Procalcitonin (PCT)

Number: 0771

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses procalcitonin (PCT).

Medical Necessity

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.
Experimental and Investigational

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):
1. As a biomarker of neonatal bacterial infection
2. As a biomarker of rhino-sinusitis
3. As a diagnostic marker of bacterial meningitis
4. As a diagnostic marker for sepsis after cardiac surgery
5. As a marker for the severity of COVID-19 and a prognostic marker of its progression
6. As a predictor for development of acute kidney injury
7. Diagnosis and monitoring of surgical infections (e.g., intra-abdominal infection after elective colorectal surgery, and peri-prosthetic joint infection)
8. Diagnosis and prognosis of bacterial infections in persons with rheumatoid arthritis or severe acute malnutrition
9. Diagnosis of acute pyelonephritis
10. Diagnosis of anastomotic leakage after colorectal surgery
11. Diagnosis of appendicitis
12. Diagnosis of bacterial infections in individuals with systemic lupus erythematosus
13. Diagnosis of chronic renal insufficiency
14. Diagnosis of early-onset neonatal sepsis (including culture-positive sepsis)
15. Diagnosis of hypersensitivity pneumonitis
16. Diagnosis of infective endocarditis
17. Diagnosis of medullary thyroid carcinoma
18. Diagnosis of non-alcoholic fatty liver disease
19. Diagnosis of parapneumonic pleural effusions
20. Diagnosis of pancreatic necrosis
21. Diagnosis of post-operative pancreatic fistula after pancreatoduodenectomy
22. Diagnosis of spontaneous bacterial peritonitis
23. Diagnosis of urinary tract infection
24. Diagnosis of ventilator-associated pneumonia
25. Differential diagnosis between bacteremia and candidemia
26. Differential diagnosis between bacterial and viral pneumonia (guide to antibiotic therapy in the community setting)
27. Differential diagnosis between infected diabetic foot ulcer (DFU) and non-infected DFU
28. Differentiation of infection from other inflammatory complications following hematopoietic stem cell transplantation
29. Distinguishing pneumonia from bronchitis or exacerbation of chronic respiratory diseases
30. Evaluation of fever of uncertain source in infants
31. Evaluation of individuals with suspected lower respiratory tract infection or sepsis in the ambulatory care/emergency department setting
32. Evaluation of community-acquired pneumonia
33. Guidance of antibiotic use in individuals with acute exacerbations of chronic obstructive pulmonary disease or diabetic foot ulcers
34. Management of immunocompromised individuals
35. Prediction and prevention of stroke
36. Prediction of the development of moderate-to-severe acute respiratory distress syndrome (ARDS)
37. Prediction of mortality risk in persons with pulmonary tuberculosis
38. Prediction of neurological deficits following carotid endarterectomy
39. Prediction of pneumonia in persons with acute cough
40. Prediction of pneumonia in persons with acute exacerbations of chronic obstructive pulmonary disease (COPD)
41. Prediction of severity of acute cholangitis and need for urgent biliary decompression
42. Prognostication in critically injured (major trauma) persons
43. Prognostication in persons with acute coronary syndrome
44. Prognostication of outcomes in persons following cardiac arrest.

Table:
CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
CPT codes covered if selection criteria are met:
84145	Procalcitonin (PCT)
Other CPT codes related to the CPB:
33016 – 33997	Surgery; Heart and pericardium
35301	Thromboendarterectomy, including patch graft, if performed; carotid, vertebral, subclavian, by neck incision
47533 – 47537	Placement of biliary drainage catheter. Conversion, exchange, and removal of external biliary drainage catheter
47538 – 47540	Placement of stent(s) into a bile duct
48150 – 48154	Pancreatectomy, proximal subtotal with total duodenectomy
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] [not covered as a bio-marker for rhino-sinusitis]
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):
A15.0 - A15.9	Respiratory tuberculosis [prediction of mortality risk]
A30.0 - A49.9	Other bacterial diseases
B37.0 - B37.9	Candidiasis
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]
G00.0 - G00.9	Bacterial meningitis, not elsewhere classified
I20.0	Unstable angina
I33.0	Acute and subacute infective endocarditis
I46.2 - I46.9	Cardiac arrest
I63.00 - I63.9	Cerebral infarction [prediction or prevention of stroke]
J12.0 - J12.9	Viral pneumonia
J15.0 - J15.9	Bacterial pneumonia
J18.0 - J18.9	Pneumonia, unspecified organism [evaluation of community-acquired pneumonia]
J20.0 - J20.9	Acute bronchitis
J32.8 - J32.9	Chronic sinusitis [not covered as a bio-marker for rhino-sinusitis]
J40 - J47.9	Chronic lower respiratory diseases
J67.0 - J67.9	Hypersensitivity pneumonitis due to organic dust
J80	Acute respiratory distress syndrome
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
K83.01 – K83.09	Cholangitis [acute] [prediction of severity]
K86.89	Other specified diseases of pancreas [pancreatic necrosis]
K91.89	Other postprocedural complications and disorders of digestive system [anastomotic leakage after colorectal surgery] [diagnosis of post-operative pancreatic fistula after pancreatoduodenectomy]
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]
M32.0 – M32.9	Systemic lupus erythematosus (SLE) [Diagnosis of bacterial infections]
N10	Acute pyelonephritis
N17.9	Acute kidney failure, unspecified
N18.9	Chronic kidney disease, unspecified [chronic renal insufficiency]
N30.00 – N30.9	Cystitis
N39.0	Urinary tract infection, site not specified
P36.0 - P36.9	Bacterial sepsis of newborn [early-onset]
P81.9	Disturbances of temperature regulation of newborn, unspecified [fever of uncertain source]
R05.1 - R05.9	Cough [acute] [pneumonia in persons with acute cough]
R78.81	Bacteremia
T79.8xxA - T79.8xxS	Early complications of trauma
T79.9xxA - T79.9xxS	Unspecified early complication of trauma
T81.44XA - T81.44XS	Sepsis following a procedure [cardiac surgery]
T81.49xA - T81.49xS	Infection following a procedure, other surgical site
T86.5	Complications of stem cell transplant
U07.1	COVID-19
Z98.0	Intestinal bypass and anastomosis status [colorectal surgery]
Z98.0 - Z98.89	Other postprocedural status

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:

fever of unknown source in children 1 to 36 months of age; and
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.

