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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 13  |  Issue : 3  |  Page : 173-177

Diagnostic value of procalcitonin for differentiation between bacterial infection and noninfectious inflammation in febrile children with systemic autoimmune diseases


Department of Pediatrics Unit II, Christian Medical College, Vellore, Tamil Nadu, India

Date of Web Publication21-Aug-2018

Correspondence Address:
Dr. Sathish Kumar
Department of Paediatrics Unit II, Christian Medical College, Vellore - 632 004, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_54_18

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  Abstract 


Objectives: The objective of this study is to determine the diagnostic value of procalcitonin (PCT) for differentiation between bacterial infection and noninfectious inflammation in febrile children with systemic autoimmune disease.
Methods: It was a cross-sectional study and children with systemic autoimmune disease such as systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA) presenting with fever (>38°C) were recruited.
Results: Out of 24 children included, 16 had SLE (11 in disease flare group and 5 in infection group) and 8 had disease flare of Systemic JIA. Two children in SLE infection group died. Mean PCT was 92.2 ng/ml in SLE infectious group and 3.50 ng/ml in SLE flare group which was statistically significant (P = 0.009). However, the mean C-reactive protein was 98 mg/dl in SLE infectious group and 52 mg/dl in SLE flare group which was not statistically significant (P = 0.25). PCT concentration cutoff value >1.2 ng/ml has the sensitivity of 83% (95% confidence interval [CI] 43.6–0.97) and specificity of 72% (95% CI 49.1–87.5), positive predictive value of 50% (95% CI 23.6–76.3) and negative predictive value 93% (95% CI 68.5–98.7).
Conclusions: PCT levels >1.2 ng/ml in febrile SLE patients should point to a bacterial infection, whereas PCT levels <1.2 ng/ml might indicate disease flare that could reduce unnecessary antibiotic use. PCT may serve as a useful marker for the detection of systemic bacterial infection in patients with the systemic autoimmune disease.

Keywords: Procalcitonin, systemic autoimmune disease, systemic juvenile idiopathic arthritis, systemic lupus erythematosus


How to cite this article:
Loganathan S, Kumar S. Diagnostic value of procalcitonin for differentiation between bacterial infection and noninfectious inflammation in febrile children with systemic autoimmune diseases. Indian J Rheumatol 2018;13:173-7

How to cite this URL:
Loganathan S, Kumar S. Diagnostic value of procalcitonin for differentiation between bacterial infection and noninfectious inflammation in febrile children with systemic autoimmune diseases. Indian J Rheumatol [serial online] 2018 [cited 2019 Oct 17];13:173-7. Available from: http://www.indianjrheumatol.com/text.asp?2018/13/3/173/238100




  Introduction Top


Children with active autoimmune diseases are immunocompromised through the disease, as well as through immunosuppressive therapy, and therefore are at high risk of developing severe systemic infections. Fever is one the major manifestations for both flare and infection. In these children, however, the differential diagnosis between active autoimmune disease and invasive infection is often difficult. Managing both these conditions is difficult without knowing the proper diagnosis.

In autoimmune disease, differentiating the disease flare and infection is difficult in view of similar clinical presentation and laboratory findings. Total white blood cell count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) are not always useful to differentiate, because these markers are not only elevated during disease flares but also elevated during infection.

Procalcitonin (PCT), a 116 amino acid protein, with molecular weight of 13 KDa, the precursor in the synthesis of calcitonin, is a calcium-regulating peptide with a role in calcium homeostasis. Calcitonin production results from transcription of CALC-1 gene which in a normal individual is a restricted to neuroendocrine cells, mainly C cells of the thyroid gland.[1],[2] PCT production during infection is considered to be extra thyroidal in view of demonstrate its production in the lung, liver, pancreas, colon, and other organs. PCT is an acute phase reactant which is increased during inflammatory stimuli and infections.[3],[4],[5],[6] In 2015, Song et al. published a meta-analysis which demonstrates that PCT is more specific and has better diagnostic accuracy than CRP for bacterial infection in systemic rheumatic diseases.[7]

We conducted this study to evaluate whether PCT will be a better acute phase reactant to differentiate disease flare and infection, PCT compared with other acute phase reactants.


  Methods Top


Children with systemic autoimmune disease who presented to us with fever were recruited From the recruited children blood samples were collected for complete blood count, ESR, CRP, PCT, serum creatinine, serum complements, and anti-double stranded DNA and blood culture. Children with systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA) admitted with fever received parenteral ceftriaxone and amikacin after blood culture.

