences in clinical outcomes were assumed, consistent with clinical trials and observational data, PCT protocols cost $10 to $54 more per patient than usual care in CAP patients.  Under these assumptions, results were most sensitive to variations in: antibiotic cost, the likelihood that antibiotic therapy was initiated less frequently or over shorter durations, and the likelihood that physicians were non-adherent to PCT protocols.  Probabilistic sensitivity analyses, incorporating PCT protocol-related changes in quality of life, found that protocol use was unlikely to be economically reasonable if physician protocol non-adherence was high, as observational study data suggested.  However, PCT protocols were favored if they decreased hospital length of stay.  The authors concluded that PCT protocol use in hospitalized CAP patients, although promising, lacks physician non-adherence and resource use data in routine care settings, which are needed to evaluate its potential role in patient care.

Page and colleagues (2014) stated that early recognition of bacterial infections is crucial for their proper management, but is particularly difficult in children with severe acute malnutrition (SAM).  These researchers evaluated the accuracy of CRP and PCT for diagnosing bacterial infections and assessing the prognosis of hospitalized children with SAM, and determined the reliability of CRP and PCT rapid tests suitable for remote settings.  From November 2007 to July 2008, these investigators prospectively recruited 311 children aged 6 to 59 months hospitalized with SAM plus a medical complication in Maradi, Niger.  Blood, urine, and stool cultures and chest radiography were performed systematically on admission.  C-reactive protein and PCT were measured by rapid tests and by reference quantitative methods using frozen serum sent to a reference laboratory.  Median CRP and PCT levels were higher in children with bacteremia or pneumonia than in those with no proven bacterial infection (p < 0.002).  However, both markers performed poorly in identifying invasive bacterial infection, with AUC of 0.64 and 0.67 before and after excluding children with malaria, respectively.  At a threshold of 40 mg/L, CRP was the best predictor of death (81 % sensitivity, 58 % specificity).  Rapid test results were consistent with those from reference methods.  The authors concluded that CRP and PCT are not sufficiently accurate for diagnosing invasive bacterial infections in this population of hospitalized children with complicated SAM.  However, a rapid CRP test could be useful in these settings to identify children most at risk for dying.

The AHRQ’s assessment of “Future research needs on procalcitonin-guided antibiotic therapy” (Noorani et al, 2013) identified 3 priority populations that were most in need of rigorous research:

• The critically ill patient (all ages) with suspected lower respiratory tract infection (LRTI) or general infection
• The patient (all ages) with suspected LRTI in the ambulatory care/emergency department setting in the United States
• The immunocompromised patient (all ages)

An UpToDate review on “Evaluation and management of severe sepsis and septic shock in adults” (Schmidt and Mandel, 2014) states that “There is no single test that immediately confirms the diagnosis of severe sepsis or septic shock.  However, several laboratory tests, all of which are still investigational, have been studied as diagnostic markers of active bacterial infection:

• Elevated serum procalcitonin levels are associated with bacterial infection and sepsis.  Despite this, a meta-analysis of 18 studies found that procalcitonin distinguished sepsis from non-septic systemic inflammation poorly (sensitivity of 71 percent and specificity of 71 percent) and another meta-analysis of six trials (four in patients with sepsis and two in patients with other infections) found that using clinical algorithms based upon procalcitonin levels did not affect mortality”.

Acute Pyelonephritis

In a meta-analysis, Zhang and colleagues (2016) evaluated the diagnostic value of serum PCT for acute pyelonephritis (APN) in infants and children with urinary tract infections (UTIs) and compared the performance of 2 commonly used cut-off values. The process of search strategy, publications selection and data analysis was in accordance with the preferred reporting items for systematic reviews and meta-analyses guidelines. A total of 18 high-quality studies with a total of 831 APN patients and 651 individuals with lower UTIs were analyzed. The overall performance of serum PCT greater than or equal to 0.5 ng/ml was as follows: pooled sensitivity of 0.86 (95 % CI: 0.73 to 0.93), pooled specificity of 0.76 (95 % CI: 0.66 to 0.83), DOR of 18.90 (95 % CI: 6.78 to 52.71) and AUROC of 0.86 (95 % CI: 0.83 to 0.89), with significant heterogeneity. However, use of 1.0 ng/ml as a cut-off value produced an improved specificity of 0.91 (95 % CI: 0.86 to 0.94), a DOR of 55.06 (95 % CI: 22.57 to 115.48) and an AUROC of 0.94 (95 % CI: 0.92-0.96), without obvious heterogeneity. The authors concluded that in pediatrics with UTIs, the cut-off value of serum PCT, 1.0 ng/ml, has a preferable diagnostic performance compared with 0.5 ng/ml for APN. Moreover, they stated that additional prospective studies that propose an appropriate cut-off value and validate the performance of PCT for young with APN are needed in the future.