The Centers for Disease Control and Prevention (CDC, 2020) case definition of multisystem inflammatory syndrome in children with current or recent SARS-CoV-2 infection, requires laboratory evidence of inflammation, Including, but not limited to, one or more of the following: an elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes and low albumin. Riphagen et al (2020) noted that during a period of 10 days in mid-April, 2020, an unprecedented cluster of 8 children with hyper-inflammatory shock, showing features similar to atypical Kawasaki disease, Kawasaki disease shock syndrome, or toxic shock syndrome (typical number is 1 or 2 children per week). This case cluster formed the basis of a national alert. All children were previously fit and well; 6 of the children were of Afro-Caribbean descent, and 5 of the children were boys. All children except 1 were well above the 75th centile for weight; 4 children had known family exposure to coronavirus disease 2019 (COVID-19). All children tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on broncho-alveolar lavage or nasopharyngeal aspirates. Despite being critically unwell, with laboratory evidence of infection or inflammation including elevated concentrations of C-reactive protein, procalcitonin, ferritin, triglycerides, and D-dimers, no pathological organism was identified in 7 of the children. Adenovirus and enterovirus were isolated in 1 child. The authors suggested that this clinical picture represented a new phenomenon affecting previously asymptomatic children with SARS-CoV-2 infection manifesting as a hyper-inflammatory syndrome with multi-organ involvement similar to Kawasaki disease shock syndrome. The multi-faceted nature of the disease course underlined the need for multi-specialty input (intensive care, cardiology, infectious diseases, immunology, and rheumatology).

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 interleukin-6 (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 (receiver operator characteristic [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.

Chaurasia et al (2023) noted that it is unclear if serum PCT estimated at sepsis suspicion could aid in detecting culture-positive sepsis in neonates. In a prospective study, these researchers examined the diagnostic performance of PCT in culture-positive sepsis in neonates. This trial was carried out in 4 level-III units in India. These researchers enrolled neonates suspected of sepsis in the first 28 days of life. Neonates with birthweight of 750 g or less, asphyxia, shock, and major malformations were excluded. Blood for PCT assay was drawn along with the blood culture at the time of suspicion of sepsis and before antibiotic initiation. The investigators labeled the neonates as having culture-positive sepsis or "no sepsis" based on the culture reports and clinical course. PCT assay was carried out by electrochemiluminescence immunoassay, and the clinicians were masked to the PCT levels while assigning the label of sepsis. Primary outcomes were the sensitivity, specificity, and likelihood ratios to identify culture-positive sepsis. The mean birthweight (SD) and median gestation (IQR) were 2,113 (727) g and 36 (32 to 38) weeks, respectively. Of the 1,204 neonates with eligible cultures, 155 (12.9 %) had culture-positive sepsis. Most (79.4 %) were culture-positive within 72 hours of birth. The sensitivity, specificity, and PLR NLR at 2 ng/ml PCT threshold were 52.3 % (95 % CI: 44.1 to 60.3), 64.5 % (60.7 to 68.1), 1.47 (1.23 to 1.76), and 0.74 (0.62 to 0.88), respectively. Adding PCT to assessing neonates with 12.9 % pretest probability of sepsis generated post-test probabilities of 18 % and 10 % for positive and negative test results, respectively. The authors concluded that serum PCT did not reliably identify culture-positive sepsis in neonates.

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:

venous WBCs count,
CRP,
PCT, and
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 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.

Biomarker of Rhino-Sinusitis

Dilger and colleagues (2019) described the existing literature on PCT as a biomarker in patients with acute rhino-sinusitis (ARS), analyzed outcomes in ARS patients who were treated with PCT-guided therapy versus traditional management, and compared PCT to other biomarkers used in diagnosis of bacterial ARS. These investigators carried out a search in the PubMed and Embase databases to identify studies related to PCT as a biomarker in ARS. After critical appraisal of validity by 2 authors, 6 studies with a total of 313 patients were selected for data extraction and analysis. They identified 2 randomized control trials (RCTs) of PCT-based guidelines for antibiotic management of ARS in out-patient settings and 4 observational studies that compared PCT to other biomarkers in patients with ARS. The 2 RCTs demonstrated a reduction (41.6 % in 1 study and 71 % in the other) in antibiotic prescription rate in the PCT-guided group versus the control group with no change in the number of days with impaired activity due to illness (9.0 versus 9.0 days [p = 0.96]; 8.1 versus 8.2 days [95 % CI: -0.7 to 0.7]), number of days of work missed, and percentage of patients with persistent symptoms at 28 days. In the observational cohort studies, PCT did not consistently correlate with CRP, body temperature, and/or WBC. The authors concluded that literature on PCT as a serum biomarker for diagnosis and appropriate antibiotic treatment of ARS is limited, and no studies have addressed the role of PCT in management of chronic rhino-sinusitis (CRS). Existing data on PCT-guided antibiotic treatment of acute lower respiratory tract infections (RTIs), including ARS, have shown non-inferior outcomes despite decreased antibiotic use; PCT does not consistently correlate with CRP; however, CRP is not currently used as a biomarker for ARS, thus this lack of correlation does not negate the role for PCT in management of ARS. These researchers stated that there is a need for further research, such as a large-scale RCT, to examine the potential utility of PCT-guided management of ARS.

The authors stated that given the relatively small number of studies that had examined the role of PCT in diagnosing and treating rhino-sinusitis, this review had several drawbacks; 3 of the 6 studies analyzed included patients with ARS as diagnosed by participating physicians but did not include specific diagnostic criteria. Furthermore, the subgroup analyses in these studies did not stratify data specifically with regard to sinusitis. Data were either generally reported without regard to diagnostic subgroup or subgroup analysis was performed only at the level of upper respiratory tract versus lower RTIs. In addition, the inclusion criteria for 4 of the 5 studies did not include a defined time period of symptoms. Therefore, selection bias may be present in that some of the patients included in these studies could meet criteria for CRS as opposed to ARS. The majority of the patients in the trials of PCT-guided antibiotics had resolution of symptoms at 28 days. This was inconsistent with a diagnosis of CRS, and thus it could be deduced that the majority of these patients were suffering from acute infections; however, there was no long-term follow-up data available to evaluate for recurrence or persistence of symptoms at 3 months. Two of the studies comparing CRP and PCT included relatively few patients with ARS. This may be why a significant association between CRP and PCT was not appreciated in these studies. These investigators stated that despite these drawbacks, the existing literature suggested that there may be a role for PCT in management of ARS, especially in developing new criteria to reduce antibiotic over-use.

Differential Diagnosis Between Bacteremia and Candidemia

Cortegiani and colleagues (2019) the role of PCT in the differential diagnosis between bacteremia and candidemia is unclear. In a systematic review, these investigators evaluated the evidence on PCT values for differentiating bacteremia from candidemia. PubMed and Embase were searched for studies reporting data on the diagnostic performance of serum PCT levels in ICU or non-ICU adult patients with candidemia, in comparison to patients with bacteremia. These researchers included 16 studies for a total of 45,079 patients and 785 cases of candidemia. Most studies claimed to report data relating to the use of PCT values for differentiating between candidemia and bacteremia in septic patients in the ICU. However, the studies identified were all retrospective, except for 1 secondary analysis of a prospective data-set, and clinically very heterogeneous and involved different assessment methods. Most studies did show lower PCT values in patients with candidemia compared to bacteremia. However, the evidence supporting this observation was of low quality and the difference appeared insufficiently discriminative to guide therapeutic decisions. None of the studies retrieved actually studied guidance of anti-fungal treatment by PCT; PCT may improve diagnostic performance regarding candidemia when combined with other biomarkers of infection (e.g., beta-D-glucan); however, more data are needed. The authors concluded that PCT should not be used as a stand-alone tool for the differential diagnosis between bacteremia and candidemia due to limited supporting evidence. These researchers stated that PCT should be further examined in anti-fungal stewardship programs, in association with other biomarkers or non-culture diagnostic tests.