Chest radiograph and urine analysis were done based on the clinical scenario. Disease activity was measured using the SLE disease activity index (SLEDAI) scores for SLE.[8] Lupus flare was defined as an increase of more than three points compared to the patient's previous score. For children with JIA, Wallace criteria [9] were used to define flare.

All children with systemic autoimmune diseases presented with fever were divided into two groups either disease flare or infection based on final diagnosis.

Statistical methods

All categorical variables were presented using the frequencies and percentages. For continuous variables, results of descriptive statistics were expressed as mean ± standard deviation and median (range). Comparisons of continuous variables were carried out using Student's t-test or Mann–Whitney test; for categorical variables, the Chi-square statistics was used. Continuous variables were described as median and interquartile range and categorical variables as absolute and relative (%) frequencies.

The accuracies of PCT, CRP, and ESR to diagnose a bacterial infection were evaluated with sensitivity, specificity, and positive and negative predictive values (NPVs). For PCT and CRP, this accuracy was evaluated at different thresholds. Receiver operating characteristic (ROC) curves were plotted for PCT and CRP levels, and the overall diagnostic accuracy of each test was assessed by calculating the area under the ROC curve (AUC). Two-sided P < 0.05 was considered statistically significant. Data analysis was done with SPSS (Version 17.0, SPSS Inc., IBM Corporation, USA).

Ethical approval

This study was approved by the Research and Ethics Committee of our institution. Informed written consent from parents of all children were obtained. In addition assent from children above the 8 years was also obtained.


  Results Top


In this study, a total of 24 children were recruited as per inclusion criteria. Out of 24 children, 16 had SLE (11 in disease flare group and 5 in infection group) and 8 had disease flare of Systemic JIA as shown in [Table 1].
Table 1: The demographic details of children with systemic autoimmune diseases

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The common age group was between 8 and 10 years (35%) followed by 5–7 years group (26%).

Out of 24 children, 19 (79%) were girls and 5 (21%) were boys. Of 16 children with SLE 14 (88%) were girls and 2 (12%) were boys. In JIA patient group, 5 (63%) were girls and 3 (37%) were boys.

Mean PCT was 92.2 ng/ml in SLE infectious group and 3.50 ng/ml in SLE flare group which was statistically significant (P = 0.009). However, mean CRP was 98 mg/dl in SLE infectious group and 52 mg/dl in SLE flare group which was not statistically significant (P = 0.25) [Figure 1].
Figure 1: Mean C-reactive protein and procalcitonin levels in children with systemic lupus erythematosus disease flare and infection

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For detecting bacterial infection, the AUC (0.822), sensitivity (83%), and specificity (72.2%) of PCT at the value of >1.2 ng/mL cutoff value were significantly better than those of CRP the AUC (0.611), sensitivity (83.3%), and specificity (44.4%) as revealed in [Figure 2].
Figure 2: Predictive value of C-reactive protein and procalcitonin for detecting infection by calculating the area under the receiver operating characteristic curve in febrile patients with systemic lupus erythematosus

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As for infections, serum PCT concentration (cutoff value >1.2 ng/ml) gave a sensitivity of 83% (95% confidence interval [CI] 43.6–0.97), a specificity of 72% (95% CI 49.1–87.5), a positive predictive value (PPV) of 50% (95% CI23.6–76.3), and a NPV of 93% (95% CI 68.5–98.7) [Table 2].
Table 2: Cutoff values, sensitivity, specificity, negative, and positive predictive value of procalcitonin, CRP and ESR

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To achieve the same sensitivity (as of PCT) of 83%, the cutoff value for CRP was 34 mg/dl and ESR was 76 mm/h.

Out of five children in SLE with infection group, two died due to septicemia with multiorgan dysfunction.


  Discussion Top


We evaluated the role of PCT in children with systemic autoimmune disease. Our data confirm a role for PCT in discrimination between infectious and noninfectious etiology in febrile children with systemic autoimmune diseases.

We choose PCT as biomarker as it is not influenced by disease flare or viral infection. It has good sensitivity to diagnose the bacterial infection. Serum PCT is not influenced by kidney function and is normally undetectable (<0.1 ng/ml) in a well-child. PCT increases in initial 6 h and maintains a plateau for more than a day.[10]

Studies performed in patients affected by various systemic autoimmune diseases showed that PCT levels in patients with an underlying infection are generally higher than those with disease flare.[11],[12] Like our observation, Shin et al.[10] reported in a series of 19 febrile SLE patients a significant elevation of PCT levels in patients with nonviral infection, compared with patients with viral infection and with the control group.