Antibiotic Use for Acute Exacerbations of Chronic Obstructive Pulmonary Disease

The VA/DoD’s clinical practice guideline on “The management of chronic obstructive pulmonary disease” (2014) stated that “There is insufficient evidence to recommend for or against procalcitonin-guided antibiotic use for patients with acute COPD exacerbations”.

Early-Onset Neonatal Sepsis

In a systematic review, Chiesa and colleagues (2015) evaluated the accuracy and completeness of diagnostic studies of PCT for early-onset neonatal sepsis (EONS) using the Standards for Reporting of Diagnostic Accuracy (STARD) initiative. Early-onset neonatal sepsis, diagnosed during the first 3 days of life, remains a common and serious problem. Increased PCT is a potentially useful diagnostic marker of EONS, but reports in the literature are contradictory. There are several possible explanations for the divergent results including the quality of studies reporting the clinical usefulness of PCT in ruling in or ruling out EONS. These investigators systematically reviewed PubMed, Scopus, and the Cochrane Library databases up to October 1, 2014. Studies were eligible for inclusion in the review if they provided measures of PCT accuracy for diagnosing EONS. A data extraction form based on the STARD checklist and adapted for neonates with EONS was used to appraise the quality of the reporting of included studies. These researchers found 18 articles (1998 to 2014) fulfilling the eligibility criteria that were included in the final analysis. Overall, the results of the analysis showed that the quality of studies reporting diagnostic accuracy of PCT for EONS was suboptimal leaving ample room for improvement. Information on key elements of design, analysis, and interpretation of test accuracy were frequently missing. They stated that authors should be aware of the STARD criteria before starting a study in this field. These researchers welcome stricter adherence to this guideline. They stated that well-reported studies with appropriate designs will provide more reliable information to guide decisions on the use and interpretations of PCT test results in the management of neonates with EONS.

Medullary Thyroid Carcinoma

Trimboli et al (2015) performed a systematic review of published studies to provide an estimation of the use of PCT as a diagnostic marker of medullary thyroid carcinoma (MTC), with particular focus on its specificity and negative predictive value (NPV) in excluding MTC. These researchers performed a comprehensive computer literature search to find relevant published articles on the topic. They used a search algorithm based on a combination of the terms “medullary”, “thyroid”, and “ProCT”. The search was updated until February 2015. To expand the search, references of the retrieved articles were also screened. A total of 39 articles were retrieved, of which 9 original papers published from 2003 to 2014 were selected for the review. Some of these studies used PCT in the pre-operative diagnosis of MTC, whereas others measured PCT during the follow-up of patients who had been previously treated for MTC. Other laboratory measurements were performed in some of the included studies. The authors concluded that the results of the majority of the studies indicated that PCT measurement appears to be a very promising and reliable serum marker for the diagnosis of MTC, and it is not inferior to calcitonin (CT). The sample handling is less laborious, and in the few CT-negative cases reviewed, the assay had even greater sensitivity. These investigators stated that it would be worthwhile to establish cut-off levels using larger patient series, because they speculate that this assay could potentially replace CT measurement in the future.

Ventilator-Associated Pneumonia

Zagli et al (2014) proposed a new score based on PCT level and chest echography with the aim of improving diagnosis of ventilator-associated pneumonia (VAP): the Chest Echography and Procalcitonin Pulmonary Infection Score (CEPPIS). This retrospective pilot study recruited patients admitted to the Intensive Care Unit of the Emergency Department, Careggi University Hospital (Florence, Italy), from January 2009 to December 2011. Patients were retrospectively divided into a microbiologically confirmed VAP group or a control group based on diagnosis of VAP and positive tracheal aspirate culture. A total of 221 patients were included, with 113 in the microbiologically confirmed VAP group and 108 in the control group. A CEPPIS greater than 5 retrospectively fixed was significantly better in predicting VAP (OR, 23.78; sensitivity, 80.5 %; specificity, 85.2 %) than a Clinical Pulmonary Infection Score (CPIS) greater than 6 (OR, 3.309; sensitivity, 39.8 %; specificity, 83.3 %). The receiver operating characteristic area under the curve analysis also showed a significantly higher diagnostic value for CEPPIS greater than 5 than CPIS greater than 6 (0.829 versus 0.616, respectively; p < 0.0001). The authors concluded that in this pilot, exploratory analysis, CEPPIS is effective in predicting VAP. Moreover, they stated that prospective validation is needed to confirm the potential value of this score to facilitate VAP diagnosis.