The authors stated that this systematic review had several drawbacks. First, these investigators could not proceed with meta-analysis because the studies identified were clinically very heterogeneous, involving different assessment methods and comparators. This may limit the impact of these findings, but should be mostly noted as a limitation of the available evidence rather than of the review. Second, the inability to separate the results and conclusions according to septic state (e.g., sepsis, septic shock). However, most studies did use sepsis as inclusion criteria or included mostly septic patients (13 out of 16 studies). These researchers were unable to select studies where a surrogate of fungal infection (e.g., beta-d-glucan) was sampled alongside PCT since only 1 study included such data. Third, the timing of blood sampling for PCT levels varied among the included studies. However, for all studies, the authors considered the value of the 1st available PCT sampled during the diagnostic process.

Differential Diagnosis Between Bacterial and Viral Pneumonia (Guide to Antibiotic Therapy In the Community Setting)

Kamat and colleagues (2020) noted that because of the diverse etiologies of community acquired pneumonia (CAP) and the limitations of current diagnostic modalities, serum PCT levels have been proposed as a novel tool to guide antibiotic therapy. Outcome data from PCT-guided therapy trials have shown similar mortality, but the essential question is whether the sensitivity and specificity of PCT levels enable the practitioner to distinguish bacterial pneumonia, which requires antibiotic therapy, from viral pneumonia, which does not. In this meta-analysis of 12 studies of 2,408 patients with CAP, that included etiologic diagnoses and sufficient data to enable analysis, the sensitivity and specificity of serum PCT were 0.55 (95 % CI: 0.37 to 0.71; I2 = 95.5 %) and 0.76 (95 % CI: 0.62 to 0.86; I2 = 94.1 %), respectively. The authors concluded that a PCT level is unlikely to provide reliable evidence either to mandate administration of antibiotics or to enable withholding such treatment in patients with CAP.

Differential Diagnosis Between Infected Diabetic Foot Ulcer and Non-Infected Diabetic Foot Ulcer

Korkmaz and colleagues (2018) examined the roles of IL-6, PCT, and fibrinogen levels in the differential diagnosis of the patients with infected diabetic foot ulcer (IDFU) and non-infected diabetic foot ulcer (NIDFU) and compared those with CRP, WBC, and ESR. Patients over 18 years with a diagnosis of type 2 diabetes mellitus (T2DM) and DFU who were followed-up in the authors’ hospital between January 1, 2016 and January 1, 2017 were included in the study. In addition to this patient group, patients with diabetes but without DFU were determined as the control group. A total of 38 patients with IDFU, 38 patients with NIDFU, and 43 patients as the control group were included in the study; 56.3 % of the patients who participated in the study were men, and the mean age was 61.07 ± 11.04 years; WBC, ESR, CRP, IL-6, and fibrinogen levels of the cases with IDFU were determined to be significantly higher compared to the cases in NIDFU (p < 0.01). The area under the ROC curve (AUROC) value was highest for CRP (0.998; p < 0.001), and the best cut-off value for CRP was 28 m/L. The best cut-off values for fibrinogen, IL-6, ESR, and WBC were 480 mg/dL, 105.8 pg/ml, 31 mm/h, and 11.6 (103 μ/L), respectively. The authors concluded that serum PCT levels were not found to be effective in the differentiation of IDFU and NIDFU; serum IL-6 and fibrinogen levels appeared to be 2 promising inflammatory markers in the discrimination of IDFU.

Prediction of Mortality Risk in Persons with Pulmonary Tuberculosis

Osawa and colleagues (2020) noted that globally, tuberculosis is the leading infectious cause of death; discovering biomarkers that predict a high mortality-risk may improve treatment outcomes. These researchers prospectively enrolled 252 pulmonary tuberculosis patients who were not co-infected with human immunodeficiency virus (HIV) and initiated anti-tuberculosis treatment, measured serum PCT levels, and evaluated mortality. Serum PCT levels of higher than 0.13 ng/ml (day 0), 0.05 ng/ml (day 7), 0.12 ng/ml (day 14), and 0.06 ng/ml (day 28) predicted non-survivors with ORs of 7.9, 14.3, 20.0, and 7.3 (p ≤ 0.005, for all), respectively. The authors concluded that serum PCT levels are a promising mortality-risk indicator for pulmonary tuberculosis patients.

Prognostication in Critically Injured (Major Trauma) Persons

AlRawahi and colleagues (2019) stated that major trauma is associated with high incidence of septic complications and multiple organ dysfunction (MOD), which markedly influence the outcome of injured patients. Early identification of patients at risk of developing post-traumatic complications is crucial to provide early treatment and improve outcomes. These researchers examined the prognostic value of serum PCT levels following trauma as related to severity of injury, sepsis, organ dysfunction, and mortality. They searched PubMed, Medline, Embase, the Cochrane Database, and references of included articles. Two investigators independently identified eligible studies and extracted data. They included original studies that assessed the prognostic value of serum PCT levels in predicting severity of injury, sepsis, organ dysfunction, and mortality among critically injured adult patients. Among 2,015 citations, 19 studies (17 prospective; 2 retrospective) met inclusion criteria. Methodological quality of included studies was moderate. All studies showed a strong correlation between initial PCT levels and Injury Severity Score (ISS); 12 out of 16 studies showed significant elevation of initial PCT levels in patients who later developed sepsis after trauma. PCT level appeared a strong predictor of MOD in 7 of 9 studies. While 2 studies did not show association between PCT levels and mortality, 4 studies demonstrated significant elevation of PCT levels in non-survivors versus survivors; 1 study reported that the PCT level of greater than or equal to 5 ng/ml was associated with significantly increased mortality (OR 3.65; 95 % CI 1.03 to 12.9; p = 0.04). The authors concluded that PCT appeared promising as a surrogate biomarker for trauma. Initial peak PCT level may be used as an early predictor of sepsis, MOD, and mortality in trauma population. Moreover, these researchers stated that further studies, preferably prospective, open-label, multi-center RCTs are needed to examine the impact of PCT-guided decision-making on the clinical outcomes in the trauma setting.

The authors stated that this review had several drawbacks. First, they did not include non-English publications in this review. Second, studies carried out in mixed Medical-Surgical intensive care unit (ICU) that included trauma cohort were excluded due to combined data. Third, the quality of the primary studies varied with main issue related to confounding variables. Fourth, statistical methods used in the outcome assessment varied across studies, which made combining results in a meta-analysis difficult. Finally, there was lack of a consensus definition of the term, severe trauma, which could have induced a high heterogeneity among trauma patients due to variations in the immunological responses depending on the injury pattern.