In 1997, Eberhard [13] in a series of 18 SLE patients without infection and 35 patients with systemic antineutrophil cytoplasmic antibody-associated vasculitis (11 of whom were infected), reported that PCT increased in patients with autoimmune disease with systemic infection. However, none of the SLE patients were infected. In our study, we confirmed the elevation of PCT values in children with systemic autoimmune disease presenting with fever and diagnosed to have infections. Sixteen (66%) children in our study group had SLE and eight (34%) systemic JIA. Out of 16 SLE children, 11 (69%) had disease flare and 5 (31%) had infections. None of the systemic JIA children had infection. Hence, most of our observations are applicable to SLE children.

The mean PCT was 92.2 ng/ml in SLE infectious group and 3.50 ng/ml in SLE flare group which was statistically significant (P = 0.009). However, mean CRP was 98 mg/dl in SLE infectious group and 52 mg/dl in SLE flare group which was not statistically significant (P = 0.25). Similarly, mean ESR level (38 mm/h) in SLE infectious group and in SLE flare group (66 mm/h) was not statistically significant (P = 0.35). Our results were similar to Bador's et al.[14] observation. Their analysis of flare patients showed that PCT (0.33 vs. 0.08 ng/ml, P = 0.019) but not CRP (3.20 vs. 0.77 mg/dl, P = 0.195) was higher with infection. Conversely, among remission patients, CRP (1.69 vs. 0.18 mg/dl, P = 0.036) but not PCT (0.14 vs. 0.05 ng/ml, P = 0.103) was higher with infection.

In our study, as for infections, we observed serum PCT concentration (cutoff value >1.2 ng/ml) gave a sensitivity of 83% (95% CI 43.6–0.97), a specificity of 72% (95% CI 49.1–87.5), a PPV of 50% (95% CI 23.6–76.3) and a NPV of 93% (95% CI 68.5–98.7). To achieve the same sensitivity (as of PCT) of 83%, the cutoff value for CRP was 34 mg/dl and ESR was 76 mm/hr. The low sensitivity of PCT at a threshold value of 0.5 ng/ml was previously demonstrated in the study by Lanoix et al.[15] using the same Brahms PCT assays. They reported that PCT was <0.5 ng/ml in all five patients who had systemic infection. The only raised PCT level occurred in a male patient with flare.

In our study, we observed PCT sensitivity was 83.3% as same compared to CRP (83.3%), specificity was 72.2% and high compared to CRP (33.3%) and high NPV (88.9%) compared to CRP (88.9%) and ESR (85.7%). Ho et al. observed PCT is a better marker compared to CRP to differentiate bacterial infection and SLE disease activity.[16] Bador et al. reported the same finding like our study that PCT is very good negative predictive with cut off value of 0.12 ng/ml to rule out bacterial infection.[14],[17]

In a meta-analysis, Wu et al. observed the AUC for PCT was 0.91 (95% [95% CI] 0.88–0.93). In our study, we observed the same finding for PCT (0.8).[18]

In our study, in a total of 16 patients, four patient's blood culture grew bacteria (one of each such as Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas, and Enterococcus). Candida grew in one blood culture. In contrast, Choi et al. observed candida is the most common opportunistic infection in SLE.[19]

In our study, two children with SLE with infection group died during hospitalization. In 2008, Quintana et al.[20] compared 21 SLE patients with SLEDAI ≤5 with 32 patients and with SLEDAI >5. PCT levels were not significantly different between the two groups (0.08 ng/ml vs. 0.418 ng/ml, normal levels <0.5). Only three of the 32 patients with SLEDAI >5 had abnormal PCT levels (>0.53 ng/ml), and none had severe sepsis (one had lobar pneumonia and one had urinary tract infection).

We suggest that the PCT level is the most discriminatory parameter, followed by CRP when evaluating febrile children with SLE. PCT levels >1.2 ng/ml in febrile patients with SLE should point to bacterial infection, whereas PCT levels <1.2 ng/ml might indicate noninfectious inflammation that could reduce unnecessary antibiotic use. Our study evaluated for the first time PCT in febrile pediatric patients with fever and systemic autoimmune disease. In this setting, PCT determination could be regarded as the better available test in identifying a possible infectious etiology and a useful laboratory tool in therapeutic decision-making.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C, et al. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 1993;341:515-8.  Back to cited text no. 1
    
2.
Müller B, Becker KL, Schächinger H, Rickenbacher PR, Huber PR, Zimmerli W, et al. Calcitonin precursors are reliable markers of sepsis in a medical Intensive Care Unit. Crit Care Med 2000;28:977-83.  Back to cited text no. 2
    
