Prognostic value of procalcitonin in hospitalized patients with lower respiratory tract infections

Nobre, Vandack; Borges, Isabela; ,

doi:10.5935/0103-507X.20160019

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Revista Brasileira de Terapia Intensiva

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REVIEW ARTICLE • Rev. bras. ter. intensiva 28 (02) • Apr-Jun 2016 • https://doi.org/10.5935/0103-507X.20160019 copy

Prognostic value of procalcitonin in hospitalized patients with lower respiratory tract infections

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Lower respiratory tract infections are common and potentially lethal conditions and are a major cause of inadequate antibiotic prescriptions. Characterization of disease severity and prognostic prediction in affected patients can aid disease management and can increase accuracy in determining the need for and place of hospitalization. The inclusion of biomarkers, particularly procalcitonin, in the decision taken process is a promising strategy. This study aims to present a narrative review of the potential applications and limitations of procalcitonin as a prognostic marker in hospitalized patients with lower respiratory tract infections. The studies on this topic are heterogeneous with respect to procalcitonin measurement techniques, cutoff values, clinical settings, and disease severity. The results show that procalcitonin delivers moderate performance for prognostic prediction in patients with lower respiratory tract infections; its predictive performance was not higher than that of classical methods, and knowledge of procalcitonin levels is most useful when interpreted together with other clinical and laboratory results. Overall, repeated measurement of the procalcitonin levels during the first days of treatment provides more prognostic information than a single measurement; however, information on the cost-effectiveness of this procedure in intensive care patients is lacking. The results of studies that evaluated the prognostic value of initial procalcitonin levels in patients with community-acquired pneumonia are more consistent and have greater potential for practical application; in this case, low procalcitonin levels identify those patients with a low risk of adverse outcomes.

Keywords:
Infection; Respiratory system; Sepsis; Prognosis; Biomakers; Procalcitonin