Prognostication of Outcomes in Persons Following Cardiac Arrest

In a systematic review and meta-analysis, Shin and colleagues (2019) examined the evidence on the usefulness of the PCT as a prognostic blood biomarker for outcomes in post-cardiac arrest patients. These investigators searched Medline, Embase, and the Cochrane Library (search date: January 8, 2019). Studies on patients who experienced return of spontaneous circulation, who had out-of-hospital cardiac arrest and had their level of PCT measured and outcomes assessed at and after hospital discharge, were included. In addition, these investigators performed subgroup analyses for confounding factors affecting patients' outcomes. To assess the risk of bias of each included study, the Quality in Prognosis Studies tool was used. A total of 1,065 patients from 10 studies were finally included. Elevated PCT level during hospital admission (at 0 to 24 hours) was associated with in-hospital mortality (standardized mean difference (SMD) 0.64, 95 % CI: 0.33 to 0.95, I2 = 26 %). The elevation of PCT level (at 0 to 48 hours) was also associated with poor neurologic outcomes (at 0 to 24 hours, SMD 0.61; 95 % CI: 0.44 to 0.79, I2 = 0 %; at 24 to 48 hours, SMD 0.58, 95 % CI: 0.35 to 0.82, I2 = 0 %) as well as at 1 to 6 months (at 24 to 48 hours, SMD 0.62; 95 % CI: 0.36 to 0.88, I2 = 0 %). The authors concluded that the findings suggested that an elevated PCT level measured at 0 to 48 hours of post-cardiac arrest syndrome was associated with poor outcomes. These findings need to be validated by well-designed studies.

Acute Kidney Injury

Feng and colleagues (2021) stated that PCT was recently used in predicting the development of acute kidney injury (AKI) in several studies. In a meta-analysis, these investigators examined the accuracy of PCT for predicting AKI. Studies that examined the predictive performance of PCT for the development of AKI in adult patients were searched from Medline, Embase, and the Cochrane Library from inception to June 2020. These researchers calculated the pooled sensitivities and specificities and the area under the summary receiver-operating characteristic (SROC) curves; I2 was used to test the heterogeneity and the potential heterogeneity was examined by meta-regression. A total of 9 studies with 4,852 patients were included, 1,272 were diagnosed with AKI. In the overall analysis, the area under the SROC curve was 0.82 (95 % CI: 0.79 to 0.85) and the pooled sensitivity and specificity were 0.76 (95 % CI: 0.64 to 0.85) and 0.75 (95 % CI: 0.61 to 0.86), respectively. In the subgroup analysis among septic patients, the pooled sensitivity and specificity were 0.59 (95 % CI: 0.29 to 0.84) and 0.53 (95 % CI: 0.31 to 0.74), and the area under the SROC was 0.57 (95 % CI: 0.53 to 0.62). The authors concluded that PCT may be a potential early biomarker of AKI; however, these findings should be further validated.

The authors stated that this meta-analysis had several drawbacks. First, substantial heterogeneity between the included studies could not be explained by subgroup analysis. Second, the included studies were mostly retrospective that may lead to inevitable bias. Third, these investigators also found that the cut-off for PCT varied considerably from study to study and the best diagnostic threshold for PCT was unknown.

Bacterial Meningitis

Kim and colleagues (2021) noted that early diagnosis and treatment of bacterial meningitis in children are essential, due to the high mortality and morbidity rates; however, lumbar puncture is often difficult, and cerebrospinal fluid (CSF) culture takes time. In a systematic review and meta-analysis, these investigators examined the diagnostic accuracy of blood PCT for detecting bacterial meningitis in children. They carried out a search on electronic databases to identify relevant studies. Pooled sensitivity, specificity, and DOR were calculated, and a hierarchical summary receiver operating characteristic curve and AUC)were determined. A total of 18 studies with 1,462 children were included in the analysis. The pooled sensitivity, specificity, and the DOR of blood PCT for detecting bacterial meningitis were 0.87 (95 % CI: 0.78 to 0.93); 0.85 (95 % CI: 0.75 to 0.91), and 35.85 (95 % CI: 10.68 to 120.28), respectively. The AUC for blood PCT was 0.921. Blood PCT also showed higher diagnostic accuracy for detecting bacterial meningitis than other conventional biomarkers, including serum CRP and leukocyte count, CSF leukocyte and neutrophil count, and CSF protein and glucose levels. The authors concluded that blood PCT could be a good supplemental biomarker with high diagnostic accuracy in detecting bacterial meningitis in children. Moreover, these researchers stated that future studies are needed to examine if blood PCT could serve as a stand-alone biomarker for the diagnosis of pediatric bacterial meningitis in various clinical settings.

The authors stated that this review/meta-analysis had 2 main drawbacks. First, significant heterogeneity was observed in the meta-analysis. The heterogeneity across studies may be the consequence of the use of different reference standards, cut-off values, types of PCT assays, and different clinical conditions. They accepted the researchers’ definitions of bacterial meningitis if they were based on the World Health Organization (WHO)’s case definition criteria. They also carried out subgroup analysis according to the cut-off values; but could not conduct subgroup analyses according to the other factors because of the limited information available. Second, these investigators could not compare the pooled estimates of the diagnostic accuracy of CSF: blood glucose ratio and CSF PCT compared with blood PCT because there were too few studies that provided data with which these comparisons could have been performed.

COVID-19

In a systematic review, Ahmed and colleagues (2021) examined the published literature on the prognostic role of serum PCT in COVID-19 cases. These investigators reviewed the literature available on PubMed, Medline, LitCovid NLM, and WHO to evaluate the use of PCT in prognosis of coronavirus disease. Scrutiny for eligible studies comprising articles that have examined the prognostic use of PCT; and data compilation was carried out by 2 separate investigators. Original articles in human subjects reporting the prognostic role of PCT in adult COVID-19 patients were included. The Quality in Prognosis Studies (QUIPS) tool was employed to examine the strength of evidence; results were reported as narrative syntheses. Of the total 426 citations, 52 articles passed through screening. The quality of evidence and methodology of included studies was overall acceptable. The total sample size of the studies comprised of 15,296 COVID-19-positive subjects. The majority of the studies were from China (40 [77 %]). The PCT cut-off was 0.05 ng/ml by 18 (35 %) studies, followed by 0.5 ng/ml by 9 (17.5 %); 85 % (n = 44) studies reported statistically significant association (p < 0.05) between PCT and severity. The authors concluded that PCT appeared as a promising prognostic biomarker of COVID-19 progression in conjunction with the clinical context. Moreover, these researchers stated that to expansively evaluate the prognostic use of PCT, large-scale, cross-sectional, multi-center studies are needed.