Community-Acquired Pneumonia

Lopardo and colleagues (2015) stated that CAP in adults is a common cause of morbidity and mortality particularly in the elderly and in patients with co-morbidities. Most episodes are of bacterial origin, Streptococcus pneumoniae is the most frequently isolated pathogen.  Epidemiological surveillance provides information about changes in microorganisms and their susceptibility.  In recent years, there has been an increase in cases caused by community-acquired methicillin-resistant Staphylococcus aureus and Legionella sp.  The chest radiograph is essential as a diagnostic tool; CURB-65 score and pulse oximetry allow stratifying patients into those who require out-patient care, general hospital room or admission to ICU.  Diagnostic studies and empirical anti-microbial therapy are also based on this stratification.  The use of biomarkers such as PCT or CRP is not part of the initial evaluation because its use has not been shown to modify the initial approach.  These investigators recommend treatment with amoxicillin for out-patients under 65 years of age and without co-morbidities, for patients 65 years or older or with co-morbidities amoxicillin-clavulanic/sulbactam, for patients hospitalized in general ward ampicillin-sulbactam with or without the addition of clarithromycin, and for patients admitted to ICU ampicillin-sulbactam plus clarithromycin; suggested treatment duration is 5 to 7 days for out-patients and 7 to 10 days for those who are hospitalized.  During the influenza season addition of oseltamivir for hospitalized patients and for those with co-morbidities is suggested.

Self and associates (20160 noted that predicting intensive care need among adults with CAP remains challenging. Using a multi-center prospective cohort study of adults hospitalized with CAP, these researchers evaluated the association of serum PCT concentration at hospital presentation with the need for invasive respiratory and/or vasopressor support (IRVS) within 72 hours.  Logistic regression was used to model this association, with results reported as the estimated risk of IRVS for a given PCT concentration.  They also examined if the addition of PCT changed the performance of established pneumonia severity scores, including the pneumonia severity index and American Thoracic Society minor criteria, for prediction of IRVS.  Of 1,770 enrolled patients, 115 (6.5 %) required IRVS.  Using the logistic regression model, PCT concentration had a strong association with IRVS risk.  Undetectable PCT (less than 0.05 ng/ml) was associated with a 4.0 % (95 % CI: 3.1 % to 5.1 %) risk of IRVS.  For concentrations less than 10 ng/ml, PCT had an approximate linear association with IRVS risk; for each 1 ng/ml increase in PCT, there was a 1 to 2 % absolute increase in the risk of IRVS.  With a PCT concentration of 10 ng/ml, the risk of IRVS was 22.4 % (95 % CI: 16.3 % to 30.1 %) and remained relatively constant for all concentrations greater than 10 ng/ml.  When added to each pneumonia severity score, PCT contributed significant additional risk information for prediction of IRVS.  The authors concluded that serum PCT concentration was strongly associated with the risk of requiring IRVS among adults hospitalized with CAP and is potentially useful for guiding decisions about ICU admission.

Intra-Abdominal Infection After Elective Colorectal Surgery

Facy and co-workers (2016) stated that intra-abdominal infections (IAIs) are frequent and life-threatening complications after colorectal surgery. An early detection could diminish their clinical impact and permit safe early discharge.  In a prospective, observational study, these researchers determined the most accurate marker for the detection of post-operative IAI and the appropriate moment to measure it.  Consecutive patients undergoing elective colorectal surgery with anastomosis were included; CRP and PCT were measured daily until the 4th post-operative day.  Post-operative infections were recorded according to the definitions of the Centers for Diseases Control (CDC).  The areas under the ROC curve were analyzed and compared to assess the diagnostic accuracy of each marker.  A total of 501 patients were analyzed.  The incidence of IAI was 11.8 %, with 24.6 % of patients presenting at least 1 infectious complication.  Overall mortality was 1.2 %.  At the 4rth post-operative day, CRP was more discriminating than PCT for the detection of IAI (areas under the ROC curve: 0.775 versus 0.689, respectively, p = 0.03); PCT levels showed wide dispersion.  For the detection of all infectious complications, CRP was also significantly more accurate than PCT on the 4th post-operative day (areas under the ROC curve: 0.783 versus 0.671, p = 0.0002).  The authors concluded that CRP is more accurate than PCT for the detection of infectious complications and should be systematically measured at the 4th post-operative day.  It is a useful tool to ensure a safe early discharge after elective colorectal surgery.

