Analisis Dinamika dan Peran Prognostik Neutrophil-Lymphocyte Ratio (NLR) terhadap Derajat Keparahan Infeksi Dengue pada Pasien Pediatrik: Systematic Literature Review 2020–2025

Rifat Makarim

doi:10.55606/termometer.v4i1.5797

Authors

Rifat Makarim Universitas Lampung

DOI:

https://doi.org/10.55606/termometer.v4i1.5797

Keywords:

Dengue Shock Syndrome, Indonesia, Neutrophil-Lymphocyte Ratio, Pediatric Dengue, Risk Stratification

Abstract

Dengue virus infection remains a significant hyperendemic health challenge in Indonesia, where early detection of massive plasma extravasation risk is paramount to reducing mortality rates within the pediatric population. Although routine hematological parameters such as the Neutrophil-Lymphocyte Ratio (NLR) have emerged as applicable prognostic biomarker candidates, existing literature frequently presents contradictory findings. This study analyzes the dynamics and validity of the NLR as a predictor of dengue severity in children through a synthesis of empirical evidence from 2020 to 2025, utilizing a systematic literature review (SLR) following PRISMA protocols. Data synthesis reveals a Biphasic Model explaining NLR fluctuations throughout the disease course; specifically, during the critical phase (days 4–5 of illness), a low NLR (<0.8) consistently serves as a potent independent predictor of Dengue Shock Syndrome (DSS), with an increased risk of up to 39 times due to significant viral-induced myelosuppression. Conversely, in the late shock phase, the NLR tends to rise (>2.0) as a manifestation of adrenergic stress responses or secondary bacterial co-infections. Consequently, the NLR is a valid, cost-effective, and applicable prognostic biomarker for clinical triage, and serial monitoring is highly recommended to distinguish the pre-shock phase from the recovery phase to ensure early optimization of clinical management.

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References

Adeli, K., Higgins, V., Trau, M. K., & Nieuwesteeg, D. (2017). The CALIPER Project: Reference intervals for pediatric clinical chemistry. Critical Reviews in Clinical Laboratory Sciences, 54(1), 1-19. https://doi.org/10.1080/10408363.2016.1265448

Amri, I., Rahma, R., Hutasoit, G. A., Putri, A. S. D., Harun, H., & Rasyid, R. (2025). Comparison of neutrophil-to-lymphocyte ratio between dengue haemorrhagic fever and dengue shock syndrome in pediatric patients at Anutapura Hospital. Journal of Health and Nutrition Research, 4(1), 162-171. https://doi.org/10.56303/jhnresearch.v4i1.360

Arfan, R., Irmayanti, I., Irwan, A. A., Kartika, I. D., & Hidayati, P. H. (2024). Analisis neutrofil dan limfosit pada pasien anak demam berdarah dengue di instalasi rawat inap RS. Ibnu Sina Kota Makassar. Innovative: Journal of Social Science Research, 4(1), 9240-9256.

Aziz, M. A., Hasan, S., & Ahsan, A. (2020). Hematological profiles in dengue infection and their relationship with disease severity. Journal of Advances in Medicine and Medical Research, 32(4), 1-9.

Bierman, W. F. W., Yeung, W. C., & Thuring, D. (2020). Hematological parameters in the early phase of dengue virus infection. The Netherlands Journal of Medicine, 78(4), 167-173.

Borenstein, M., Hedges, L. V, Higgins, J. P. T., & Rothstein, H. R. (2021). Introduction to meta-analysis (2nd ed.). John Wiley & Sons. https://doi.org/10.1002/9781119558378

Campbell, M., McKenzie, J., Sowden, A., Katikireddi, S., Brennan, S., & Ellis, S. (2020). Synthesis without meta-analysis (SWiM) reporting guideline: Annotated checklist and explanations. BMJ, 368, l6890. https://doi.org/10.1136/bmj.l6890

Djalilah, G. N., Diwangkara, A. P., Ambar, N. S., & Hartati, E. (2022). Hubungan neutrophil lymphocyte ratio (NLR) terhadap infeksi dengue anak di instalasi rawat inap anak RSUD RA Basoeni Kabupaten Mojokerto. Proceeding Series (Seminar Kedokteran), 1(2), 123-136.