The authors stated that this review had several drawbacks. First, exclusion of non-English publications mostly from China. Second, existing co-morbidities including renal dysfunction, prior bacterial infection, and prophylactic antibiotic initiation that could alter PCT levels were not extensively evaluated. Third, a meta-analysis could not be conducted due to the lack of uniformity of the statistical models adopted by various studies. Fourth, microbiological culture results for co-infecting bacterial and fungal infections were not appraised.

In a meta-analysis, Shen and associates (2021) estimated the adjusted relationship between elevated PCT on admission and the severity of COVID-19. These investigators searched 1,805 articles from PubMed, Web of Science, and Embase databases up to April 2, 2021. They selected articles that reported the adjusted relationship applying multi-variate analysis between PCT and the severity of COVID-19 . The pooled effect estimate was calculated by the random-effects model. The meta-analysis included 10 cohort studies with a total of 7,716 patients. Patients with elevated PCT on admission were at a higher risk of severe and critical COVID-19 (pooled effect estimate: 1.77, 95 % CI: 1.38 to 2.29; I2 = 85.6 %, p < 0.001). Similar results were also observed in dead patients (pooled effect estimate: 1.77, 95 % CI: 1.36 to 2.30). After adjusting for diabetes mellitus, the positive association between PCT and the severity of COVID-19 decreased. Subgroup analysis revealed heterogeneity between studies and sensitivity analysis showed that the results were robust. There was no evidence of publication bias by Egger's test (p = 0.106). The authors concluded that higher PCT is positively associated with the severity of COVID-19, which is a potential biomarker to evaluate the severity of COVID-19 and predict the prognosis. Moreover, these researchers stated that further investigations are needed to confirm these finding.

The authors this meta-analysis had several drawbacks. First, noticeable heterogeneity exists in this study. Although sensitivity analysis manifested that these findings were robust, they also needed to control the magnitude of heterogeneity by selecting appropriate sample sizes and other methods. Second, the selected studies were mainly from China, and only 2 studies were from foreign countries. Third, most studies in this meta-analysis were retrospective, whose information is mainly from electronic medical records, so the lack of data and subjective information was inevitable. Fourth, this study was under-powered to examine the underlying mechanism of PCT with the severity of COVID-19, and the specific molecular mechanisms of the disease need to be further studied.

Sepsis After Cardiac Surgery

Li and colleagues (2021) noted that cardiac surgery with cardio-pulmonary bypass (CPB) induces an acute inflammatory response that may lead to a systemic inflammatory response syndrome. The interest in PCT in the diagnosis of bacterial infection in patients following cardiac surgery remains less defined. In a systematic review and meta-analysis, these investigators examined the discriminatory power of PCT as markers of infection in hospitalized patients after cardiac surgery. The bi-variate generalized non-linear mixed-effect model and the hierarchical SROC (HSROC) model were used to estimate the pooled sensitivity, specificity and SROC. The pooled sensitivity and specificity were 0.81 (95 % CI: 0.75 to 0.87) and 0.78 (95 % CI: 0.73 to 0.83), respectively. The pooled positive likelihood ratio (PLR), and negative likelihood ratio (NLR) of PCT were 3.74 (95 % CI: 2.98 to 4.69) and 0.24 (95 % CI: 0.17 to 0.32), respectively. The pooled AUC of PCT using the HSROC method was 0.87 (95 % CI: 0.84 to 0.90). The authors concluded that he findings of this study indicated that PCT is a promising marker for the diagnosis of sepsis for patients who had undergone cardiac surgery.

Ventilator-Associated Pneumonia

Alessandri and colleagues (2021) noted that ventilator-associated pneumonia (VAP) is one of the most common nosocomial infection, associated with considerable mortality and morbidity in critically ill patients; however, its diagnosis and management remain challenging since clinical assessment is often poorly reliable. In a systematic review, these investigators examined the role of PCT in the diagnosis and management of critical ill patients affected by VAP. They carried out a review of the evidence published over the last 10 years and currently available in medical literature search databases (PubMed, Embase, Web of Knowledge, Cochrane Libraries) and searching clinical trial registries. They regarded as pre-defined outcomes the role of PCT in diagnosis, therapeutic monitoring, antibiotic discontinuation and prognosis. A total of 761 articles were retrieved and 18 studies (1,774 patients) were selected and analyzed according to inclusion criteria. In this 2020 update, the systematic review showed that currently, conflicting and inconclusive data are available regarding the role of PCT in the diagnosis of VAP and in the prediction of the efficacy of antibiotic therapy, and of the clinical outcome. These studies, instead, appeared to agree on the use of PCT in the management of antibiotic therapy discontinuation. The authors concluded that there is currently insufficient evidence to support the use of PCT in the routine assessment of patients with VAP. The value of the results published appeared to be limited by the deep methodological differences that characterized the various studies available at the present settings.

Diagnosis of Anastomotic Leakage After Colorectal Surgery

Su'a et al (2020) noted that anastomotic leakage (AL) is a dreaded complication after colorectal surgery; PCT is one of many biomarkers studied and research has suggested that it has improved accuracy for the diagnosis of AL compared with other inflammatory biomarkers such as CRP. In a meta-analysis, these researchers examined the accuracy of PCT in the early diagnosis of AL after colorectal surgery. Medline, Embase and PubMed were searched for studies evaluating PCT in the context of AL after colorectal surgery in the elective setting. The literature was reviewed using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. Quality of the studies was assessed using the Quality Assessment Diagnostic Accuracy Studies (QUADAS)-2 tool. Meta analyses were conducted using AUC for day 3, 4 and 5 post-surgery as a diagnostic test to detect AL. A total of 8 studies were analyzed. Results showed that the highest diagnostic accuracy for PCT was on day 5 post-surgery. The reported optimal cut-off values ranged from 0.25 to 680 ng/ml from post-operative day 3 to 5, with reported NPLs ranging from 95 % to 100 %, and PPVs of up to 34 %. The highest AUC was 0.88 on post-operative day 5. The authors concluded that PCT was a useful negative test for AL after elective colorectal surgery; however, as an isolated test, it was not useful in detecting AL.

This meta-analysis had several drawbacks, including studies employed a variety of definitions for AL. This varied from the presence of clinical symptoms of peritonitis, to contrast extravasation on a CT scan. Furthermore, the majority of patients included in this review underwent open surgery for colorectal cancer; thus, these findings may not apply to laparoscopic surgery, where a reduced inflammatory response is observed. In addition, none of the included studies distinguished biomarker levels between colonic and rectal resection nor underlying disease process, and did not take into account medications that may alter the inflammatory response such as statins and steroids.

Xu et al (2022) noted that AL is one of the most serious complications following colorectal surgery, and a reliable method for early diagnosis is urgently needed. PCT is recently considered a potential biomarker by many studies; however, this conclusion in is controversial. In a meta-analysis, these researchers examined the diagnostic value of the PCT level on post-operative day 3 (POD3) in patients undergoing colorectal surgery. This review was carried out using the PRISMA of Diagnostic Test Accuracy (PRISMA-DTA) statement. Studies were searched in PubMed, Embase, Cochrane Library, Wanfang, and China National Knowledge Infrastructure (CNKI) until August 2021. Quality of the studies was scored based on the QUADAS-2 tool. Sensitivity, specificity, PLR, NLR, DOR, and a SROC curve were used to estimate the diagnostic value. Meta-regression and subgroup analyses were performed to further examine the primary source of heterogeneity and the influence of various factors on diagnostic accuracy. A total of 11 studies (3,393 patients) were included in this meta-analysis. The derived cut-off value of PCT was 1.12 ng/ml by geometric mean and the pooled sensitivity, specificity, PLR, NLR and DOR were 0.768 (0.704 to 0.825), 0.788 (0.774 to 0.802), 4.600 (3.129 to 6.763), 0.339 (0.267 to 0.431) and 18.114 (9.872 to 33.239), respectively. The computed AUC from the SROC curve was 0.8714, and the Q* index was 0.8019. The results of meta-regression and subgroup analyses showed that the usage of laparoscopic surgery was the major factor in improving the reliability of PCT data, and 0.7 to 1.3 ng/ml may be the appropriate interval for PCT with the DOR (38.610 (16.324 to 91.321)) well above the average. The authors concluded that PCT level on POD3 has potential clinical value in the early diagnosis of AL and exhibits a better diagnostic accuracy in patients undergoing laparoscopic surgery. Cut-off values are recommended at the interval range of 0.7 to 1.3 ng/ml to ensure accurate diagnosis and safe discharge.

Diagnosis of Bacterial Infections in Patients with Systemic Lupus Erythematosus

In a systematic review and meta-analysis, Chen et al (2021) examined the diagnostic performance of PCT and CRP for distinguishing bacterial infections from lupus flares in systemic lupus erythematosus (SLE). Electronic databases were searched. The pooled standard mean difference (SMD) and 95 % CI were calculated to estimate the differences of serum PCT and CRP levels between bacterial infections and flares in SLE. Sensitivity, specificity and SROC curve were employed to evaluate the diagnostic values of PCT and CRP. The use of fixed or random effects model depended on heterogeneity. A total of 15 studies were included in the analysis. Serum PCT and CRP levels were significantly higher in SLE patients with bacterial infections compared to SLE patients with flares (PCT: SMD = 1.035, 95 % CI: 0.708 to 1.362; CRP: SMD = 1.000, 95 % CI: 0.758 to 1.242). The overall sensitivity, specificity, AUC, PLR and NLR of PCT were 0.62, 0.88, 0.862, 6.63 and 0.36, respectively, while the same indicators for CRP were 0.72, 0.70, 0.784, 2.45 and 0.38, respectively. The authors concluded that serum PCT and CRP levels were significantly increased in SLE with bacterial infections; PCT had a better diagnostic performance than CRP. PCT had a high value of PLR and could serve as a rule-in marker, while CRP testing may result in a high false-positive rate due to low PLR; both markers had a suboptimal value of NLR and are not appropriate for ruling out bacterial infections.

In a systematic review and meta-analysis, Bruera et al (2022) examined the use of ESR, CRP, and PCT in diagnosing infections in hospitalized patients with SLE. These investigators searched Medline, Embase, Web of Science, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials (CENTRAL) with a search strategy developed by a medical librarian. They included retrospective, cross-sectional, case-control, and prospective studies in their analysis. These researchers used the Quality Assessment of Diagnostic Studies (QUADAS-2) to evaluate for bias and applicability. They obtained MDs, sensitivities, and specificities in the analysis. These investigators included 26 studies in their analysis. Most studies had an unclear or high-risk of bias and these findings were widely heterogenous. For the diagnosis of infections, the CRP had a pooled sensitivity of 0.75 (95 % CI: 0.57 to 0.94) and specificity of 0.72 (0.59 to 0.85), PCT had a pooled sensitivity of 0.68 (95 % CI: 0.0.59 to 0.77) and specificity of 0.75 (0.59 to 0.90), and for ESR pooled estimates were not calculated but sensitivity ranged from 50 to 69.8 and specificity from 38.5 to 55.6. Modifying cut-offs improved sensitivities and specificities. The ESR, CRP, and PCT MDs were all greater in infection groups versus non-infection (10.1, 95 % CI: 3.2 to 17.0; 46.8, 95 % CI: 36.5 to 57.0; 0.53, 95 % CI: 0.26 to 0.80; respectively). The authors concluded that poor sensitivities and specificities were observed for the evaluated biomarkers with substantial heterogeneity in the cut-offs used to determine infection. Although mean biomarker values were increased in the infection group compared with the non-infection, these findings did not support the widespread use of ESR, CRP, or PCT in diagnosing infection in hospitalized patients with SLE due to increased heterogeneity and risk of bias. These researchers stated that further investigation is needed.

Diagnosis of Post-Operative Pancreatic Fistula following Pancreatoduodenectomy

Chen et al (2021) stated that CRP and PCT have recently been used to diagnose and screen for post-operative pancreatic fistula (POPF) following pancreatoduodenectomy (PD); however, their reliability is still unclear. In a systematic review and meta-analysis, these researchers examined the effectiveness of CRP and PCT in the diagnosis of POPF following PD. Electronic databases such as PubMed, Excerpta Medica (Embase), the Web of Science (WOS) and the China National Knowledge Infrastructure (CNKI) were used to search for studies and full-text articles that examined the diagnostic efficacy of CRP and PCT for POPF. Review Manager 5.4 and STATA 14.0 were used to estimate the pooled diagnostic value of CRP and PCT. Sensitivity analyses and Deeks' funnel plot tests were performed on the selected studies. A total of 20 studies that met the established selection criteria were included in this analysis. Both CRP and PCT were shown to be highly effective in diagnosing POPF, each with a high AUC. The AUC of CRP on POD4 had a value of 0.86, with a sensitivity and specificity of 0.85 and 0.69, respectively. The AUC of PCT on POD5 had a value of 0.87, with a sensitivity and specificity of 0.84 and 0.74, respectively. The authors concluded that these findings supported the hypothesis that CRP and PCT were valuable diagnostic tools for predicting POPF, especially given the CRP levels on POD4 and PCT levels on POD5. Moreover, these researchers stated that limited by the small number of the studies analyzed, they recommended that more RCTs be performed to verify these findings.

The authors stated that this review had several drawbacks. First, the International Study Group for Pancreatic Fistula (ISGPF) published 2 slightly different versions of POPF in 2005 and 2016. Most of the studies included in this meta-analysis adopted the 2005 version, although some adopted the 2016 version, which may impact the results. Second, there were differences in the cut-off values of CRP and PCT in each study, which would have a certain impact on the final sensitivity and specificity and consequently affected the results of the AUC. Third, the number of studies on the diagnosis of POPF by PCT was small, and more studies are needed to confirm its accuracy.

Diagnosis of Urinary Tract Infection

Choi et al (2022) stated that the diagnosis of urinary tract infection (UTI) is challenging among hospitalized older adults, especially among those with altered mental status. In a prospective cohort study, these researchers examined the diagnostic accuracy of PCT for UTI in hospitalized older adults. This trial included elder individuals (65 years of age or older) admitted to a single hospital with evidence of pyuria on urinalysis. PCT was tested on initial blood samples. The reference standard was a clinical definition that included the presence of a positive urine culture and any symptom or sign of infection referable to the genitourinary tract. These investigators also surveyed the treating physicians for their clinical judgment and carried out expert adjudication of cases for the determination of UTI. Subjects entailed 229 patients at a major academic medical center. Main outcome measures included the AUC of PCT for the diagnosis of UTI. In this study cohort, 61 (27 %) subjects met clinical criteria for UTI. The median age of the overall cohort was 82.6 (IQR 74.9 to 89.7) years. The AUC of PCT for the diagnosis of UTI was 0.56 (95 % CI: 0.46 to 0.65). A series of sensitivity analyses on UTI definition, which included using a decreased threshold for bacteriuria, the treating physicians' clinical judgment, and independent infectious disease specialist adjudication, confirmed the negative result. The authors concluded that these findings showed that PCT has limited value in the diagnosis of UTI among hospitalized older adults. Clinicians should be cautious using PCT for the diagnosis of UTI in hospitalized older adults.

The authors stated that this study had several drawbacks. First, the lack of a gold standard. It was possible that both over-diagnosis and under-diagnosis of UTI in this trial occurred, even in patients with intact mental status. Second, this was a highly selected sample from a single center as a relatively high proportion of eligible patients had to be excluded for a variety of reasons. Third, there was incorporation bias given that the reference standard for UTI includes the presence of pyuria on urinalysis, which was part of the study inclusion criteria. Furthermore, there were 13 occurrences of PCT testing as part of clinical care, which were available to the attending physicians and outcome adjudicators. Incorporation bias may over-estimate both sensitivity and specificity of the index test. Fourth, over 70 % of patients did not undergo imaging to examine for radiographic evidence of a UTI, introducing a partial verification bias to this trial. This may over-estimate the sensitivity of the index test given the potential under-detection of false negatives. Given the overwhelming negative result of this trial, these researchers believed that the incorporation bias and partial verification bias were ultimately not consequential for the interpretation of the study results.

Prediction of Pneumonia in Acute Exacerbations in Chronic Obstructive Pulmonary Disease (COPD) Patients

Mou et al (2022) noted that patients with community-acquired pneumonia (CAP) and acute exacerbations of chronic obstructive pulmonary disease (AECOPD) could have a higher risk of acute and severe respiratory illness than those without CAP in AECOPD. Consequently, early identification of pneumonia in AECOPD is quite important. In a prospective, observational study, a total of 52 subjects with AECOPD + CAP and 93 subjects with AECOPD from 2 clinical centers were enrolled. The values of osteopontin (OPN), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), CRP, PCT, eosinophil (EOS) counts, and neutrophil (Neu) counts in blood on the 1st day of admission and clinical symptoms were compared in AECOPD and AECOPD + CAP. Furthermore, subgroup analyses of biomarker difference were carried out based on the current use of inhaled glucocorticoids (ICS) or systemic corticosteroids (SCS). Patients with AECOPD + CAP had increased sputum volume, sputum purulence, diabetes mellitus, and longer hospital stays than AECOPD patients (p < 0.05). A clinical logistic regression model showed among the common clinical symptoms, purulent sputum can independently predict pneumonia in AECOPD patients after adjusting for a history of diabetes. At day 1, AECOPD + CAP patients had higher values of Neu, CRP, PCT, and OPN, while serum sTREM-1 levels and EOS counts were similar in the 2 groups. CRP fared best at predicting AECOPD with CAP (p < 0.05 for the test of difference), while OPN had similar accuracy with Neu, PCT, and purulent sputum (p > 0.05 for the test of difference). Multi-variate analysis, including clinical symptoms and biomarkers, suggested that CRP 15.8 mg/dL or higher at day 1 was the only promising predictor of pneumonia in AECOPD; CRP and OPN were not affected by ICS or SCS. The authors concluded that CRP 15.8 mg/dL or higher is an ideal promising predictor of pneumonia in AECOPD, and its plasma level is not affected by ICS or SCS. The diagnostic performance of CRP is not significantly improved when combined with clinical symptoms or other markers (OPN, PCT, and Neu).

Prediction of Severity of Acute Cholangitis and Need for Urgent Biliary Decompression

Silangcruz et al (2022) noted that serum PCT has been reported as a potential biomarker to predict the severity of acute cholangitis (AC) or the need for urgent biliary decompression. These investigators examined the available evidence on serum PCT and the severity of AC. Following the PRISMA guidelines for scoping reviews, Medline, Embase, and Google Scholar were searched for all peer-reviewed articles with relevant keywords including "cholangitis" and "procalcitonin" from their inception to July 13, 2021. These researchers identified 6 studies. All 6 studies employed a case-control design and aimed to examine the usefulness of serum PCT to predict the severity of AC with key identified outcomes. While the potential cut-off values of serum PCT for severe AC ranged from 1.8 to 3.1 ng/ml, studies used different severity criteria and the definition of urgent biliary decompression. No studies proposed cut-off PCT values for the need for urgent biliary decompression. The authors concluded that this review identified the current level of evidence regarding the usefulness of serum PCT in evaluating the severity of AC. These investigators stated that further prospective studies with standardized outcome measurements are needed to examine if elevated PCT may aid in determining those who benefit from emergent interventions among patients with AC due to biliary obstructions from different etiologies.

The authors stated that the drawbacks of the studies included in this analysis were that all of the currently available research were case-control studies (5 retrospective and 1 prospective) with small sample sizes. Furthermore, the considerable heterogeneity of the basic demographics among the studies needs to be noted. All the studies were conducted in Asian countries, including Japan, South Korea, and China. In addition, the etiology of AC may be different; for instance, 9.8 % of patients in the study by Lee et al (2018) had malignant biliary strictures, while Shinya et al (2014) included only patients with choledocholithiasis. All the factors limited the generalizability of the results. Additionally, due to the urgent need for evidence on this topic and limited time, these researchers did not contact authors to clarify the details of the data described in the literature. Also, these investigators only included peer-reviewed articles in this scoping review; therefore, non-peer-reviewed articles or conference abstracts, which might have been useful, were excluded from the study.

Distinguishing Pneumonia from Bronchitis or Exacerbation of Chronic Respiratory Diseases

Raupach et al (2023) stated that LRTIs are often the reasons for patients to visit their general practitioners or lung specialists; however, physicians tend to prescribe antibiotics less frequently than necessary. A readily available biomarker could aid in distinguishing between viral and bacterial cause of LRTI. These researchers examined the diagnostic accuracy of point-of-care testing (POCT) of PCT in identifying bacterial pneumonia in outpatients with LRTI. All patients aged 18 years or older with signs and symptoms of LRTI who visited a respiratory physician were included in the study and their PCT levels were measured. In 110 patients enrolled in the study, 3 patients (2.7 %) had PCT values above the threshold of 0.25 µg/L without proven bacterial infection, in contrast to 7patients with typical radiological signs of pneumonia without elevated POCT PCT levels. The AUC for PCT for the detection of pneumonia was 0.56 (p = 0.685). The authors concluded that POCT PCT showed limited specificity and sensitivity in distinguishing pneumonia from bronchitis or exacerbation of chronic respiratory diseases. These investigators noted that PCT is a marker of severe bacterial infections and not suitable for milder infections in outpatient care.

Predicting the Development of Moderate-to-Severe Acute Respiratory Distress Syndrome (ARDS)

In a retrospective study, Li et al (2023) examined the changes of serum PCT level in patients who underwent cardiac surgery with cardiopulmonary bypass (CPB); and assessed the best cut-off of PCT for predicting the progression to moderate and severe acute respiratory distress syndrome (ARDS). Medical records of patients undergoing cardiac surgery with CPB in Fujian Provincial Hospital from January 2017 to December 2019 were analyzed. Adult patients who were admitted to the ICU for more than 1 day and had PCT values on the 1st post-operative day were enrolled. Clinical data such as patient demographics, past history, diagnosis, and New York Heart Association (HYHA) classification, and the operation mode, procedure duration, CPB duration, aortic clamp duration, intra-operative fluid balance, calculation of 24 hours post-operative fluid balance and vasoactive-inotropic score (VIS); 24 hours post-operative CRP, N-terminal B-type natriuretic peptide precursor (NT-proBNP) and PCT levels were collected. Two clinicians independently made the diagnosis of ARDS according to the Berlin definition, and the diagnosis was established only in patients with a consistent diagnosis. The differences in each parameter were compared between patients with moderate-to-severe ARDS and those without or with mild ARDS. Analysis of the ability of PCT to predict moderate-to-severe ARDS was examined by ROC curve. Multi-variate logistic regression was carried out to determine the risk factors of the development of moderate-to-severe ARDS. A total of 108 patients were enrolled, including 37 patients with mild ARDS (34.3 %), 35 patients with moderate ARDS (32.4 %), 2 patients with severe ARDS (1.9 %), and 34 patients without ARDS. Compared with patients with no or mild ARDS, patients with moderate-to-severe ARDS were older (years old: 58.5 ± 11.1 versus 52.8 ± 14.8, p < 0.05), with a higher proportion of combined hypertension [45.9 % (17/37) versus 25.4 % (18/71), p < 0.05], longer operative time (mins: 363.2 ± 120.6 versus 313.5 ± 97.6, p < 0.05), and higher mortality (8.1 % versus 0, p < 0.05), but there were no differences in the VIS score, incidence of acute renal failure (ARF), CPB duration, aortic clamp duration, and intra-operative bleeding, transfusion volume, and fluid balance between the 2 groups. Serum PCT and NT-proBNP levels in patients with moderate-to-severe ARDS at post-operative day 1 were significantly higher than those in patients with no or mild ARDS [PCT (μg/L): 16.33 (6.96 to 32.56) versus 2.21 (0.80 to 5.76), NT-proBNP (ng/L): 2,405.0 (1,543.0 to 6,456.5) versus 1,680.0 (1,388.0 to 4,667.0), both p < 0.05]. ROC curve analysis showed that the AUC for PCT to predict the occurrence of moderate-to-severe ARDS was 0.827 (95 % CI: 0.739 to 0.915, p < 0.05]. When PCT cut-off value was 7.165 μg/L, the sensitivity was 75.7 % and the specificity was 84.5 %, for differentiating patients who developed moderate-to-severe ARDS from who did not. Multi-variate logistic regression showed that age and the elevated PCT concentration were independent risk factors for the development of moderate-to-severe ARDS [age: OR = 1.105, 95 % CI: 1.037 to 1.177, p = 0.002; PCT: OR = 48.286, 95 % CI: 10.282 to 226.753, p < 0.001]. The authors concluded that patients with moderate-to-severe ARDS undergoing CPB cardiac surgery had a higher serum concentration of PCT than patients with no or mild ARDS. These researchers stated that serum PCT level may be a promising biomarker in predicting the development of moderate-to-severe ARDS, the cut-off value was 7.165 μg/L.

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The above policy is based on the following references:

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Last Review 10/26/2023

Effective: 11/21/2008

Next Review: 08/22/2024
Review History
Definitions

Procalcitonin (PCT)

Table Of Contents

Policy

Scope of Policy

Medical Necessity

Experimental and Investigational

CPT Codes / HCPCS Codes / ICD-10 Codes

CPT codes covered if selection criteria are met:

Other CPT codes related to the CPB:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

Background

Acute Pyelonephritis

Antibiotic Use for Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Early-Onset Neonatal Sepsis

Medullary Thyroid Carcinoma

Ventilator-Associated Pneumonia

Community-Acquired Pneumonia

Intra-Abdominal Infection After Elective Colorectal Surgery

Rheumatoid Arthritis

Stroke

Guidance of Antibiotic Use in Individuals with Diabetic Foot Ulcer

Biomarker for Neonatal Bacterial Infection

Diagnosis of Hypersensitivity Pneumonitis

Diagnosis of Pancreatic Necrosis

Diagnosis of Peri-Prosthetic Joint Infection

Management of Immunocompromised Individuals

Biomarker of Rhino-Sinusitis

Differential Diagnosis Between Bacteremia and Candidemia

Differential Diagnosis Between Bacterial and Viral Pneumonia (Guide to Antibiotic Therapy In the Community Setting)

Differential Diagnosis Between Infected Diabetic Foot Ulcer and Non-Infected Diabetic Foot Ulcer

Prediction of Mortality Risk in Persons with Pulmonary Tuberculosis

Prognostication in Critically Injured (Major Trauma) Persons

Prognostication of Outcomes in Persons Following Cardiac Arrest

Acute Kidney Injury

Bacterial Meningitis

COVID-19

Sepsis After Cardiac Surgery

Ventilator-Associated Pneumonia

Diagnosis of Anastomotic Leakage After Colorectal Surgery

Diagnosis of Bacterial Infections in Patients with Systemic Lupus Erythematosus

Diagnosis of Post-Operative Pancreatic Fistula following Pancreatoduodenectomy

Diagnosis of Urinary Tract Infection

Prediction of Pneumonia in Acute Exacerbations in Chronic Obstructive Pulmonary Disease (COPD) Patients

Prediction of Severity of Acute Cholangitis and Need for Urgent Biliary Decompression

Distinguishing Pneumonia from Bronchitis or Exacerbation of Chronic Respiratory Diseases

Predicting the Development of Moderate-to-Severe Acute Respiratory Distress Syndrome (ARDS)

References

Policy History

Additional Information