Cousin and associates (2016) noted that IAIs after elective colorectal surgery impact significantly the short- and long-term outcomes. In the era of fast-track surgery, they often come to light after discharge from hospital.  Early diagnosis is therefore essential; CRP levels have proved to be accurate in this setting.  Procalcitonin has been evaluated in several studies with conflicting results.  This meta-analysis compared the predictive abilities of CRP and PCT in the occurrence of IAIs after elective colorectal surgery.  This meta-analysis included studies analyzing CRP and/or PCT levels at post-operative days 2, 3, 4, and/or 5 as markers of IAI after elective colorectal surgery.  Methodological quality was assessed by the QUADAS2 tool.  The area under the curve summary ROC was calculated for each day and each biomarker, using a random-effects model in cases of heterogeneity.  The meta-analysis included 11 studies (2,692 patients).  An IAI occurred in 8.9 % of the patients.  On post-operative day 3, area under the curve was 0.80 (95 % CI: 0.76 to 0.85) for CRP and 0.78 (95 % CI: 0.68 to 0.87) for PCT.  On post-operative day 5, their predictive accuracies were 0.87 (95 % CI: 0.80 to 0.93) and 0.90 (95 % CI: 0.82 to 0.98), respectively.  The accuracy of CRP and PCT did not differ at any post-operative day.  The authors concluded that levels of inflammatory markers under the cut-off value between post-operative days 3 and 5 ensure safe early discharge after elective colorectal surgery.  They stated that PCT did not appear to have added value as compared to CRP in this setting.

Rheumatoid Arthritis

Tsujimoto et al (2018) evaluated the diagnostic values of presepsin and PCT in patients with rheumatoid arthritis (RA) by identifying those with bacterial infection. During June 2014 to September 2015, a total of 126 patients with RA and 25 healthy controls were enrolled; RA patients were divided into an infection group and a non-infection group.  Infection was diagnosed by clinical symptoms, microbiological or radiographic methods, and good response to antibiotics.  Concentrations of plasma presepsin, serum PCT, CRP, and WBC were measured and compared in each group.  The correlations with the Sequential Organ Failure Assessment (SOFA) Score and these markers were calculated.  Rheumatoid arthritis patients included 26 patients in the infection group, 45 patients in the CRP-positive non-infection group (CRP greater than 0.3 mg/dL), and 55 patients in the CRP-negative non-infection group (CRP less than 0.3 mg/dL).  Levels of presepsin and PCT in the infection group were highest and significantly higher than those in the CRP-positive non-infection group (presepsin 682.8 ± 158.1 pg/ml versus 192.0 ± 12.0 pg/ml [p < 0.0001]; PCT 4.052 ± 1.637 ng/ml versus 0.120 ± 0.032 ng/ml [(p < 0.0001]).  According to ROC analysis, presepsin and PCT levels appeared to have a higher diagnostic accuracy for infection than CRP or WBC.  For the infection group, the SOFA Score positively correlated with the concentration of presepsin but not with that of PCT.  The authors concluded that presepsin and PCT may be useful to identify infection in RA patients; presepsin may better reflect infection severity than PCT.

Stroke

Katan and colleagues (2016) stated that chronic infections and neuroendocrine dysfunction may be risk factors for ischemic stroke (IS). These researchers hypothesized that selected blood biomarkers of infection (PCT), hypothalamic-pituitary-axis function (copeptin), and hemodynamic dysfunction (mid-regional pro-atrial natriuretic peptide [MRproANP]) are associated with incident IS risk in the multi-ethnic, urban Northern Manhattan Study (NOMAS) cohort.  A nested case-control study was performed among initially stroke-free participants.  Cases were defined as first IS (n = 172).  These investigators randomly selected controls among those who did not develop an event (n = 344).  They calculated Cox proportional hazards models with inverse probability weighting to estimate the association of blood biomarkers with risk of stroke after adjusting for demographic, behavioral, and medical risk factors.  Those with PCT and MRproANP, but not copeptin, in the top quartile, compared with the lowest quartile, were associated with IS (for PCT adjusted hazard ratio [HR], 1.9; 95 % CI: 1.0 to 3.8 and for MRproANP adjusted HR, 3.5; 95 % CI: 1.6 to 7.5).  The associations of PCT and MRproANP differed by stroke etiology; PCT levels in the top quartile were particularly associated with small vessel stroke (adjusted HR, 5.1; 95 % CI: 1.4 to 18.7) and MRproANP levels with cardio-embolic stroke (adjusted HR, 16.3; 95 % CI: 3.7 to 70.9).  The authors concluded that higher levels of PCT, a marker of infection, and MRproANP, a marker for hemodynamic stress, were independently associated with IS risk; PCT was specifically associated with small vessel and MRproANP with cardio-embolic stroke risk.  They stated that further investigation is needed to validate these biomarkers and determine their significance in stroke risk prediction and prevention.

