|Ahead of print
Evaluation of serum procalcitonin, serum interleukin-6, and interleukin-8 as predictors of serious infection in children with febrile neutropenia and cancer
Arathi Srinivasan, Nuthan Kumar, Julius X Scott
Department of Pediatric Oncology, Kanchi Kamakoti CHILDS Trust Hospital, The CHILDS Trust Medical Research Foundation, Chennai, Tamil Nadu, India
|Date of Submission||13-Dec-2018|
|Date of Decision||27-May-2019|
|Date of Acceptance||28-May-2019|
Department of Pediatric Oncology, Kanchi Kamakoti CHILDS Trust Hospital, The CHILDS Trust Medical Research Foundation, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Early diagnosis of sepsis in children with febrile neutropenia remains difficult owing to non-specific clinical and laboratory signs of infection. There is a need to assess the utility of inflammatory markers in clinical risk assessment for their ability to discriminate between low-risk and high-risk neutropenic patients since presently there is insufficient data to recommend their routine use.
Methods: This is a prospective study of children on therapy admitted with febrile neutropenia and sampled for serum procalcitonin (PCT), interleukin-6 (IL-6), and interleukin-8 (IL-8) at admission. The febrile neutropenia episodes were categorized into two groups - Group I: no focus of infection and Group II: clinically/microbiologically documented infection. Statistical analyses for comparison were performed using Z-test and receiver operating curves at various cut-off levels.
Results: A total of 46 episodes of febrile neutropenia in 33 children were analyzed. In total, 76% were categorized as group I and 24% as group II. The mean value of PCT in group II was higher (28.07 ng/mL) than group I (1.03 ng/mL) though there was no significant statistical difference. At a cut-off level of 2 ng/mL for PCT, sensitivity of 63%, specificity of 91%, positive predictive values (PPV) of 70%, and negative predictive value (NPV) of 88% were observed. There was no significant difference in the IL-6 and IL-8 levels between both the groups. However, at an optimal cut-off value of 50 pg/mL, IL-6 had an NPV of 80% and at a cut-off level of 130 pg/mL, IL-8 had an NPV of 73%, however, with low sensitivity and specificity.
Conclusion: IL-6, IL-8, and PCT can be utilized to define a group of patients with a low risk of sepsis in view of their favorable NPV. The use of these biomarkers together can facilitate early discharge from the hospital, and the use of oral antimicrobial therapy, in turn, reducing the cost of supportive therapy in a developing country.
Keywords: Children, febrile neutropenia, interleukins, malignancies, procalcitonin
Key Message: Procalcitonin has a better diagnostic ability to predict bacteremia in children with febrile neutropenia. Serum Procalcitonin, serum IL-6, and IL-8 together can define a group of children with low risk of sepsis with febrile neutropenia at presentation.
|How to cite this URL:|
Srinivasan A, Kumar N, Scott JX. Evaluation of serum procalcitonin, serum interleukin-6, and interleukin-8 as predictors of serious infection in children with febrile neutropenia and cancer. Indian J Cancer [Epub ahead of print] [cited 2021 Apr 13]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=297036
| » Introduction|| |
Neutropenic patients with malignancies are at high risk of contracting life-threatening infections and can be fatal if not treated early and aggressively. The intensity and duration of neutropenia substantially add to the risk of serious infections. However, not all febrile neutropenic patients are at the same risk for developing infection-related complications. It is important to risk stratify these children with febrile neutropenia as it is also vital to facilitate early discharge of low-risk children to prevent hospital-acquired infections. We aimed to evaluate the diagnostic accuracy of serum procalcitonin (PCT), serum interleukin-6 (IL-6), and interleukin-8 (IL-8) in predicting serious infection in febrile neutropenia patients with cancer.
| » Subjects and Methods|| |
This was a prospective study carried out from 2015-2017 in children on cancer therapy and admitted with febrile neutropenia, aged 1 month to 18 years. This study was approved by the ethics committee of our institute. Fever was defined as a single oral temperature measurement of >38.3°C (101°F) or a temperature of >38.0°C (100.4°F) sustained over a 1 hour period. Neutropenia is defined as an absolute neutrophil count (ANC) of <500 cells/mm3 or an ANC that is expected to decrease to <500 cells/mm3 during the next 48 hours.
A thorough clinical evaluation was done by detailed history and physical examination at the onset of fever. Laboratory tests included a complete blood cell count with differential leukocyte count and platelet count; measurement of serum levels of creatinine and blood urea nitrogen; and measurement of electrolytes, hepatic transaminase enzymes, and total bilirubin. At least two sets of blood cultures were taken, with a set collected simultaneously from each lumen of an existing central venous catheter, if present, and from a peripheral vein site; two blood culture sets from separate venipunctures were sent if no central catheter was present. Sample for serum PCT, IL-6, and IL-8 levels was drawn at the presentation of febrile neutropenia to the hospital.
PCT was measured using an enzyme linked fluorescent assay using BioMeriux kits on VIDAS immunoassay systems. The upper limit of normal range for serum PCT in our laboratory is 2 ng/mL. Quantitative analyses of IL-6 and IL-8 were done by solid phase sandwich ELISA method using GEN-PROBE kits for research purpose.
The febrile neutropenia episodes were categorized into two groups - Group I: no focus of infection, and Group II: clinically/microbiologically documented infection. Group I included those episodes where clinically there was no focus of infection and no identifiable organism on any cultures. Group II included those episodes where there was an identifiable cause either clinically like an abscess or radiologically like pneumonia on chest radiograph. Statistical analyses for comparison were performed using Z-test, and receiver operating curves were constructed for deriving sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) at various cut-off levels using SPSS software.
| » Results|| |
A total of 46 episodes of febrile neutropenia in 33 children with cancer undergoing therapy and admitted with febrile neutropenia were analyzed for serum PCT levels, serum IL-6, and serum IL-8 at admission of the episode. Majority (21; 45.6%) of the episodes were seen in the age group of 1 to 5 years as shown in [Figure 1]. Male:Female ratio was 1.5:1. The underlying primary diagnosis was acute lymphoblastic leukemia in 27 (58%) febrile neutropenia episodes. ANC of ≤200 was seen in 32 (69%) episodes, 200–500 in seven (15%) episodes, and 500–1000 were seen in seven (15%) episodes.
In total, 76% were categorized as group I and 24% as group II. In those children in group II with clinically/microbiologically documented infection, bacteremia was seen in six (E. coli: one, Acinetobacter: one, Klebsiella: one, MSSA: one, Enterobacter: one, and serratia: one); urine microbiological evidence were seen in three (Klebsiella: one, Ecoli: one, and Pseudomonas: one); and positive pus culture included two (Pseudomonas: one and CONS: one). Urine microscopy showed pus cells in all the three with positive urine cultures, and pus cells were seen on microscopy for positive pus cultures.
[Table 1] shows the mean values of PCT, IL-6, and IL-8 in the two groups. The mean values of PCT (28.07 ng/mL) and IL-6 (82.45) in group II were higher than PCT (1.03 ng/mL) and IL-6 (76.03) in group I, while there was no statistical significance.
[Table 2] illustrates the significance of PCT, IL-6, and IL-8 at the various cut-off levels. IL-6 and IL-8 had low sensitivity, specificity, and PPV, but at a cut-off value of 50 pg/mL, IL-6 had an NPV of 80% and at a cut-off level of 130 pg/mL, IL-8 had an NPV of 73%.
|Table 2: Diagnostic relevance of IL-8, IL-6, and PCT for predicting serious infection|
Click here to view
The area under curve for PCT, IL-6, and IL-8 were 0.745, 0.574, and 0.551, respectively as shown in [Figure 2].
The mean number of days of hospitalization was 5.89 days.
| » Discussion|| |
Febrile neutropenia is the most common cause for hospital admission in a child with cancer on chemotherapy. The need to initiate early intravenous antibiotics to prevent mortality is emphasized. Initiation of empirical intravenous broad-spectrum antibiotic regimens at the first signs of fever has drastically reduced morbidity and eliminated mortality. For high-risk patients, this treatment is appropriate considering the possibility of rapid deterioration. However, approximately two-thirds of all children are treated without having a source of the fever identified. Several serum biomarkers have been identified in recent years that have the potential to aid the diagnosis of local and systemic infections, differentiate bacterial and fungal infections from viral syndromes or non-infectious conditions, prognosticate outcomes, and ultimately guide management, particularly antibiotic therapy. The utility of biomarkers in clinical decision for febrile neutropenia is still being evaluated. An ideal biomarker should be able to risk stratify febrile neutropenia patients early in the clinical course.
PCT is a precursor of the hormone calcitonin; its levels have been found to increase during infection and different degrees of inflammation. PCT, when compared with other biomarkers, is more specific for bacterial infections, with serum levels rising early after the onset of infection and falling rapidly as the infection resolves. There is evidence that PCT values clearly differentiate between tumor-associated fever and systemic infection, although PCT is not a valuable marker for distinguishing tumor-associated fever from minor infection in non-neutropenic cancer patients.
The PCT cut-off values in most studies have varied between 0.5 ng/mL and 2 ng/mL.,, A study by Hemming et al. showed that PCT >2 ng/mL was strongly associated with increased risk of severe infection. A study by Reitman et al. observed that serial PCT levels within 24 hours allowed a better prediction of bacteremia than the PCT level at admission. Three studies had a sensitivity between 93% and 96.5% for febrile neutropenia and severe infection. The specificity was between 70.6 and 97%.,, In our study, although PCT had low sensitivity and PPV, high specificity of 91% and NPV of 88% at a cut-off level of 2 ng/mL were observed. This is comparable to the findings of Lin et al., stating that PCT is more specific than being sensitive. A systematic review by Haeusler also showed that PCT had better discriminatory power than C-reactive protein (CRP) to predict serious infections in children with febrile neutropenia. The area under the curve for PCT in our study was 0.74 and, hence, had a better diagnostic ability to predict sepsis in children with febrile neutropenia.
IL-6 is produced by T-cells, macrophages, and endothelial cells. IL-6 induces the synthesis of acute-phase proteins in the liver and stimulates the production of neutrophils and growth and proliferation of B-lymphocytes. IL-8 or CXCL-8 is released from leukocytic cells and nonleukocytic somatic cells such as endothelial cells or fibroblasts. IL-8 production is induced by bacteria, viruses, and other proinflammatory cytokines [IL-1 and tumor necrosis factor (TNF)]. Data reported by various studies showed the potential usefulness of IL-6 and IL-8 as early indicators for life-threatening infections in febrile cancer patients with neutropenia.,,
De Bont et al. found that IL-6 and IL-8 values correlated in determining a group of cancer patients with neutropenia and fever who had a low risk for septicemia. A study by Diepold also showed the usefulness of defining a low-risk group for sepsis. Our study showed that IL-6, at an optimum cut-off level of 50 pg/mL, had a sensitivity and specificity of 54% and 57%, respectively, with a PPV of only 28%, but a high NPV of 80%. IL-8 had comparable sensitivity and specificity of 45% and 49%, with a PPV of 21% and NPV of 73% at a cut-off level of 130 pg/mL. A study by Chaudhary et al. also showed that low levels of IL-6 may help to differentiate patients with fever of unknown origin (FUO) from those with documented infections. Urbonas et al. reported similar results with higher specificity and NPV than sensitivity and PPV. Hence, early evaluation of IL-6 or IL-8 could enable physicians in decision-making, regarding the exclusion of patients with sepsis or bacteremia. Study by Aggarwal et al. also suggested that the negative predictive value of IL-6, IL-8, and TNF-α exceeded 80%. As IL-6 and IL-8 have been found to significantly correlate in multiple studies, measurement of any one marker may be sufficient.
Engel et al. compared serum levels of PCT with IL-8 and showed that IL-8 was more sensitive and specific than PCT in the prediction of gram-negative bacteremia. A similar result was shown by Bal et al., wherein IL-6 and IL-8 were higher during infections, and IL-8 had greater sensitivity and specificity in determining gram-negative bacterial infections. Strychjewski et al. echoed a similar opinion where they studied a combination of PCT with IL-8 as a marker of bacterial sepsis in febrile, neutropenic children. IL-8 was increased in septic children compared with those without bacterial sepsis, but there were no significant differences in the values of IL-6 between septic and non-septic patients. In contrast, Fleischhack et al. suggested that PCT is a more useful diagnostic parameter in febrile cancer patients than IL-6 and IL-8, which is more in line with our findings.
Conflicting results regarding the usefulness of PCT, IL-6, and IL-8 determinations in patients with febrile neutropenia can probably be attributed to different infection etiologies, different methods of concentration determination, and different time points of blood sampling regarding the occurrence of fever; the latter is only rarely well-defined in published studies. Multiple day testing has been previously examined in a few studies. Santolaya et al. showed that PCT levels did not discriminate between severe sepsis and non-severe infection at admission but did at day two. However, data are limited and the significance is uncertain.
The cost of intravenous antibiotics and hospitalization for a day at our institute is approximately INR 3,500 and the cost of antibiotics as outpatient for a day costs approximately INR 500. If the group of patients with low-risk for sepsis can be identified with a set of biomarkers in additional to clinical findings, this will facilitate in reducing the cost of supportive care therapy.
The limitations of our study are the small sample size and lack of serial evaluation of PCT during the course of hospitalization, but a prospective study with evaluation of three serum markers at admission are the positive points.
Serum PCT is a better predictor of serious infection in a child with febrile neutropenia. IL-6, IL-8, and PCT can be utilized to define a group of patients with a low-risk of sepsis in view of their favorable NPV. The use of these biomarkers together can facilitate early discharge from the hospital, and lead to risk-based antimicrobial therapy, in turn, reducing the cost of supportive therapy in a developing country.
Financial support and sponsorship
Study was funded by The CHILDS Trust Medical Research Foundation.
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al
. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52:e56-93.
Von Lilienfeld-Toal M, Dietrich MP, Glasmacher A, Lehmann L, Breig P, Hahn C, et al
. Markers of bacteremia in febrile neutropenic patients with hematological malignancies: Procalcitoninand IL-6 are more reliable than C-reactive protein. Eur J Clin MicrobiolInfect Dis 2004;23:539-44.
Mian A, Becton D, Saylors R, James L, Tang X, Bhutta A, et al
. Biomarkers for risk stratification of febrile neutropenia among children with malignancy: A pilot study. Pediatr Blood Cancer 2012;59:238-45.
Reitman AJ, PiskRM, Gates III JV, Ozeran JD. Serial procalcitonin levels to detect bacteremia in febrile neutropenia. Clini Pediatr (Phila) 2012;51:1175-83.
Haeusler GM, Carlesse F, Phillips RS. An updated systematic review and meta-analysis of the predictive value of serum biomarkers in the assessment of fever during neutropenia in children with cancer. Pediatr Infect Dis J 2013;32:e390-6.
Hemming V, Jakes AD, Shenton G, Phillips B. Prospective cohort study of procalcitonin levels in children with cancer presenting with febrile neutropenia. BMC Pediatr 2017;17:2.
Hatzistilianou M, Rekleity A, Athanassiou K, DeLutiis MA, Conti P, Catriu D. Serial procalcitonin responses in infection of children with secondary immunodeficiency. Clin Invest Med 2007;30:E75-85.
Hitoglou-Hatzi S, Hatzistilianou M, Gougoustamou D, Rekliti A, Agguridaki CH, Athanassiadou F, et al
. Serum adenosine deaminase and procalcitonin concentrations in neutropenic febrile children with acute lymphoblastic leukemia. Clin Exp Med 2005;5:60-5.
Kitanovski L, Jazbec J, Hojker S, Gubina M, Derganc M. Diagnostic accuracy of procalcitonin and interleukin-6 values for predicting bacteremia and clinical sepsis in febrile neutropenia children with cancer. Eur J Clin Microbiol Infect Dis 2006;25:413-5.
Lin SG, Hou TY, Huang DH, He SY, Lin YD, Zhang LY, et al
. Role of procalcitonin in the diagnosis of severe infection in pediatric patients with fever and neutropenia - Asystemic review and meta-analysis. Pediatr Infect Dis J 2012;31:e182-8.
Diepold M, Noellke P, Duffner U, Kontny U, Berner R. Performance of interleukin-6 and interleukin-8 serum levels in pediatric oncology patients with neutropenia and fever for the assessment of low-risk. BMC Infect Dis 2008;8:28.
Kern WV, Heiss M, Steinbach G. Prediction of gram-negative bacteremia in patients with cancer and febrile neutropenia by means of interleukin-8 levels in serum: Targeting empirical monotherapy versus combination therapy. Clin Infect Dis 2001;32:832-5.
De Bont ES, Vellenga E, Swaanenburg JC, Fidler V, BrummenPJ, Kamps WA. Plasma IL-8 and IL-6 levels can be used to define a group with low risk of septicaemia among cancer patients with fever and neutropenia. Br J Haematol 1999;107:375-80.
Chaudhary N, Kosaraju K, Bhat K, Bairy I, Borker A. Significance of interleukin-6 (IL-6) and C-reactive protein (CRP) in children and young adults with febrile neutropenia during chemotherapy for cancer: Aprospective study. J Pediatr Hematol Oncol2012;34:617-23.
Urbonas V, Eidukaitė A, Tamulienė I. The predictive value of soluble biomarkers (CD14 subtype, interleukin-2 receptor, human leucocyte antigen-G) and procalcitonin in the detection of bacteremia and sepsis in pediatric oncology patients with chemotherapy-induced febrile neutropenia. Cytokine 2013;62:34-7.
Aggarwal R, Bansal D, Bansal F, Nanda N, Ray P, Trehan A, et al
. Interleukin-5, interleukin-6, interleukin-8 and tumour necrosis factor-alpha levels obtained within 24-h of admission do not predict high-risk infection in children with febrile neutropenia. Indian J Med Microbiol 2013;31:226-9.
] [Full text]
Engel A, Steinbach G, Kern P, Kern WV. Diagnostic value of procalcitonin serum levels in neutropenic patients with fever: Comparison with Interleukin-8. Scand J Infect Dis 1999;31:185-9.
Bal ZŞ, Özdemir NK, Şen S, Karapınar DY, Azarsız E, Aydemir Ş, et al
. Diagnostic accuracy of interleukin-6, interleukin-8, and interleukin-10 for predicting bacteremia in children with febrile neutropenia. Turk J Hematol 2017;34:254-7.
Stryjewski GR, Nylen ES, Bell MJ, Snider RH, Becker KL, Wu A, et al
. Interleukin-6, interleukin-8, and a rapid and sensitive assay for calcitonin precursors for the determination of bacterial sepsis in febrile neutropenic children. Pediatr Crit Care Med 2005;6:129-35.
Fleischhack G, Kambeck I, Cipic D, Hasan C, Bode U. Procalcitonin in paediatric cancer patients: Its diagnostic relevance is superior to that of C-reactive protein, interleukin 6, interleukin 8, soluble interleukin 2 receptor and soluble tumour necrosis factor receptor II. Br J Haematol 2000;111:1093-102.
Santolaya ME, Alvarez AM, Aviles CL, Becker A, King A, Mosso C, et al
. Predictors ofsevere sepsis not clinically apparent during the first twenty-four hours of hospitalization inchidren with cancer, neutropenia, and fever: A prospective, multicenter trial. Pediatr Infect Dis J 2008;27:538-43.
[Figure 1], [Figure 2]
[Table 1], [Table 2]