Author	Year	Country	Study design	Sample size (N)	Inclusion criteria	Outcomes	Results	Observations
Alba et al.⁽²⁶26 Alba GA, Truong QA, Gaggin HK, Gandhi PU, De Berardinis B, Magrini L, Bajwa EK, Di Somma S, Januzzi JL Jr; Global Research on Acute Conditions Team (GREAT) Network. Diagnostic and Prognostic utility of procalcitonin in patients presenting to the emergency department with dyspnea. Am J Med. 2016;129(1):96-104.e7.⁾	2015	United States Italy	Bicenter, prospective cohort	453	Dyspnea	Primary: diagnosis of pneumonia Secondary: one-year mortality	Primary outcome: AUC 0.84 for PCT > 0.1 ng/mL Secondary outcome: PCT as an independent predictor of one-year mortality (HR: 1.8; 95%CI: 1.4-2.3). No correlation in patients with pneumonia	Prognostic value as secondary outcome
Travaglino et al.⁽²⁷27 Travaglino F, De Berardinis B, Magrini L, Bongiovanni C, Candelli M, Silveri NG, et al S. Utility of Procalcitonin (PCT) and Mid regional pro-Adrenomedullin (MR-proADM) in risk stratification of critically ill febrile patients in Emergency Department (ED). A comparison with APACHE II score. BMC Infect Dis. 2012;12:184.⁾	2012	Italy	Multicenter, prospective cohort	128	Fever	Levels of MR-proADM and PCT compared with APACHE II	Positive correlation between APACHE II scores and MR-proADM (r = 0.66) and between MR-proADM and PCT (r = 0.54). No correlation between PCT and APACHE II	Small sample size, LRTI as subgroup
Ugajin et al.⁽²⁸28 Ugajin M, Yamaki K, Hirasawa N, Yagi T. Predictive values of semi-quantitative procalcitonin test and common biomarkers for the clinical outcomes of community-acquired pneumonia. Respir Care. 2014;59(4):564-73.⁾	2014	Japan	Single-center, retrospective	213	CAP	28-day mortality and need for intensive care	No correlation with mortality. PCT ≥ 10ng/mL was associated with a higher probability of need for intensive care	Semiquantitative measurement
Huang et al.⁽²⁹29 Huang DT, Weissfeld LA, Kellum JA, Yealy DM, Kong L, Martino M, Angus DC; GenIMS Investigators. Risk prediction with procalcitonin and clinical rules in community-acquired pneumonia. Ann Emerg Med. 2008;52(1):48-58.e2.⁾	2008	United States	Multicenter, prospective cohort	1,651	CAP	30-day mortality	Low PCT values (< 0.1ng/mL) were associated with lower mortality in high-risk patients (Negative LR of 0.09)	Large sample size. Wide confidence interval
Krüger et al.⁽³⁰30 Krüger S, Ewig S, Marre R, Papassotiriou J, Richter K, von Baum H, Suttorp N, Welte T; CAPNETZ Study Group. Procalcitonin predicts patients at low risk of death from community-acquired pneumonia across all CRB-65 classes. Eur Respir J. 2008;31(2):349-55.⁾	2008	Germany	Multicenter, prospective cohort	1,671	CAP	28-day mortality Correlation with CRP, WBC, and CURB-65	Accuracy similar to that of CURB-65. Positive correlation with 28-day mortality. Identification of patients with low risk of death	Large sample size but few high-risk patients
Schuetz et al.⁽³¹31 Schuetz P, Suter-Widmer I, Chaudri A, Christ-Crain M, Zimmerli W, Mueller B; Procalcitonin-Guided Antibiotic Therapy and Hospitalisation in Patients with Lower Respiratory Tract Infections (ProHOSP) Study Group. Prognostic value of procalcitonin in community-acquired pneumonia. Eur Respir J. 2011;37(2):384-92⁾	2011	Switzerland	Multicenter, retrospective	925	CAP	30-day mortality Adverse events in 30 days	Initial levels were weak predictors of mortality (AUC: 0.6). Sequential levels were more useful in predicting adverse events	Large sample size, sequential measurements
Ramirez et al.⁽³²32 Ramírez P, Ferrer M, Martí V, Reyes S, Martínez R, Menéndez R, et al. Inflammatory biomarkers and prediction for intensive care unit admission in severe community-acquired pneumonia. Crit Care Med. 2011;39(10):2211-7.⁾	2011	Spain	Bicenter, prospective cohort	685	CAP	Admission to intensive care	PCT < 0.35ng/dL safely ensured the lack of need of intensive care for severe CAP	Patients with higher severity criteria were excluded
Kutz et al.⁽³³33 Kutz A, Briel M, Christ-Crain M, Stolz D, Bouadma L, Wolff M, et al. Prognostic value of procalcitonin in respiratory tract infections across clinical settings. Crit Care. 2015;19:74⁾	2015	Switzerland	Systematic review and meta-analysis	2,065	CAP	30-day mortality Treatment failure	PCT < 0.25ng/dL with VPN of 89.2% for treatment failure and 97.5% for mortality	Secondary analysis of clinical trials. Without observational data
Park et al.⁽³⁴34 Park JH, Wee JH, Choi SP, Oh SH. The value of procalcitonin level in community-acquired pneumonia in the ED. Am J Emerg Med. 2012;30(7):1248-54.⁾	2012	South Korea	Single-center, prospective	126	CAP	28-day mortality	AUC of 0.82. Addition of prediction to classical scores	Small sample size

Author	Year	Country	Study design	Sample size (N)	Inclusion criteria	Outcomes	Results	Observations
Andrijevic et al.⁽³⁵35 Andrijevic I, Matijasevic J, Andrijevic L, Kovacevic T, Zaric B. Interleukin-6 and procalcitonin as biomarkers in mortality prediction of hospitalized patients with community acquired pneumonia. Ann Thorac Med. 2014;9(3):162-7.⁾	2014	Serbia	Single-center, prospective cohort	101	CAP	30-day mortality	Weak predictor of mortality (AUC: 0.66). PCT > 2.56ng/mL with sensitivity of 76% and specificity of 61.8%	Small sample size
Kasamatsu et al.⁽³⁶36 Kasamatsu Y, Yamaguchi T, Kawaguchi T, Tanaka N, Oka H, Nakamura T, et al. Usefulness of a semi-quantitative procalcitonin test and the A-DROP Japanese prognostic scale for predicting mortality among adults hospitalized with community-acquired pneumonia. Respirology. 2012;17(2):330-6.⁾	2012	Japan	Single-center, prospective cohort	170	CAP	30-day mortalitys	AUC of 0.8. Correlation with PSI (0.56) and CURB-65 (0.58)	Semiquantitative measurement
Menéndez et al.⁽³⁷37 Menéndez R, Cavalcanti M, Reyes S, Mensa J, Martinez R, Marcos MA, et al. Markers of treatment failure in hospitalised community acquired pneumonia. Thorax. 2008 May;63(5):447-52.⁾	2008	Spain	Bicenter, prospective cohort	453	CAP	Treatment failure (septic shock, mechanical ventilation, or death)	High PCT on day 1 as good predictor of early failure (OR of 2.7). Decreased levels had a strong VPN (0.95)	Cutoff values were not defined