3.
Russwurm S, Stonans I, Stonane E, Wiederhold M, Luber A, Zipfel PF, et al. Procalcitonin and CGRP-1 mRNA expression in various human tissues. Shock 2001;16:109-12.  Back to cited text no. 3
    
4.
Müller B, White JC, Nylén ES, Snider RH, Becker KL, Habener JF, et al. Ubiquitous expression of the calcitonin-i gene in multiple tissues in response to sepsis. J Clin Endocrinol Metab 2001;86:396-404.  Back to cited text no. 4
    
5.
Nijsten MW, Olinga P, The TH, de Vries EG, Koops HS, Groothuis GM, et al. Procalcitonin behaves as a fast responding acute phase protein in vivo and in vitro. Crit Care Med 2000;28:458-61.  Back to cited text no. 5
    
6.
Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999;340:448-54.  Back to cited text no. 6
    
7.
Song GG, Bae SC, Lee YH. Diagnostic accuracies of procalcitonin and C-reactive protein for bacterial infection in patients with systemic rheumatic diseases: A meta-analysis. Clin Exp Rheumatol 2015;33:166-73.  Back to cited text no. 7
    
8.
Urowitz MB, Gladman DD. Measures of disease activity and damage in SLE. Baillieres Clin Rheumatol 1998;12:405-13.  Back to cited text no. 8
    
9.
Wallace CA, Ruperto N, Giannini E; Childhood Arthritis and Rheumatology Research Alliance, Pediatric Rheumatology International Trials Organization, Pediatric Rheumatology Collaborative Study Group, et al. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol 2004;31:2290-4.  Back to cited text no. 9
    
10.
Shin KC, Lee YJ, Kang SW, Baek HJ, Lee EB, Kim HA, et al. Serum procalcitonin measurement for detection of intercurrent infection in febrile patients with SLE. Ann Rheum Dis 2001;60:988-9.  Back to cited text no. 10
    
11.
Sitter T, Schmidt M, Schneider S, Schiffl H. Differential diagnosis of bacterial infection and inflammatory response in kidney diseases using procalcitonin. J Nephrol 2002;15:297-301.  Back to cited text no. 11
    
12.
Delèvaux I, André M, Colombier M, Albuisson E, Meylheuc F, Bègue RJ, et al. Can procalcitonin measurement help in differentiating between bacterial infection and other kinds of inflammatory processes? Ann Rheum Dis 2003;62:337-40.  Back to cited text no. 12
    
13.
Eberhard OK, Haubitz M, Brunkhorst FM, Kliem V, Koch KM, Brunkhorst R, et al. Usefulness of procalcitonin for differentiation between activity of systemic autoimmune disease (systemic lupus erythematosus/systemic antineutrophil cytoplasmic antibody-associated vasculitis) and invasive bacterial infection. Arthritis Rheum 1997;40:1250-6.  Back to cited text no. 13
    
14.
Bador KM, Intan S, Hussin S, Gafor AH. Serum procalcitonin has negative predictive value for bacterial infection in active systemic lupus erythematosus. Lupus 2012;21:1172-7.  Back to cited text no. 14
    
15.
Lanoix JP, Bourgeois AM, Schmidt J, Desblache J, Salle V, Smail A, et al. Serum procalcitonin does not differentiate between infection and disease flare in patients with systemic lupus erythematosus. Lupus 2011;20:125-30.  Back to cited text no. 15
    
16.
Ho WL, Lan JL, Chen DY, Chen YH, Huang WN, Hsieh TY, et al. Procalcitonin may be a potential biomarker for distinguishing bacterial infection from disease activity in febrile patients with systemic lupus erythematosus. Formos J Rheumatol 2009;23:52-8.  Back to cited text no. 16
    
17.
Anolik JH, Barnard J, Cappione A, Pugh-Bernard AE, Felgar RE, Looney RJ, et al. Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum 2004;50:3580-90.  Back to cited text no. 17
    
18.
Wu JY, Lee SH, Shen CJ, Hsieh YC, Yo PH, Cheng HY, et al. Use of serum procalcitonin to detect bacterial infection in patients with autoimmune diseases: A systematic review and meta-analysis. Arthritis Rheum 2012;64:3034-42.  Back to cited text no. 18
    
19.
Choi SJ, Rho YH, Lee YH, Ji JD, Song GG. Disseminated candidiasis in systemic lupus erythematosus. Clin Exp Rheumatol 2007;25:503.  Back to cited text no. 19
    
20.
Danza A, Ruiz-Irastorza G. Infection risk in systemic lupus erythematosus patients: Susceptibility factors and preventive strategies. Lupus 2013;22:1286-94.  Back to cited text no. 20
    


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