Guidance of Antibiotic Use in Individuals with Diabetic Foot Ulcer

Jonaidi Jafari and associates (2014) noted that the differentiation of infected diabetic foot ulcers (IDFU) from non-infected diabetic foot ulcers (NIDFU) is challenging for clinicians; and PCT was recently introduced as an inflammatory marker.  These researchers evaluated the accuracy of PCT in comparison to other inflammatory markers for distinguishing IDFU from NIDFU.  They evaluated serum PCT level as a marker of bacterial infection in patients with DFU.  A total of patients with DFU were consecutively enrolled in the study.  A total of 30 patients were clinically identified as IDFU by an expert clinician, taking as criteria for purulent discharges or at least 2 of manifestations of inflammation including warmth, redness, swelling and pain.  Procalcitonin, white blood cells (WBCs), erythrocyte sedimentation rate (ESR), CRP, were found significantly higher in the IDFU group compared to the NIDFU group.  The best cut-off value, sensitivity and specificity were 40.5 mm/hour, 90 % and 94 % for ESR, 7.1 mg/dL, 80 % and 74 % for CRP, 0.21, 70 % and 74 % for PCT, and 7.7×10(9)/L, 66 % and 67 % for WBCs, respectively.  The area under the receiver operating characteristic curve for ESR was the greatest (0.967; p < 0.001), followed by CRP (0.871; p < 0.001), PCT (0.729; p < 0.001), and finally WBCs (0.721; p = 0.001).  The authors concluded that these findings suggested that PCT can be a diagnostic marker in combination with other markers like ESR and CRP to distinguish IDFU from NIDFU, when clinical manifestations are un specific.  Moreover, they stated that additional research is needed before the routine use of PCT to better define the role of PCT in IDFU.

Saeed and co-workers (2014) stated that data regarding the role of PCT in localized infections without systemic inflammatory response syndrome are scarce.  These investigators examined the clinical value of PCT measurements in localized infections such as skin and skin structure infections, diabetic foot infections, septic arthritis (SA) and osteomyelitis.  It appeared that serum PCT is unlikely to change the clinical practice in skin and skin structure infection.  However, serum PCT could have a role in diagnosis and monitoring of diabetic foot infections in hospitalized settings.  There are conflicting reports regarding the ability of serum PCT to distinguish SA from non-SA; synovial PCT may be more appropriate in these settings, including in implant-related infections.  The authors concluded that better designed studies are needed to evaluate the usefulness of PCT with or without other biomarkers in localized infections.

Ingram and colleagues (2018) noted that deciding if a DFU is infected in a community setting is challenging without validated point-of-care tests.  In a prospective study, these investigators examined the use of 4 inflammatory biomarkers in developing a composite algorithm for mildly IDFU:

1. venous WBCs count,
2. CRP,
3. PCT, and
4. wound exudate calprotectin assay (calprotectin is a marker of neutrophilic inflammation). 

Individuals with NIDFU or mildly IDFU who had not received oral antibiotics in the preceding 2 weeks were recruited from community podiatry clinics for measurement of inflammatory biomarkers.  Antibiotic prescribing decisions were based on clinicians' baseline assessments and participants were reviewed 1 week later; ulcer infection was defined by clinicians' overall impression from their 2 assessments.  Some 363 potential participants were screened, of whom 67 were recruited, 29 with mildly IDFU and 38 with NIDFU; 1 subject withdrew early in each group.  Ulcer area was 1.32 cm2 [interquartile range (IQR) 0.32 to 3.61 cm2 ] in infected ulcers and 0.22 cm2 (IQR 0.09 to 1.46 cm2 ) in uninfected ulcers.  Baseline CRP for mild infection was 9.00 mg/ml and 6.00 mg/ml for uninfected ulcers; most PCT levels were undetectable.  Median calprotectin level in IDFU was 1,437 ng/ml and 879 ng/ml in NIDFU.  Area under the receiver operating characteristic curve for a composite algorithm incorporating calprotectin, CRP, WBCs count and ulcer area was 0.68 (95 % CI: 0.52 to 0.82), sensitivity 0.64, specificity 0.81.  The authors concluded that a composite algorithm including CRP, calprotectin, WBCs count and ulcer area may help to distinguish NIDFU from mildly IDFU; however, venous PCT is unhelpful for mild DFU infection.

Biomarker for Neonatal Bacterial Infection

Quadir and Britton (2018) stated that neonates are predisposed to bacterial infection which are an important cause of early childhood morbidity and mortality globally.  It has been proposed that PCT has significant utility as a diagnostic marker for bacterial infection in febrile neonates when compared to CRP.  These investigators carried out a literature search to find the best available evidence to answer the clinical question of the utility of PCT when compared to CRP as a predictor of bacterial infection in febrile neonates.  Medline/PubMed was searched using the terms “procalcitonin”, “C-reactive protein”, “bacterial infection” and “neonatal sepsis”.  A total of 3 systematic reviews relevant to the clinical question were identified.  The appraised literature concluded that PCT had moderate accuracy in diagnosing neonatal sepsis, but suggested it should be considered only within the context of other clinical parameters and other relevant investigations.  The studies included in the systematic review were of variable quality, showed considerable heterogeneity in their methods and evidence of possible publication bias.  The authors concluded that further research is needed before definitive recommendations can be made about the utility of PCT compared with CRP as a diagnostic marker for neonatal sepsis and bacterial infection in clinical practice.