Author	Year	Country	Study design	Sample size (N)	Inclusion criteria	Outcomes	Results	Observations
Shi et al.⁽³⁸38 Shi Y, Xu YC, Rui X, Zhang HM, Wang Y, Du W. Procalcitonin kinetics and nosocomial pneumonia in older patients. Respir Care. 2014;59(8):1258-66.⁾	2014	China	Single-center, prospective cohort	60	Nosocomial pneumonia	Clinical efficacy and microbiological response	No correlations with absolute PCT values. PCT kinetics was the best single indicator of clinical efficacy (AUC: 0.79)	Older people
Boussekey et al.⁽³⁹39 Boussekey N, Leroy O, Alfandari S, Devos P, Georges H, Guery B. Procalcitonin kinetics in the prognosis of severe community-acquired pneumonia. Intensive Care Med. 2006;32(3):469-72.⁾	2006	France	Single-center, prospective cohort	100	Severe CAP	Mortality in the ICU	Increased PCT levels on days 1 to 3 were associated with mortality (OR: 4.539)	Semiquantitative measurement
Rammaert et al.⁽⁴⁰40 Rammaert B, Verdier N, Cavestri B, Nseir S. Procalcitonin as a prognostic factor in severe acute exacerbation of chronic obstructive pulmonary disease. Respirology. 2009;14(7):969-74.⁾	2009	France	Single-center, prospective cohort	116	Exacerbated COPD	Mortality in the ICU	PCT was independently associated with mortality (HR 1.01; 1.00 - 1.03)	Only patients who underwent invasive ventilation were included
Bloos et al.⁽⁴¹41 Bloos F, Marshall JC, Dellinger RP, Vincent JL, Gutierrez G, Rivers E, et al. Multinational, observational study of procalcitonin in ICU patients with pneumonia requiring mechanical ventilation: a multicenter observational study. Crit Care. 2011;15(2):R88.⁾	2011	Canada United States Europe	Multicenter, prospective cohort	175	CAP and nosocomial pneumonia, including VAP	28-day mortality	AUC of 0.70 and 0.74 as initial and maximum PCT levels. Cutoff PCT values of 1.1ng/mL (OR, 7.0; 95%CI, 2.6 - 25.2) and 7.8ng/mL (OR, 5.7; 95%CI, 2.5 -13.1), respectively	Semiquantitative measurement. Wide confidence interval for cutoff values
Kutz et al.⁽³³33 Kutz A, Briel M, Christ-Crain M, Stolz D, Bouadma L, Wolff M, et al. Prognostic value of procalcitonin in respiratory tract infections across clinical settings. Crit Care. 2015;19:74⁾	2015	Switzerland	Systematic review and meta-analysis	598	CAP, nosocomial pneumonia, including VAP and other	30-day mortality. Treatment failure	No correlation found. AUC of 0.50 (95%CI, 0.44 - 0.56) OR of 1.05 (95%CI, 0.81 - 1.37)	Secondary analysis of clinical trials. Without observational data
Luyt et al.⁽⁴²42 Luyt CE, Guérin V, Combes A, Trouillet JL, Ayed SB, Bernard M, et al. Procalcitonin kinetics as a prognostic marker of ventilator-associated pneumonia. Am J Respir Crit Care Med. 2005;171(1):48-53.⁾	2005	France	Single-center, prospective cohort	63	VAP	Combined outcome: 28-day mortality, VAP recurrence, or extrapulmonary infection	PCT levels on days 1, 3 and 7 were strong predictors of poor outcome (OR: 12.3 on day 1 and 64.22 on day 7)	Small sample size. High incidence rate for the outcome
Seligman et al.⁽⁴³43 Seligman R, Meisner M, Lisboa TC, Hertz FT, Filippin TB, Fachel JM, et al. Decreases in procalcitonin and C-reactive protein are strong predictors of survival in ventilator-associated pneumonia. Crit Care. 2006;10(5):R125.⁾	2006	Brazil	Single-center, prospective cohort	71	VAP	28-day mortality	PCT kinetics was an independent associated factor (OR, 4.43; 95%CI, 43.44 - 59.03)	Small sample size and wide confidence interval
Hillas et al.⁽⁴⁴44 Hillas G, Vassilakopoulos T, Plantza P, Rasidakis A, Bakakos P. C-reactive protein and procalcitonin as predictors of survival and septic shock in ventilator-associated pneumonia. Eur Respir J. 2010;35(4):805-11.⁾	2010	Greece	Single-center, prospective cohort	45	VAP	28-day mortality and septic shock	AUC for mortality on day 1 of 0.79 (0.66 - 0.92) and 0.88 on day 7 (0.77 - 0.99). No correlation in the multivariate analysis	Small sample size
Boeck et al.⁽⁴⁵45 Boeck L, Eggimann P, Smyrnios N, Pargger H, Thakkar N, Siegemund M, et al. Midregional pro-atrial natriuretic peptide and procalcitonin improve survival prediction in VAP. Eur Respir J. 2011;37(3):595-603.⁾	2011	United States Switzerland	Multicenter, prospective cohort	101	VAP	28-day mortality	PCT on admission was higher among non-survivors (1.36 versus 0.58ng/mL; p = 0.017)	Secondary outcome
Tanriverdi et al.⁽⁴⁶46 Tanriverdi H, Tor MM, Kart L, Altin R, Atalay F, SumbSümbüloglu V. Prognostic value of serum procalcitonin and C-reactive protein levels in critically ill patients who developed ventilator-associated pneumonia. Ann Thorac Med. 2015;10(2):137-42.⁾	2015	Turkey	Single-center, prospective cohort	45	VAP	28-day mortality	PCT > 1ng/mL on day 3 was the strongest predictor (OR, 5.95; 95%CI, 1.58 - 22.32)	Small sample size. Wide confidence interval