Djamiatun, K., Farnaningsih, D., & Naftali, Z. (2021). Stress response and neutrophil dynamics in dengue viral infection. Indonesian Journal of Tropical and Infectious Disease, 9(1), 45-52.

Falagas, M. E., Pitsouni, E. I., Malietzis, G. A., & Pappas, G. (2008). Comparison of PubMed, Scopus, Web of Science, and Google Scholar: Strengths and weaknesses. The FASEB Journal, 22(2), 338-342. https://doi.org/10.1096/fj.07-9492LSF

Fransisco, A. S. M. (2021). Perbandingan antara rasio neutrophil limfosit dan trombosit pada kebocoran plasma anak. Nommensen Journal of Medicine, 7(1), 1-3. https://doi.org/10.36655/njm.v7i1.332

Gasparyan, A. Y., Ayvazyan, L., Mukanova, U., Yessirkepov, M., & Kitas, G. D. (2019). The platelet-to-lymphocyte ratio as an inflammatory marker in rheumatic diseases. Annals of Laboratory Medicine, 39(4), 345-357. https://doi.org/10.3343/alm.2019.39.4.345

Gusenbauer, M. (2019). Google Scholar, Web of Science, and Scopus: Which is best for me? Research Synthesis Methods, 10(4), 506-522. https://doi.org/10.1002/jrsm.1373

Gusenbauer, M., & Haddaway, N. R. (2020). Which academic search systems are suitable for systematic reviews or meta-analyses? Evaluating retrieval qualities of Google Scholar, PubMed, and 26 other resources. Research Synthesis Methods, 11(2), 181-217. https://doi.org/10.1002/jrsm.1378

Halstead, S. B. (2020). Dengue antibody-dependent enhancement: Knowns and unknowns. Microbiology Spectrum, 8(6).

Harapan, H., Michie, A., Mudatsir, M., Sasmono, S., & Imrie, A. (2019). Epidemiology of dengue in Southeast Asia: Current knowledge and future prospects. Journal of Infection and Public Health, 12(1), 3-10. https://doi.org/10.1016/j.jiph.2018.12.013

Hariyanto, T., Andarini, S., & Barlianto, W. (2021). The role of NLR and PLR as biomarkers of disease severity in dengue infection: A systematic review. Journal of Tropical Medicine and Health, 12(2), 45-56.

Herzog, R., Alvarez, M. J., Schwartz, S. H., & Koch, M. C. (2013). Evaluating quality of cross-sectional studies: A modification of the Newcastle-Ottawa Scale. Epidemiology Research International.

Higgins, J. P. T., Thomas, J., Chandler, J., Cumpston, M., Li, T., Page, M. J., & Welch, V. A. (2019). Cochrane handbook for systematic reviews of interventions (2nd ed.). John Wiley & Sons. https://doi.org/10.1002/9781119536604

Indonesia, K. K. R. (2024). Profil kesehatan Indonesia 2023. Kementerian Kesehatan Republik Indonesia.

Jimenez, A. M. D., & Tiu, J. M. (2025). Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as early predictive markers of dengue severity in pediatric patients: A retrospective analysis. Journal of the Pediatric Infectious Disease Society of the Philippines, 26(1). https://doi.org/10.56964/pidspj20252601006

Karyanti, M. R., Uiterwaal, C. S. P. M., Kusriastuti, R., Hadinegoro, S. R., Rovers, M. M., Heesterbeek, H., & Bruijning-Verhagen, P. (2022). The changing incidence of dengue haemorrhagic fever in Indonesia: A 45-year registry-based analysis. BMC Infectious Diseases, 14(1), 412. https://doi.org/10.1186/1471-2334-14-412

Kencana, I. G. A. A. W., Adiwinoto, R. P., Pikir, R. R., Rusli, C., Biutifasari, V., & Utami, P. D. (2025). Neutrophil-lymphocyte ratio as a predictor of dengue hemorrhagic fever severity in Indonesian pediatric patients: A single-center retrospective study. Svāsthya: Trends in General Medicine and Public Health, 2(4), e104. https://doi.org/10.70347/svsthya.v2i4.104

Khoirunisa, S., Wardhani, P., & Aryati, A. (2022). Diagnostic value of neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) in dengue infection. Indonesian Journal of Clinical Pathology and Medical Laboratory, 28(2), 140-144.

Kusuma, G. A., Hanum, D. W., & Sakdiah, S. (2025). Correlation of neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) in children with dengue hemorrhagic fever (DHF) infection in Northern Kalimantan. Proceeding International Conference Health Polytechnic of Jambi, 5, 128-132.

Lam, P. K., Nguyet, T. T.-T., Ha, T. T. N., Hung, N. T., Chau, N. V. V., & Farrar, J. (2013). The value of daily hematology parameters in predicting severe dengue: A case-control study. The Journal of Infectious Diseases, 207(10), 1568-1580. https://doi.org/10.1093/infdis/jit072

Methley, A. M., Campbell, S., Chew-Graham, C., McNally, R., & Cheraghi-Sohi, S. (2014). PICO, PICOS and SPIDER: A comparison study of specificity and sensitivity in information retrieval for environmental health reviews. BMC Health Services Research, 14, 579. https://doi.org/10.1186/s12913-014-0579-0

Moher, D., Liberati, A., Tetzlaff, J., & Altman, D. G. (2009). Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Medicine, 6(7), e1000097. https://doi.org/10.1371/journal.pmed.1000097

Moher, D., Shamseer, L., Clarke, M., Ghersi, D., Liberati, A., & Petticrew, M. (2015). Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Systematic Reviews, 4, 1. https://doi.org/10.1186/2046-4053-4-1

Munn, Z., Stern, C., Lisy, K., Riordan, T., & Pearson, A. (2018). What kind of systematic review should I conduct? A proposed typology and guidance for systematic reviewers in the medical and health sciences. BMC Medical Research Methodology, 18, 5. https://doi.org/10.1186/s12874-017-0468-4

Nguyen-Huu, C. D., Pham, N.-H., Nguyen, T. L., Vo, Q. B., Le, H., Manh, T. T., Dang, T. T., & Nguyen, V.-T. (2025). Predictive value of mean platelet volume and other CBC indices for thrombocytopenia in pediatric dengue fever: A prospective observational study. SAGE Open Pediatrics, 12, 1-9. https://doi.org/10.1177/30502225251388755

Oktariana, D., Luthfiah, Q., Rahardiyanto, K. Y., Liana, P., Reagan, M., & Hafizzanovian, H. (2025). Correlation between neutrophil-to-lymphocyte ratio (NLR) and length of hospital stay in pediatric patients with dengue hemorrhagic fever. EJournal Kedokteran Indonesia, 13(2). https://doi.org/10.23886/ejki.13.1132.1

Opasawatchai, A., Amornsupawat, P., Jiravejchakul, N., Chan-In, W., Spoerk, N. J., Manopwisedjaroen, K., & Loison, F. (2019). Neutrophil activation and early features of fatal dengue infection. Frontiers in Immunology, 9, 3007. https://doi.org/10.3389/fimmu.2018.03007

Organization, W. H. (2009). Dengue guidelines for diagnosis, treatment, prevention and control. World Health Organization.

Organization, W. H. (2011). Comprehensive guidelines for prevention and control of dengue and dengue haemorrhagic fever. SEARO Regional Publication.

Organization, W. H. (2023). Dengue and severe dengue.

Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., & Moher, D. (2021). The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ, 372. https://doi.org/10.1136/bmj.n71

Polanin, J. R., Pigott, T., Espelage, D. L., & Grotpeter, J. G. (2019). Best practice guidelines for abstract screening in evidence-based practice. Journal of Evidence-Based Social Work, 16(3), 330-342. https://doi.org/10.1080/26408066.2019.1584405

Popay, J., Roberts, H., Sowden, A., Petticrew, M., Arai, L., Rodgers, M., & Duffy, S. (2006). Guidance on the conduct of narrative synthesis in systematic reviews. A product from the ESRC Methods Programme, 1, 92.

Prayon, K. M., & Oncog, A. S. (2022). Absolute neutrophil counts and neutrophil to lymphocyte ratio as early predictive markers of dengue severity among children admitted in Governor Celestino Gallares Memorial Hospital: A 5-year retrospective study. Acta Scientific Paediatrics, 5(7), 37-45.

Pribadi, M. I., Umma, H. A., & Siregar, R. (2025). Neutrophil-lymphocyte ratio as an indicator of recovery phase in children with dengue fever. Trends in Pediatrics, 6(1), 25-32. https://doi.org/10.59213/TP.2025.199

Prijanto, S. A., Suryawan, I. W. B., & Suarca, I. K. (2023). Rasio neutrophil-limfosit sebagai prediktor kejadian syok pada demam berdarah dengue pada anak di Rumah Sakit Umum Daerah Wangaya, Denpasar. Sari Pediatri, 24(5), 307-313. https://doi.org/10.14238/sp24.5.2023.307-13

Richardson, W. S., Wilson, M. C., Nishikawa, J., & Hayward, R. S. (1995). The well-built clinical question: A key to evidence-based decisions. ACP Journal Club, 123(3), A12-A13. https://doi.org/10.7326/ACPJC-1995-123-3-A12

Sanglah, T. P. R., Putra, I. G. N., Utama, I. M. G. D. L., & Suartha, I. N. (2025). Characteristics of severe dengue infection with compensated and decompensated shock in children. ResearchGate Publication.

Satari, H. I., & Gunardi, H. (2021). Management of dengue infection in children: Current status. Paediatrica Indonesiana, 61(1), 55-63.

Sirait, M. D. S., Permatasari, R., & Loesnihari, R. (2025). The relationship between neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) and the severity of dengue virus infection patients. Majalah Kedokteran Bandung, 57(1). https://doi.org/10.24198/mkk.v8i2.65863

Snyder, H. (2019). Literature review as a research methodology: An overview and guidelines. Journal of Business Research, 104, 333-339. https://doi.org/10.1016/j.jbusres.2019.07.039

Srikiatkhachorn, A., Rothman, A. L., Gibbons, R. V., Sittisombut, N., Malasit, P., Ennis, F. A., & Green, S. (2017). Dengue hemorrhagic fever: The sensitivity and specificity of the world health organization definition in a prospective study in Thailand. Clinical Infectious Diseases, 50(9), 1235-1240.

Stang, A. (2010). Critical evaluation of the Newcastle-Ottawa scale for assessing the quality of nonrandomized studies in meta-analyses. European Journal of Epidemiology, 25(9), 603-605. https://doi.org/10.1007/s10654-010-9491-z

Vandenbroucke, J. P., von Elm, E., Altman, D. G., Gøtzsche, P. C., Mulrow, C. D., & Pocock, S. J. (2014). Strengthening the reporting of observational studies in epidemiology (STROBE): Explanation and elaboration. International Journal of Surgery, 12(12), 1500-1524. https://doi.org/10.1016/j.ijsu.2014.07.014

Wells, G. A., Shea, B., O'Connell, D., Peterson, J., Welch, V., Losos, M., & Tugwell, P. (2014). The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute.