Abstract
Identifying the etiology of an acute respiratory infection in children is a well-known challenge. In this study, we evaluated the correlation between salivary C-reactive protein (CRP) and its serum counterpart, which is known to be higher in bacterial infections but necessitates a venipuncture. Salivary and serum CRPs were measured in children with an acute respiratory illness, aged 2 months to 18 years. Pearson’s correlation coefficients were used to measure correlation. Discrimination of the salivary CRP levels for predicting serum levels above 100 mg/L was calculated and compared to serum CRP levels. Sensitivity and specificity were similarly calculated. Salivary CRP was measured in 104 samples. Levels correlated significantly and positively with serum CRP levels (r = 0.670, p<0.001). Area under the curve for predicting serum CRP levels of 100 mg/L was 0.848. For a salivary CRP concentration above 32,610 ng/L, the sensitivity and specificity were 69% and 93%, respectively, for accurately predicting a serum CRP level ≥100 mg/L.
Conclusions: Salivary CRP can be used in the pediatric acute setting due to its high specificity for predicting elevated serum levels without the need for venipuncture. Further studies are required to achieve higher sensitivity rates.
What is known: • Salivary C-reactive protein has shown correlation to its serum counterpart, mainly in healthy children, adults, and ill neonates. | |
What is new: • In a large population of children with acute respiratory illness, aged 2 months to 18 years, salivary C-reactive protein showed high specificity for predicting elevated serum levels, thus indicating its potential as a diagnostic tool. |
Similar content being viewed by others
Availability of data and material
All data and materials support our claims in the manuscript. Limitations found in the data were mentioned in the text.
Code availability
N/A
Abbreviations
- CRP:
-
C-reactive protein
- IQR:
-
Interquartile range
- ROC:
-
Receiver–Operator Characteristic
- AUC:
-
Area Under the Curve
References
Harris M, Clark J, Coote N et al (2011) British Thoracic Society guidelines for the management of community acquired pneumonia in children: update 2011. Thorax 66(Suppl 2):ii1–i23. https://doi.org/10.1136/thoraxjnl-2011-200598
Walker CLF, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA, O'Brien KL, Campbell H, Black RE (2013) Global burden of childhood pneumonia and diarrhoea. Lancet 381:1405–1416. https://doi.org/10.1016/S0140-6736(13)60222-6
Principi N, Esposito S (2003) Paediatric community-acquired pneumonia: current concept in pharmacological control. Expert Opin Pharmacother 4:761–777. https://doi.org/10.1517/14656566.4.5.761
Bhuiyan MU, Blyth CC, West R, Lang J, Rahman T, Granland C, de Gier C, Borland ML, Thornton RB, Kirkham LAS, Martin A, Richmond PC, Smith DW, Jaffe A, Snelling TL (2019) Combination of clinical symptoms and blood biomarkers can improve discrimination between bacterial or viral community-acquired pneumonia in children. BMC Pulm Med 19:71. https://doi.org/10.1186/s12890-019-0835-5
Flood RG, Badik J, Aronoff SC (2008) The utility of serum C-reactive protein in differentiating bacterial from nonbacterial pneumonia in children: a meta-analysis of 1230 children. Pediatr Infect Dis J 27:95–99. https://doi.org/10.1097/INF.0b013e318157aced
Thomas J, Pociute A, Kevalas R, Malinauskas M, Jankauskaite L (2020) Blood biomarkers differentiating viral versus bacterial pneumonia aetiology: a literature review. Ital J Pediatr 46:4. https://doi.org/10.1186/s13052-020-0770-3
Esposito S, Bianchini S, Gambino M, Madini B, di Pietro G, Umbrello G, Presicce ML, Ruggiero L, Terranova L, Principi N (2016) Measurement of lipocalin-2 and syndecan-4 levels to differentiate bacterial from viral infection in children with community-acquired pneumonia. BMC Pulm Med 16:103. https://doi.org/10.1186/s12890-016-0267-4
Taddio A, Shah V, Gilbert-MacLeod C, Katz J (2002) Conditioning and hyperalgesia in newborns exposed to repeated heel lances. JAMA 288:857–861. https://doi.org/10.1001/jama.288.7.857
Mutlu B, Balcı S (2015) Effects of balloon inflation and cough trick methods on easing pain in children during the drawing of venous blood samples: a randomized controlled trial. J Spec Pediatr Nurs 20:178–186. https://doi.org/10.1111/jspn.12112
Lee AHH, Qi SD, Chiang N (2020) Acute upper limb ischemia due to delayed presentation of a brachial artery pseudoaneurysm post-venipuncture. Vasc Endovasc Surg 54:80–84. https://doi.org/10.1177/1538574419877620
Dogan OF, Demircin M, Ucar I et al (2006) Iatrogenic brachial and femoral artery complications following venipuncture in children. Heart Surg Forum 9:E675–E680. https://doi.org/10.1532/HSF98.2005-1036
Mittal S, Bansal V, Garg SK, et al. (2011) The diagnostic role of saliva: a review.
Pappa E, Kousvelari E, Vastardis H (2019) Saliva in the “omics” era: a promising tool in paediatrics. Oral Dis 25:16–25. https://doi.org/10.1111/odi.12886
Byrne ML, O’Brien-Simpson NM, Reynolds EC, Walsh KA, Laughton K, Waloszek JM, Woods MJ, Trinder J, Allen NB (2013) Acute phase protein and cytokine levels in serum and saliva: a comparison of detectable levels and correlations in a depressed and healthy adolescent sample. Brain Behav Immun 34:164–175. https://doi.org/10.1016/j.bbi.2013.08.010
Lages AS, Frade JG, Oliveira D et al (2019) Late-night salivary cortisol: cut-off definition and diagnostic accuracy for Cushing’s syndrome in a Portuguese population. Acta Medica Port 32:381–387. https://doi.org/10.20344/amp.11265
Estrada-Y-Martin RM, Orlander PR (2011) Salivary cortisol can replace free serum cortisol measurements in patients with septic shock. Chest 140:1216–1222. https://doi.org/10.1378/chest.11-0448
VanBruggen MD, Hackney AC, McMurray RG, Ondrak KS (2011) The relationship between serum and salivary cortisol levels in response to different intensities of exercise. Int J Sports Physiol Perform 6:396–407. https://doi.org/10.1123/ijspp.6.3.396
Grewen KM, Davenport RE, Light KC (2010) An investigation of plasma and salivary oxytocin responses in breast- and formula-feeding mothers of infants. Psychophysiology 47:625–632. https://doi.org/10.1111/j.1469-8986.2009.00968.x
Manolopoulou J, Mulatero P, Maser-Gluth C, Rossignol P, Spyroglou A, Vakrilova Y, Petersenn S, Zwermann O, Plouin PF, Reincke M, Bidlingmaier M (2009) Saliva as a medium for aldosterone measurement in repeated sampling studies. Steroids 74:853–858. https://doi.org/10.1016/j.steroids.2009.05.006
Jinrui H, Itoh N, Nitta T et al (1994) Changes in the salivary testosterone level in aged. Hinyokika Kiyo 40:807–811
Heine RP, McGregor JA, Goodwin TM et al (2000) Serial salivary estriol to detect an increased risk of preterm birth. Obstet Gynecol 96:490–497. https://doi.org/10.1016/s0029-7844(00)01004-8
Laidi F, Bouziane A, Lakhdar A, Khabouze S, Amrani M, Rhrab B, Zaoui F (2014) Significant correlation between salivary and serum Ca 15-3 in healthy women and breast cancer patients. Asian Pac J Cancer Prev 15:4659–4662. https://doi.org/10.7314/APJCP.2014.15.11.4659
Agha-Hosseini F, Mirzaii-Dizgah I, Rahimi A (2009) Correlation of serum and salivary CA125 levels in patients with breast cancer. The journal of …
Gupta S, Sandhu SV, Bansal H, Sharma D (2015) Comparison of salivary and serum glucose levels in diabetic patients. J Diabetes Sci Technol 9:91–96. https://doi.org/10.1177/1932296814552673
Aydin S, Aydin S, Kuloglu T, Yilmaz M, Kalayci M, Sahin İ, Cicek D (2013) Alterations of irisin concentrations in saliva and serum of obese and normal-weight subjects, before and after 45 min of a Turkish bath or running. Peptides 50:13–18. https://doi.org/10.1016/j.peptides.2013.09.011
Mirzaii-Dizgah I, Riahi E (2013) Salivary troponin I as an indicator of myocardial infarction. Indian J Med Res 138:861–865
Malamud D (1997) Oral diagnostic testing for detecting human immunodeficiency virus-1 antibodies: a technology whose time has come. Am J Med 102:9–14. https://doi.org/10.1016/s0002-9343(97)00032-6
Vasudev A, Tripathi KD, Puri V (2002) Correlation of serum and salivary carbamazepine concentration in epileptic patients: implications for therapeutic drug monitoring. Neurol India 50:60–62
Riis JL, Out D, Dorn LD, Beal SJ, Denson LA, Pabst S, Jaedicke K, Granger DA (2014) Salivary cytokines in healthy adolescent girls: Intercorrelations, stability, and associations with serum cytokines, age, and pubertal stage. Dev Psychobiol 56:797–811. https://doi.org/10.1002/dev.21149
Nam Y, Kim Y-Y, Chang J-Y, Kho H-S (2019) Salivary biomarkers of inflammation and oxidative stress in healthy adults. Arch Oral Biol 97:215–222. https://doi.org/10.1016/j.archoralbio.2018.10.026
Williamson S, Munro C, Pickler R, Grap MJ, Elswick RK (2012) Comparison of biomarkers in blood and saliva in healthy adults. Nurs Res Pract 2012:246178–246174. https://doi.org/10.1155/2012/246178
Ouellet-Morin I, Danese A, Williams B, Arseneault L (2011) Validation of a high-sensitivity assay for C-reactive protein in human saliva. Brain Behav Immun 25:640–646. https://doi.org/10.1016/j.bbi.2010.12.020
Bhavsar NV, Dave BD, Brahmbhatt NA, Parekh R (2015) Periodontal status and oral health behavior in hospitalized patients with chronic obstructive pulmonary disease. J Nat Sci Biol Med 6:S93–S97. https://doi.org/10.4103/0976-9668.166097
Azar R, Richard A (2011) Elevated salivary C-reactive protein levels are associated with active and passive smoking in healthy youth: a pilot study. J Inflamm (Lond) 8:37. https://doi.org/10.1186/1476-9255-8-37
Out D, Hall RJ, Granger DA, Page GG, Woods SJ (2012) Assessing salivary C-reactive protein: longitudinal associations with systemic inflammation and cardiovascular disease risk in women exposed to intimate partner violence. Brain Behav Immun 26:543–551. https://doi.org/10.1016/j.bbi.2012.01.019
McGeer PL, Lee M, Kennedy K, McGeer EG (2020) Saliva diagnosis as a disease predictor. J Clin Med 9. https://doi.org/10.3390/jcm9020377
Dillon MC, Opris DC, Kopanczyk R, Lickliter J, Cornwell HN, Bridges EG, Nazar AM, Bridges KG (2010) Detection of homocysteine and C-reactive protein in the saliva of healthy adults: comparison with blood levels. Biomark Insights 5:57–61. https://doi.org/10.4137/bmi.s5305
Tvarijonaviciute A, Martinez-Lozano N, Rios R, Marcilla de Teruel MC, Garaulet M, Cerón JJ (2020) Saliva as a non-invasive tool for assessment of metabolic and inflammatory biomarkers in children. Clin Nutr 39:2471–2478. https://doi.org/10.1016/j.clnu.2019.10.034
Omran A, Maaroof A, Saleh MH, Abdelwahab A (2018) Salivary C-reactive protein, mean platelet volume and neutrophil lymphocyte ratio as diagnostic markers for neonatal sepsis. J Pediatr 94:82–87. https://doi.org/10.1016/j.jped.2017.03.006
Omran A, Ali M, Saleh MH, Zekry O (2018) Salivary C-reactive protein and mean platelet volume in diagnosis of late-onset neonatal pneumonia. Clin Respir J 12:1644–1650. https://doi.org/10.1111/crj.12723
Iyengar A, Paulus JK, Gerlanc DJ, Maron JL (2014) Detection and potential utility of C-reactive protein in saliva of neonates. Front Pediatr 2:131. https://doi.org/10.3389/fped.2014.00131
Tsai C-M, Tang K-S, Cheng M-C, Liu TY, Huang YH, Chen CC, Yu HR (2020) Use of saliva sample to detect C-reactive protein in children with pneumonia. Pediatr Pulmonol 55:2457–2462. https://doi.org/10.1002/ppul.24947
Toikka P, Irjala K, Juvén T et al (2000) Serum procalcitonin, C-reactive protein and interleukin-6 for distinguishing bacterial and viral pneumonia in children. Pediatr Infect Dis J 19:598–602. https://doi.org/10.1097/00006454-200007000-00003
Centers for Disease Control and Prevention Child Development. https://www.cdc.gov/ncbddd/childdevelopment/positiveparenting/index.html. Accessed 1 Mar 2021
Ersin Kalkan R, Öngöz Dede F, Gökmenoğlu C, Kara C (2018) Salivary fetuin-A, S100A12, and high-sensitivity C-reactive protein levels in periodontal diseases. Oral Dis 24:1554–1561. https://doi.org/10.1111/odi.12927
Hosmer Jr. DW, Lemeshow S, Sturdivant RX (2013) Applied logistic regression. https://doi.org/10.1002/9781118548387
Wilkinson L (2011) ggplot2: elegant graphics for data analysis by WICKHAM, H. Biometrics 67:678–679. https://doi.org/10.1111/j.1541-0420.2011.01616.x
Altınsoy B, Erboy F, Tanrıverdi H, Uygur F, Atalay F, Tor M, Örnek T (2016) Syncope as a presentation of acute pulmonary embolism. Ther Clin Risk Manag 12:1023–1028. https://doi.org/10.2147/TCRM.S105722
Pulliam PN, Attia MW, Cronan KM (2001) C-reactive protein in febrile children 1 to 36 months of age with clinically undetectable serious bacterial infection. Pediatrics 108:1275–1279. https://doi.org/10.1542/peds.108.6.1275
Klein Kremer A, Kuzminsky E, Bentur L, Nagler RM (2014) Salivary and serum analysis in children diagnosed with pneumonia. Pediatr Pulmonol 49:569–573. https://doi.org/10.1002/ppul.22794
Urkin J, Warshawsky SS, Press J (2000) Pediatric emergency room response to community pediatricians’ expectations. The Israel Medical Association …
Price DA, Close GC, Fielding BA (1983) Age of appearance of circadian rhythm in salivary cortisol values in infancy. Arch Dis Child 58:454–456. https://doi.org/10.1136/adc.58.6.454
Mohamed R, Campbell J-L, Cooper-White J, Dimeski G, Punyadeera C (2012) The impact of saliva collection and processing methods on CRP, IgE, and myoglobin immunoassays. Clin Transl Med 1:19. https://doi.org/10.1186/2001-1326-1-19
Acknowledgements
The author would like to thank Tal Shaar-Gofin for her support and for providing motivation throughout this study, bringing it to its completion.
Funding
This study was supported by the “Oriki grant” and by a grant from “The Major Udi Winter Endowment Fund” (local hospital grants). RF and OZS are supported by the Simms/Mann Foundation.
Author information
Authors and Affiliations
Contributions
All authors contributed to the study conception and design. Material preparation and data collection were performed by Yoel Gofin, Eliana Fanous, Yehonatan Pasternak, Zafnat Prokocimer, and Gilat Livni. Analysis was performed by Yoel Gofin, Orna Zagoory-Sharon, Ruth Feldman, Gabriel Codick, Orith Waisbourd-Zinman, and Sophia Fried. The first draft of the manuscript was written by Yoel Gofin with critical review by Gilat Livni, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval
The study was approved by the local Internal Review Board at the Rabin/Schneider Medical Center. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
Consent to participate
Freely given, informed consent to participate in the study was obtained from parents/legal guardians of all participants.
Consent for publication
Freely given, informed consent to publish study data was obtained from parents/legal guardians of all participants.
Conflict of interest
The authors declare no competing interests.
Role of Funder/Sponsor (If Any)
Resources from the funds were used for the purchase of saliva collection and analyzing equipment. The funders had no part in the study design or analysis.
Additional information
Communicated by Nicole Ritz
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary Table 1
Five reserved samples underwent four freeze-thaw cycles and were measured by the same salivary CRP kit. Coefficient of variance was calculated using the formula (100XSD)/Average. (PDF 73 kb)
Supplementary Table 2
Thirty-three saliva samples were tested by two different kits on different days. CRP values were averaged. Coefficient of variance was calculated using the formula (100Xstandard deviation)/average. (PDF 92 kb)
Rights and permissions
About this article
Cite this article
Gofin, Y., Fanous, E., Pasternak, Y. et al. Salivary C-reactive protein—a possible predictor of serum levels in pediatric acute respiratory illness. Eur J Pediatr 180, 2465–2472 (2021). https://doi.org/10.1007/s00431-021-04047-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00431-021-04047-6