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[1] Corresponding author: Vandack Nobre, Rua Padre Rolim, 383/1.601 - Santa Efigênia, Zip code: 30130-090 - Belo Horizonte (MG), Brazil, E-mail: vandack@gmail.com

Add 1 point for each variable present:
New mental confusion Urea > 42mg/dL Respiratory rate ≥ 30irpm SBP < 90mmHg or DBP ≤ 60mmHg Age ≥ 65 years
Classification	Mortality %	Recommendation
0	0.7	Low risk - outpatient treatment
1	3.2	Low risk - outpatient treatment
2	13.0	Intermediate risk - observation
3	17.0	Severe - hospitalization
4	41.5	Severe - hospitalization
5	57.0	Very severe - ICU

Consider the total sum of the points:
Age: Men - age = score Women - age -10 = score Nursing home resident: + 10 Neoplastic disease: + 30 Liver disease: + 20 Congestive heart failure: + 10 Cerebrovascular disease: + 10 Kidney disease: + 10 Altered mental status: + 20 RR > 30bpm: + 20 SBP < 90mmHg: + 20 Axillary temperature < 35 or > 40°C: + 15 HR > 125bpm: + 10 Arterial pH < 7.35: + 30 Urea > 78mg/dL: + 20 Sodium < 130mEq/L: + 20 Glucose > 250mg/dL: + 10 Hematocrit < 30%: + 10 PaO₂ < 60mmHg: + 10 Pleural effusion: + 10
Classification	Mortality %	Recommendation
I - No points	0.1-0.4	Outpatient treatment
II - < 70	0.6-0.7	Outpatient treatment
III - 70-90	0.9-2.8	Observation
IV - 90-130	8.5-9.3	Hospitalization
V - > 130	27.0-31.0	Hospitalization