Diagnosis of Hypersensitivity Pneumonitis

An UpToDate review on “Diagnosis of hypersensitivity pneumonitis (extrinsic allergic alveolitis)” (King, 2018) does not mention procalcitonin as a diagnostic tool.

Diagnosis of Pancreatic Necrosis

In a Cochrane review, Komolafe and associates (2017) compared the diagnostic accuracy of serum CRP, PCT, or lactate dehydrogenase (LDH; index test), either alone or in combination, in the diagnosis of necrotizing pancreatitis in people with acute pancreatitis and without organ failure.  These investigators searched Medline, Embase, Science Citation Index Expanded, National Institute for Health Research (NIHR HTA and DARE), and other databases until March 2017.  They searched the references of the included studies to identify additional studies.  These researchers did not restrict studies based on language or publication status, or whether data were collected prospectively or retrospectively.  They also performed a “related search” and “citing reference” search in Medline and Embase.  These investigators included all studies that evaluated the diagnostic test accuracy of CRP, PCT, and LDH for the diagnosis of pancreatic necrosis in people with acute pancreatitis using the following reference standards, either alone or in combination: radiological features of pancreatic necrosis (contrast-enhanced CT or MRI), surgeon's judgement of pancreatic necrosis during surgery, or histological confirmation of pancreatic necrosis.  Had these researchers found case-control studies, they planned to exclude them because they were prone to bias; however, they did not locate any.  Two review authors independently identified the relevant studies from the retrieved references.  Two review authors independently extracted data, including methodological quality assessment, from the included studies.  As the included studies reported CRP, PCT, and LDH on different days of admission and measured at different cut-off levels, it was not possible to perform a meta-analysis using the bivariate model as planned.  These researchers reported the sensitivity, specificity, post-test probability of a positive and negative index test along with 95 % CI on each of the different days of admission and measured at different cut-off levels.  A total of 3 studies including 242 participants met the inclusion criteria for this review.  One study reported the diagnostic performance of CRP for 2 threshold levels (greater than 200 mg/L and greater than 279 mg/L) without stating the day on which the CRP was measured.  One study reported the diagnostic performance of PCT on day 1 (1 day after admission) using a threshold level of 0.5 ng/ml.  One study reported the diagnostic performance of CRP on day 3 (3 days after admission) using a threshold level of 140 mg/L and LDH on day 5 (5 days after admission) using a threshold level of 290 U/L.  The sensitivities and specificities varied: the point estimate of the sensitivities ranged from 0.72 to 0.88, while the point estimate of the specificities ranged from 0.75 to 1.00 for the different index tests on different days of hospital admission.  However, the CIs were wide: CIs of sensitivities ranged from 0.51 to 0.97, while those of specificities ranged from 0.18 to 1.00 for the different tests on different days of hospital admission.  Overall, none of the tests assessed in this review was sufficiently accurate to suggest that they could be useful in clinical practice.  The authors concluded that the paucity of data and methodological deficiencies in the studies meant that it was not possible to arrive at any conclusions regarding the diagnostic test accuracy of the index test because of the uncertainty of the results.  They stated that further well-designed diagnostic test accuracy studies with pre-specified index test thresholds of CRP, PCT, LDH; appropriate follow-up (for at least 2 weeks to ensure that the person did not have pancreatic necrosis, as early scans may not indicate pancreatic necrosis); and clearly defined reference standards (of surgical or radiological confirmation of pancreatic necrosis) were important to reliably determine the diagnostic accuracy of CRP, PCT, and LDH.

Diagnosis of Peri-Prosthetic Joint Infection

Yoon and colleagues (2018) noted that many studies have found associations between laboratory biomarkers and peri-prosthetic joint infection (PJI), but it remains unclear whether these biomarkers are clinically useful in ruling out PJI.  This meta-analysis compared the performance of interleukin-6 (IL-6) versus PCT for the diagnosis of PJI.  In this meta-analysis, these investigators reviewed studies that evaluated IL-6 or/and PCT as a diagnostic biomarker for PJI and provided sufficient data to permit sensitivity and specificity analyses for each test.  The major databases Medline, Embase, the Cochrane Library, Web of Science, and SCOPUS were searched for appropriate studies from the earliest available date of indexing through February 28, 2017.  No restrictions were placed on language of publication.  These researchers identified a total of 18 studies encompassing 1,835 subjects; 16 studies reported on IL-6 and 6 studies reported on PCT. The area under the curve (AUC) was 0.93 (95 % CI: 0.91 to 0.95) for IL-6 and 0.83 (95 % CI: 0.79 to 0.86) for PCT.  The pooled sensitivity was 0.83 (95 % CI: 0.74 to 0.89) for IL-6 and 0.58 (95 % CI: 0.31 to 0.81) for PCT.  The pooled specificity was 0.91 (95 % CI: 0.84 to 0.95) for IL-6 and 0.95 (95 % CI: 0.63 to 1.00) for PCT.  Both the IL-6 and PCT tests had a high positive likelihood ratio (LR); 9.3 (95 % CI: 5.3 to 16.2) and 12.4 (95 % CI: 1.7 to 89.8), respectively, making them excellent rule-in tests for the diagnosis of PJI.  The pooled negative LR for IL-6 was 0.19 (95 % CI: 0.12 to 0.29), making it suitable as a rule-out test, whereas the pooled negative LR for PCT was 0.44 (95 % CI: 0.25 to 0.78), making it unsuitable as a rule-out diagnostic tool.  The authors concluded that based on the results of the present meta-analysis, IL-6 had higher diagnostic value than PCT for the diagnosis of PJI.  Moreover, the specificity of the IL-6 test was higher than its sensitivity.  Conversely, PCT is not recommended for use as a rule-out diagnostic tool.

Management of Immunocompromised Individuals

The AHRQ’s assessment of “Future research needs on procalcitonin-guided antibiotic therapy” (Noorani et al, 2013) identified 3 priority populations that were most in need of rigorous research:

• The critically ill patient (all ages) with suspected lower respiratory tract infection (LRTI) or general infection
• The patient (all ages) with suspected LRTI in the ambulatory care/emergency department setting in the United States
• The immunocompromised patient (all ages)

Markova et al (2013) noted that serum procalcitonin (PCT) has become a routinely utilized parameter with a high prediction value of the severity of bacterial infectious complications and their immediate outcomes.  Whereas the utility of PCT in differentiating between bacterial and viral infection is generally accepted, its significance in fungal infections has yet to be determined.  These researchers determined the role of PCT testing in patients at high risk for invasive fungal infections.  Immunocompromised hematological patients undergoing cyclic chemotherapy treatment or allogeneic hematopoietic stem cell transplantation with infectious complications in which the infectious agents were identified during the disease course were evaluated.  In patients with bacterial infection, positive hemo-cultures were documented, and in patients with fungal infection, the presence of either proven or probable disease was confirmed according to Ascioglu criteria.  C-reactive protein (CRP) and PCT were prospectively assessed from the day following fever onset, for 4 consecutive days.  Overall, 34 patients were evaluated, 21 with bacterial and 13 with fungal infections.  Significant elevations of CRP concentrations (i.e., above the upper normal limit) were observed in all patients, with a tendency toward higher levels in bacterial (both gram-positive [Gr+] and Gr-negative [Gr-]) than in fungal infections.  PCT levels were significantly elevated in patients with bacterial infections (e.g., predominantly in Gr- compared to Gr+), whereas in patients with fungal infections, these investigators identified minimal or no PCT elevations, p < 0.01.  For the fungal infections, according to constructed receiver operating characteristic curves, a combination of PCT less than 0.5 μg/L and CRP 100 to 300 mg/L offered the best specificity, sensitivity and positive and negative predictive values (81, 85, 73, and 89 %, respectively).  The authors concluded that these data suggested that the finding of substantially elevated CRP combined with low PCT in immunocompromised patients may indicate systemic fungal infection.  The use of this combination might simplify the diagnostic process, which otherwise can often be lengthy and arduous.

Savas Bozbas et al (2016) stated that systemic infection is among the common complications after solid-organ transplant and is associated with increased mortality and morbidity.  Because it has prognostic significance, timely diagnosis and treatment are crucial.  Procalcitonin is a pro-peptide of calcitonin and has been increasingly used as a biomarker of bacterial infection.  These researchers investigated PCT's role in identifying infectious complications in solid-organ transplant recipients.  They retrospectively evaluated the records of 86 adult patients who underwent solid-organ transplant (between 2011 and 2015) with PCT levels determined at the authors’ center.  Clinical and demographic variables and laboratory data were noted.  Relation between CRP and PCT serum levels were compared in patients who were diagnosed as having pneumonia on clinical, microbiologic, and radiologic findings.  Mean age of the patients was 45.5 ± 13.4 years (range of 18 to 70), with 61 male patients (70.9 %).  These researchers included 26 liver, 44 kidney, 14 heart, and 2 heart and renal transplant recipients.  Procalcitonin was positive in 43 patients (50 %).  Of the 39 patients who were diagnosed with pneumonia, PCT was positive in 18 patients (46.2 %).  There was a significant correlation between serum levels of PCT and CRP (r = 0.45; p < 0.001) and neutrophil count (r = 0.24; p = 0.025).  There was no correlation between mortality and PCT level, CRP level, or leukocyte count (p > 0.05).  The authors concluded that these findings indicated that PCT is a promising biomarker to detect infectious complications in transplant recipients.  Physical examination and radiologic findings of bacterial pneumonia may be non-specific, and in a considerable number of immunocompromised patients the site of infection could not be identified.  Serum levels of PCT should not be used as sole criteria for clinical decision-making; however, it can be used as a guidance in therapy of such conditions in addition to currently used serum markers of infection.

Caffarini et al (2017) stated that various PCT ranges have been established to guide anti-microbial therapy; however, there are no data that establish whether the initial PCT value can determine the likelihood of a positive culture result.  This study aimed to establish if the initial PCT value, on clinical presentation, has a positive predictive value for any positive culture result.  This was a retrospective study of 813 medical intensive care unit patients.  Data collected included patient demographics, PCT assay results, sources of infection, culture results, and lengths of stay.  Patients were excluded if they were immunocompromised.  The primary outcome of this study was to determine a PCT value that would predict any positive culture.  Secondary outcomes included the sensitivity, specificity, positive predictive value, and negative predictive value for PCT.  After exclusions, a total of 519 patient charts were reviewed to determine the impact of the initial PCT value on culture positivity.  In this analyses, the receiver operating characteristic values were 0.62 for all cultures, 0.49 for pulmonary infections, 0.43 for urinary tract infections, and 0.78 for bacteremia.  A PCT value of 3.61 ng/ml was determined to be the threshold value for a positive blood culture result (prevalence, 4 %).  For bacteremia, the sensitivity of PCT was 75 %, the specificity was 72 %, the positive predictive value was 20 %, and the negative predictive value was 97 %.  The authors concluded that PCT was a poor predictor of culture positivity.  An initial PCT value of less than 3.61 ng/ml may be useful in predicting whether bacteremia is absent.  They stated that PCT should not be used as the only predictor for determining initiation of antibiotic therapy.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
84145	Procalcitonin (PCT)
Other CPT codes related to the CPB:
35301	Thromboendarterectomy, including patch graft, if performed; carotid, vertebral, subclavian, by neck incision
ICD-10 codes covered if selection criteria are met:
J00 - J06.9	Acute upper respiratory infections [not covered for evaluation of individuals with suspected lower respiratory tract infection or sepsis in the ambulatory care/emergency department setting]
J20.0 - J21.9	Acute bronchitis and acute bronchiolitis [not covered for evaluation of individuals with suspected lower respiratory tract infection or sepsis in the ambulatory care/emergency department setting]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
A30.0 - A49.9	Other bacterial diseases
C73	Malignant neoplasm of thyroid gland [medullary thyroid carcinoma]
D80.0 - D89.9	Certain disorders involving the immune mechanism
E08.621, E09.621, E10.621. E11.621, E13.621	Diabetes mellitus with foot ulcer
E41	Nutritional marasmus [severe calorie deficiency] [severe malnutrition NOS] [Diagnosis and prognosis of bacterial infections in persons with severe acute malnutrition]
E43	Unspecified protein-calorie malnutrition [Diagnosis and prognosis of bacterial infections in persons with severe acute malnutrition]
I20.0	Unstable angina
I33.0	Acute and subacute infective endocarditis
I63.00 - I63.9	Cerebral infarction [prediction or prevention of stroke]
J18.0 - J18.9	Pneumonia, unspecified organism [evaluation of community-acquired pneumonia]
J44.1	Chronic obstructive pulmonary disease with (acute) exacerbation
J67.0 - J67.9	Hypersensitivity pneumonitis due to organic dust
J95.851	Ventilator associated pneumonia
J90	Pleural effusion, not elsewhere classified
K35.2 - K37	Appendicitis
K65.2	Spontaneous bacterial peritonitis
K76.0	Fatty (change of) liver, not elsewhere classified
K86.89	Other specified diseases of pancreas [pancreatic necrosis]
L97.401 - L97.429	Non-pressure chronic ulcer of heel and midfoot
L97.501 - L97.529	Non-pressure chronic ulcer of other part of foot
M05.00 - M05.9	Rheumatoid arthritis with rheumatoid factor [diagnosis and prognosis of bacterial infections in persons with rheumatoid arthritis]
M06.00 - M06.9	Other rheumatoid arthritis [diagnosis and prognosis of bacterial infections in persons with rheumatoid arthritis]
M08.00 - M08.99	Juvenile arthritis [diagnosis and prognosis of bacterial infections in persons with rheumatoid arthritis]
N10	Acute pyelonephritis
N18.9	Chronic kidney disease, unspecified [chronic renal insufficiency]
P36.0 - P36.9	Bacterial sepsis of newborn [early-onset]
P81.9	Disturbances of temperature regulation of newborn, unspecified [fever of uncertain source]
R05	Cough [acute] [pneumonia in persons with acute cough]
T81.4xx+	Other postoperative infection
T86.5	Complications of stem cell transplant
Z98.0 - Z98.89	Other postprocedural status

The above policy is based on the following references: