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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 5  |  Page : 229-233

Serum procalcitonin as an early inflammatory marker in pediatric ventilator-associated pneumonia: A prospective observational study


1 Department of Pediatrics, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. RML Hospital, New Delhi, India
2 Department of Microbiology, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. RML Hospital, New Delhi, India

Date of Submission29-Jun-2021
Date of Decision02-Sep-2021
Date of Acceptance06-Sep-2021
Date of Web Publication28-Sep-2021

Correspondence Address:
Dr. Manju Nimesh
Department of Pediatrics, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. RML Hospital, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpcc.jpcc_55_21

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  Abstract 


Background: Delayed diagnosis of ventilator-associated pneumonia (VAP) in pediatric patients is associated with accentuated risk of morbidities and mortality. Early diagnosis of VAP is challenging. Serum procalcitonin has been proposed as a promising inflammatory marker for the early diagnosis of VAP, but there is a lack of sufficient evidence for the use of serum procalcitonin for early diagnosis of VAP in children. The present study was conducted to determine the role of serum procalcitonin as an early inflammatory marker for an early and provisional diagnosis of VAP among clinically suspected VAP patients in pediatric intensive care unit settings.
Subjects and Methods: Seventy-nine pediatric patients (age: 1 month–18 years) with suspected VAP (Simplified Clinical Pulmonary Infection Score >6) were prospectively evaluated with quantitative bronchoalveolar lavage cultures and simultaneously tested for serum procalcitonin levels. Two groups were identified based on culture results and comparatively evaluated for procalcitonin levels, its diagnostic efficacy, antibiotic usage patterns, and mechanical ventilation duration.
Results: The VAP group had 39 patients, and the non-VAP group had 40 patients. Thirty-two (82%) patients in the VAP group had a procalcitonin value ≥10 ng/ml as against 10 (25%) from the non-VAP group. Two (5.1%) patients in the VAP group had procalcitonin levels ≤1 ng/ml as against 21 (52.5%) patients in the non-VAP group. The receiver operating characteristic area under curve for procalcitonin with a cutoff >10 ng/ml was 0.785 (95% confidence interval = 0.678–0.870) with a sensitivity of 82.05% and specificity of 75%.
Conclusions: Serum procalcitonin is a reliable biomarker to augment the provisional diagnosis of VAP in clinically suspected cases. Such diagnosis may help in an early institution of definitive therapy for VAP.

Keywords: Bronchoalveolar lavage, serum biomarker, serum procalcitonin, Simplified Clinical Pulmonary Infection Score, ventilator-associated pneumonia


How to cite this article:
Nandan D, Nimesh M, Kumar S, Manik L, Sudarshan J, Duggal N. Serum procalcitonin as an early inflammatory marker in pediatric ventilator-associated pneumonia: A prospective observational study. J Pediatr Crit Care 2021;8:229-33

How to cite this URL:
Nandan D, Nimesh M, Kumar S, Manik L, Sudarshan J, Duggal N. Serum procalcitonin as an early inflammatory marker in pediatric ventilator-associated pneumonia: A prospective observational study. J Pediatr Crit Care [serial online] 2021 [cited 2021 Oct 16];8:229-33. Available from: http://www.jpcc.org.in/text.asp?2021/8/5/229/326866




  Introduction Top


Ventilator-associated pneumonia (VAP) is a major hospital-acquired infection that accentuates morbidities in an already sick child and negatively impacts recovery and prognosis. VAP is associated with prolonged ventilation, prolonged intensive care unit (ICU) and hospital length of stay, increased antibiotic use, and increased health-care costs.[1]

Early identification of an evolving VAP helps in the early optimization of antibiotic therapy and correlates with early weaning from mechanical ventilation.[2] Microbial isolation from the bronchoalveolar fluid is considered as confirmatory of VAP, but reliance on culture results delayed clinical actions due to time constraints with results.[3] Clinical scores have been proposed as diagnostic and prognostic scores but with significant interobserver variability and may pose a challenge in a variety of situations like Acute Respiratory Distress Syndrome (ARDS).[3],[4]

Serum procalcitonin has been proposed as an early inflammatory marker of pediatric VAP and an objective tool with prompt test results to guide antibiotic therapy in the intubated patient. Pediatric literature is scarce in assessing the use of serum procalcitonin for a provisional diagnosis of pediatric VAP in clinically suspected patients and its role in guiding antibiotic therapy for VAP.

An observational study was conducted among clinically suspected VAP cases confirmed by bronchoalveolar lavage (BAL) culture by evaluating their serum procalcitonin levels and their diagnostic relevance as an early inflammatory marker, antibiotic usage pattern, and mechanical ventilation duration.


  Materials and Methods Top


A prospective observational study was conducted at the pediatric ICU (PICU) of a teaching hospital from November 2017 to April 2019. Ethical clearance was obtained from the Institutional Ethical Committee (No. TP[MD/MS][23/2017] IEC/PGIMER/RMLH/1706/17 dated October 30, 2017), and informed consent was taken from parents/guardians.

Pediatric patients in the age group of 1 month to 18 years requiring mechanical ventilation were included in the study. Standard of care was provided to all patients as necessitated by their primary disease. Patients with a primary diagnosis of pneumonia or Simplified Clinical Pulmonary Infection Score (SCPIS) values >6 at the commencement of mechanical ventilation, SCPIS ≥6 within 48 h of mechanical ventilation, fatality within 48 h, and baseline serum procalcitonin levels >1 ng/ml were excluded to avert the compounding effect of the primary clinical entity on the diagnosis of an evolving VAP [Figure 1]. Patients with CPIS ≥6 on presentation or with 48 h of admission to PICU were presumed to be having VAC. This subgroup was considered as a potential confounder for detection of newly evolving VAC and was excluded.
Figure 1: Patient flow diagram. PICU: Pediatric intensive care unit, VAP: Ventilator-associated pneumonia, Simplified CPIS: Simplified Clinical Pulmonary Infection Score, CFU: Colony-forming units

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Baseline serum procalcitonin level and SCPIS were recorded for all patients immediately on commencement of mechanical ventilation. SCPIS scoring was done every morning by the same observer in all children. Children with SCPIS progressing to >6 after 48 h were clinically suspected of VAP.[5],[6]

BAL samples were obtained within 2 h of clinical suspicion of VAP and examined by quantitative bacterial cultures. BAL samples were obtained under strict aseptic precautions using flexible fiber-optic bronchoscopy using topical airway anesthesia. Culture results with ≥105 colony-forming unit count/ml were considered significant, and these patients were categorized as a microbiologically confirmed group (VAP group). Children with negative culture or <105 colony-forming unit count/ml reports were counted in the microbiologically unconfirmed group (non-VAP group).[7],[8]

Serum procalcitonin levels were tested in all patients within 2 h of clinically suspecting VAP. The human procalcitonin enzyme-linked immunosorbent assay (ELISA) kit (BioVendor, Brno, Czech Republic) was used for the in vitro semiquantitative determination of serum PCT levels. Patients were divided into two groups for serum procalcitonin levels with values <10 ng/ml and ≥10 ng/ml. The rising trend of serum procalcitonin value with values ≥10 ng/ml in the presence of SCPIS ≥6 was considered a significant clinical event. Threshold values of serum procalcitonin were kept at 10 ng/ml to negate the effect of the primary disease entity and were interpreted in concurrence with rising SCPIS values.[7],[9] Culture results were comparatively evaluated with procalcitonin levels and its diagnostic efficacy. Antibiotic usage patterns and mechanical ventilation duration were also evaluated as secondary outcome measures for surviving patients.

Patients with a primary diagnosis of pneumonia and preexisting diagnosis of infection were considered potential confounders. Suitable clinical and investigations were done to exclude such diagnoses including baseline serum procalcitonin levels. Any subtle pulmonary infection may masquerade as an evolving VAP.

Statistical analysis was done using the Statistical Package for the Social Sciences (SPSS) version 20.0 (IBM SPSS, SPSS Inc., Chicago, IL, USA). Categorical data were expressed as numbers (proportions) and continuous variables as mean (standard deviation [SD]). Quantitative variables were compared using Mann–Whitney test. Qualitative variables were correlated using the Chi-Square test/Fisher's exact test. Receiver operating characteristic (ROC) curve was used to find out the cutoff point of parameters for predicting VAP. Statistical significance was set at a probability level of 0.05.


  Results Top


A total of 410 patients were admitted to our PICU during the study period. Of these, 331 patients were excluded based on inclusion and exclusion criteria, and therefore, 79 patients were included in the final study analysis [Figure 1]. The indications of mechanical ventilation and other baseline characteristics are depicted in [Table 1]. The median duration for threshold SCPIS was 5.46 ± 1.88 days in the VAP group and 5.25 ± 6.05 days in non-VAP patients (P = 0.124).
Table 1: Clinical characteristics of patients with suspected ventilator-associated pneumonia*

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BAL fluid culture was positive in 39 patients (49.4%, VAP group), while it was negative in 40 patients (50.6%, non-VAP group). Serum procalcitonin values less than ≤1 ng/ml were detected in 23 patients (29.1%; VAP group – 2 and non-VAP group – 21). Procalcitonin value between 1 and 10 ng/ml was detected in 14 patients (17.7%; VAP group – 5 and non-VAP group – 9) and serum procalcitonin value ≥10 ng/ml (significant clinical event) was detected in 53.2% cases (n = 42; VAP group – 32 and non-VAP group – 10).

82.1% of the patients in the VAP group (n = 32) had serum procalcitonin levels ≥10 ng/ml as against 25% of the patients in the non-VAP group (n = 10). 5.1% of the patients (n = 2) in the VAP group had serum procalcitonin levels <1 ng/ml as against 52.5% of the patients (n = 21) in the non-VAP group.

Operator characteristics of SCPIS and serum procalcitonin levels were analyzed against microbiologically confirmed VAP. The ROC curve for SCPIS was drawn to confirm the VAP. The area under curve (AUC) for SCPIS was 0.564 (95% confidence interval [CI] = 0.448–0.675). The optimal cutoff value of >6 had a sensitivity of 79.5% and a specificity of 37.5% [Figure 2]. While, the ROC AUC for procalcitonin with a cutoff >10 ng/ml was 0.785 (95% CI = 0.678–0.870) with a sensitivity of 82.1% and specificity of 75.0% [Figure 2]b.
Figure 2: (a) Receiver operative characteristic curve for Simplified Clinical Pulmonary Infection Score for diagnosis of ventilator-associated pneumonia. (b) Receiver operative characteristic curve for serum procalcitonin levels for diagnosis of ventilator-associated pneumonia

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The mean duration of mechanical ventilation was significantly higher in the VAP group (14.31 ± 10.34 days) than in the non-VAP group (5.68 ± 1.95 days) (P = 0.0001). The mean antibiotic use after clinical suspicion was also significantly higher for the VAP group (23.69 ± 12.64 days) as against the non-VAP group (12.1 ± 6.94 days) (P = 0.0001).


  Discussion Top


Our study assessed the utility of serum procalcitonin as a biomarker for pediatric VAP and identified a potential cutoff value for early detection of VAP pediatric patients. Serum procalcitonin can act as a primary screening investigation for the diagnosis of VAP in pediatric patients with prudent test qualities such as the ease of sampling, prompt results, and optimal sensitivity. Its values correlate with antibiotic use and mechanical ventilation span. The inclusion of procalcitonin in diagnostic and therapeutic protocols of VAP may guide in reducing antibiotic exposure and VAP-associated morbidities.

Tsao et al. concluded in their meta-analysis that serum procalcitonin values between ≥1 ng/ml have been associated with ongoing infection in the mechanically ventilated child. Sole reliance on this value may result in overdiagnosis of infective VAP, especially with lower range values.[10] The present study found that the rising trend of serum procalcitonin values more than 10 ng/ml in combination with SCPIS has optimally high sensitivity and specificity for infection. Combined use negates the effect of non-VAP clinical entities concurrently raising serum procalcitonin levels. It can be used as a screening test for VAP, which has clear advantage of prompt and objective results.

The SCPIS has been found to have optimal screening value but with very high false-positive rates and variable amounts of interobserver variability, thereby affecting uniform clinical applications.[6],[7] Our results also depicted the same finding of SCPIS with a very high rate of false-positive rates due to disproportionate sensitivity of 79.19% and specificity of 37.5%. The addition of serum procalcitonin in the screening array for pediatric VAP doubled the specificity. SCPIS deployment for clinical suspicion of VAP in pediatric patients obviates the need for tedious scores like CPIS.

There are mixed observations regarding biomarker-based antibiotic stewardship in pediatric VAP. Schuetz et al. concluded in their meta-analysis that procalcitonin-guided antibiotic strategy can reduce antibiotic exposure and side effects, and improves survival.[11] Hauang et al. did not find any association of antibiotic duration with serum procalcitonin essays.[12] Higher procalcitonin levels were associated with prolonged antibiotic use and longer mechanical ventilation. Truly infective VAP required prolonged antibiotic therapy and reflected in the biomarker-guided provisional diagnosis of VAP. Lesser antibiotic needs in the non-VAP group pointed toward noninfective etiology of rising SCPIS in the group.[11],[12],[13],[14] Empirical antibiotics may be started on the provisional diagnosis of VAP using a combination of simplified VAP and raised procalcitonin levels. Its exact clinical relevance to optimize antibiotic use during mechanical ventilation will require specific clinical investigations.

The number of patients with serum procalcitonin values between 1 ng/ml and 10 ng/ml was too less to draw a statistical conclusion. Small sample size and unblinded intervention limited its statistical value for detailed analysis of each subgroup. Complete exclusion of extrapulmonary infection and subclinical pulmonary infection may not be possible in all cases, which may lead to bias of false-positive diagnosis of VAP using serum procalcitonin essay. A multicenter, double-blinded, randomized control trial with a large sample size may help in deciphering the exact combined clinical utility of serum procalcitonin and SCPIS and avoiding small sample size-related biases.


  Conclusions Top


Serum procalcitonin was found to be elevated in children with VAP in our study. Serum procalcitonin could be a promising biomarker in the early diagnosis of VAP in critically ill children. A multicenter, randomized control trial with a large sample size may help in deciphering the combined clinical utility of serum procalcitonin and SCPIS in early diagnosis of VAP in children.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Chang I, Schibler A. Ventilator associated pneumonia in children. Paediatr Respir Rev 2016;20:10-6.  Back to cited text no. 1
    
2.
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Venkatachalam V, Hendley JO, Willson DF. The diagnostic dilemma of ventilator-associated pneumonia in critically ill children. Pediatr Crit Care Med 2011;12:286-96.  Back to cited text no. 3
    
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Gauvin F, Dassa C, Chaïbou M, Proulx F, Farrell CA, Lacroix J. Ventilator-associated pneumonia in intubated children: Comparison of different diagnostic methods. Pediatr Crit Care Med 2003;4:437-43.  Back to cited text no. 4
    
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da Silva PS, de Aguiar VE, de Carvalho WB, Machado Fonseca MC. Value of clinical pulmonary infection score in critically ill children as a surrogate for diagnosis of ventilator-associated pneumonia. J Crit Care 2014;29:545-50.  Back to cited text no. 5
    
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Sachdev A, Chugh K, Sethi M, Gupta D, Wattal C, Menon G. Clinical pulmonary infection score to diagnose ventilator-associated pneumonia in children. Indian Pediatr 2011;48:949-54.  Back to cited text no. 6
    
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Iosifidis E, Pitsava G, Roilides E. Ventilator-associated pneumonia in neonates and children: A systematic analysis of diagnostic methods and prevention. Future Microbiol 2018;13:1431-46.  Back to cited text no. 7
    
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Srinivasan R, Asselin J, Gildengorin G, Wiener-Kronish J, Flori HR. A prospective study of ventilator-associated pneumonia in children. Pediatrics 2009;123:1108-15.  Back to cited text no. 8
    
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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;59:564-73.  Back to cited text no. 9
    
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Tsou PY, Rafael J, Ma YK, Wang YH, Raj S, Encalada S, et al. Diagnostic accuracy of procalcitonin for bacterial pneumonia in children - A systematic review and meta-analysis. Infect Dis (Lond) 2020;52:683-97.  Back to cited text no. 10
    
11.
Schuetz P, Muller B, Christ-Crain M, Stolz D, Tamm M, Bouadma L, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Evid Based Child Health 2013;8:1297-371.  Back to cited text no. 11
    
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Huang DT, Yealy DM, Filbin MR, Brown AM, Chang CH, Doi Y, et al. Procalcitonin-guided use of antibiotics for lower respiratory tract infection. N Engl J Med 2018;379:236-49.  Back to cited text no. 12
    
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Kumar V. Ventilator associated pneumonia in children: Current status and future prospects. Indian J Pediatr 2018;85:830-1.  Back to cited text no. 13
    
14.
Schuetz P, Albrich W, Christ-Crain M, Chastre J, Mueller B. Procalcitonin for guidance of antibiotic therapy. Expert Rev Anti Infect Ther 2010;8:575-87.  Back to cited text no. 14
    


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