Open research questions in Inflammatory Biomarkers in Disease Prognosis

What the literature leaves open

• One challenge is the inconsistent findings on the association between systemic inflammatory biomarkers and GERD severity. Another challenge is the lack of large-scale prospective studies to validate the relationship between these biomarkers and disease severity. The paper also mentions the need to establish optimal cutoff thresholds for these biomarkers.

  Systemic inflammatory biomarkers in gastroesophageal reflux disease: current evidence and future perspectives · 2026 · DOI

• Further research is needed to validate the findings in a larger, more diverse population. Research should investigate the potential complementary information provided by MMI and GINI. Studies should examine the relationship between HUAC and outcomes in other patient populations.

  Prognostic Value of Masseter Muscle Index, Masseter Radiodensity, and the Global Immune-Nutrition-Inflammation Index in Laryngeal Carcinoma Treated with Definitive Radiotherapy · 2026 · DOI

• The study identifies a need for biomarkers that can predict cancer progression and survival outcomes in laryngeal cancer patients. Systemic inflammatory biomarkers and computed tomography-derived measures of muscle quantity and radiodensity have received increasing attention.

  Prognostic Value of Masseter Muscle Index, Masseter Radiodensity, and the Global Immune-Nutrition-Inflammation Index in Laryngeal Carcinoma Treated with Definitive Radiotherapy · 2026 · DOI

• further investigation into the relationship between MHR and subclinical coronary atherosclerosis, - examination of the prognostic value of MHR for cardiovascular events, - study of the potential mechanisms underlying the association between MHR and non-calcified plaques

  Association of monocyte to high-density lipoprotein cholesterol ratio with non-calcified plaques in subclinical coronary atherosclerosis: a cross-sectional study in hypertensive patients · 2026 · DOI

• Identifying inexpensive, widely available biomarkers that can stratify prognosis and inform treatment monitoring in cancer immunotherapy. Analyzing serial measurements of NLR in a real-world cohort. Addressing the lack of studies on the prognostic value of NLR in Latin American cohorts.

  Dynamic neutrophil-to-lymphocyte ratio as an independent prognostic marker of overall survival in patients receiving immune checkpoint inhibitors: a Latin American cohort study · 2026 · DOI

• Further studies are needed to validate the findings in larger and more diverse populations. Research should investigate the mechanisms underlying the association between NLR and OS. Studies should examine the utility of NLR as a biomarker in other clinical contexts. Investigations should focus on developing strategies to modify NLR and improve patient outcomes.

  Dynamic neutrophil-to-lymphocyte ratio as an independent prognostic marker of overall survival in patients receiving immune checkpoint inhibitors: a Latin American cohort study · 2026 · DOI

• The model's clinical applicability requires extremely cautious interpretation given multiple methodological limitations, - The study is a single-center, retrospective observational study, - The study has a limited sample size of 540 patients

  Association between complete blood count-derived hematological inflammatory ratios and nutritional risk in elderly patients with acute ischemic stroke · 2026 · DOI

• Few studies explore the cross-sectional associations between CBC-derived hematological inflammatory ratios and GNRI-defined concurrent nutritional risk in elderly patients with acute ischemic stroke. The existing literature lacks a comprehensive analysis of the correlation between CBC-derived hematological inflammatory ratios and nutritional status.

  Association between complete blood count-derived hematological inflammatory ratios and nutritional risk in elderly patients with acute ischemic stroke · 2026 · DOI

• The study had a limited sample size of 1553 patients, - The study only included patients with ACS undergoing PCI, - The study did not account for other potential risk factors

  Neutrophil percentage-to-albumin ratio is an independent risk factor for MACEs in patients with acute coronary syndrome undergoing percutaneous coronary intervention · 2026 · DOI

• Further studies are needed to validate the NPAR as a predictive biomarker, - Research should investigate the underlying mechanisms of the NPAR, - Studies should explore the application of the NPAR in other clinical settings

  Neutrophil percentage-to-albumin ratio is an independent risk factor for MACEs in patients with acute coronary syndrome undergoing percutaneous coronary intervention · 2026 · DOI

• Investigate the predictive value of RCII for subsequent collateral development, - Examine the relationship between RCII and clinical outcomes in patients with CTO, - Explore the potential of RCII as a therapeutic target for improving coronary collateral circulation

  The Relationship Between the Remnant Cholesterol Inflammation Index and Coronary Collateral Circulation in Patients with Chronic Total Occlusion · 2026 · DOI

• The biological factors accompanying inadequate collateralization in patients with chronic total occlusion are not fully established. The mechanisms underlying the variation in collateral development have not yet been fully elucidated.

  The Relationship Between the Remnant Cholesterol Inflammation Index and Coronary Collateral Circulation in Patients with Chronic Total Occlusion · 2026 · DOI

• There is a need for further standardization and validation of inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) in clinical practice. Acute infections, surgery, trauma, and psychological or physical stress can transiently elevate NLR, reflecting short-term immune activation rather than chronic low-grade inflammation. Pharmacological interventions, including corticosteroids, immunosuppressive agents, or chemotherapy, also alter leukocyte subpopulations and therefore affect NLR independently of disease activity.

  Silent Inflammation, Loud Consequences: Decoding NLR Across Renal, Cardiovascular and Metabolic Disorders · 2025 · DOI

• Further standardization and validation of inflammatory markers such as the NLR, - Population profiling studies aimed at establishing normative reference ranges, - Studies to establish universally accepted and standardized cut-off values for NLR, - Research on the diurnal variation of NLR and its implications

  Silent Inflammation, Loud Consequences: Decoding NLR Across Renal, Cardiovascular and Metabolic Disorders · 2025 · DOI

• Investigate the mechanisms underlying the association between PIV and mortality. Examine the potential impact of other inflammatory markers on the relationship between PIV and mortality. Validate the findings in other populations and datasets. Explore the potential use of PIV as a predictive biomarker for mortality risk in clinical and epidemiological settings

  Pan-immune-inflammation value and its association with all-cause and cause-specific mortality in the general population: a nationwide cohort study · 2025 · DOI

• Further investigation of the link between NPAR and DKD in diabetic patients is needed. Research on the NPAR-CKD relationship in different populations and subgroups is required. Studies on the pathogenesis of DKD and its difference from primary CKD should be conducted.

  Association between neutrophil-percentage-to-albumin ratio and diabetic kidney disease in type 2 diabetes mellitus patients: a cross-sectional study from NHANES 2009–2018 · 2025 · DOI

• The association between NPAR and DKD remains to be elucidated. The study aims to fill this gap by exploring the potential link between NPAR and DKD in patients with type 2 diabetes mellitus.

  Association between neutrophil-percentage-to-albumin ratio and diabetic kidney disease in type 2 diabetes mellitus patients: a cross-sectional study from NHANES 2009–2018 · 2025 · DOI

• There is limited literature exploring the association between trajectories of change in AIP and the risk of CVD. Prior studies have not investigated the association between AIP and CVD risk in individuals with CKM syndrome stage 0-3.

  Association between atherogenic index of plasma and future cardiovascular disease risk in middle-aged and elderly individuals with cardiovascular-kidney-metabolic syndrome stage 0-3 · 2025 · DOI

• Investigating the role of CLR in the onset and progression of CKD, - Examining the relationship between CLR and other inflammatory markers, - Studying the effects of controlling CLR levels on CKD clinical management

  The relationship between C-reactive protein to lymphocyte ratio and the prevalence of chronic kidney disease in US adults: a cross-sectional study · 2025 · DOI

• The role of CLR in CKD development is not well understood. There is a need to investigate the correlation between CLR and CKD prevalence. The study aims to fill this gap by exploring the associations between CLR and indicators of renal damage.

  The relationship between C-reactive protein to lymphocyte ratio and the prevalence of chronic kidney disease in US adults: a cross-sectional study · 2025 · DOI

• The current understanding of the relationship between SII, TMAO, and osteoporosis is limited. There is a need for new indicators for osteoporosis and osteoporotic fractures in overweight and obese individuals.

  Association between systemic immune-inflammation index and trimethylamine N-oxide levels in peripheral blood and osteoporosis in overweight and obese patients · 2025 · DOI

• Accurate assessment of preoperative lymph node status is important for the choice of gastric cancer treatment options. The clinical diagnosis of preoperative gastric cancer with lymph node metastasis is challenging. There is a need to develop a more accurate diagnostic model for lymph node metastasis in gastric cancer.

  Diagnostic value of systemic immune-inflammation index and prognostic nutritional index combined with CEA in gastric cancer with lymph node metastasis · 2025 · DOI

• The combined significance of CEA, SII, and PNI in gastric cancer with lymph node metastasis remains unclear. There is a need for a more accurate diagnostic model for lymph node metastasis in gastric cancer. Current auxiliary examinations cannot reliably confirm or exclude lymph node metastasis.

  Diagnostic value of systemic immune-inflammation index and prognostic nutritional index combined with CEA in gastric cancer with lymph node metastasis · 2025 · DOI

• Further studies are needed to investigate the relationship between inflammation and nutrition-based indicators and DFU, - Longitudinal studies could provide more insight into the causal relationship between these indicators and DFU

  Association of inflammation and nutrition-based indicators and diabetic foot ulcers: a cross-sectional study and a retrospective study · 2025 · DOI

• The complexity of calculating SII. The need to address non-linear relationships between SII and mortality rates. The challenge of identifying threshold effects of SII on mortality rates.

  Systemic immune inflammatory index and mortality in chronic kidney disease · 2025 · DOI

Most-cited papers in Inflammatory Biomarkers in Disease Prognosis

• Association of Fibrinogen, C-reactive Protein, Albumin, or Leukocyte Count With Coronary Heart Disease · JAMA · 1998 · 1,580 citations
• Neutrophil to Lymphocyte Ratio: An Emerging Marker of the Relationships between the Immune System and Diseases · International Journal of Molecular Sciences · 2022 · 984 citations
• Red Blood Cell Distribution Width and the Risk of Death in Middle-aged and Older Adults · Archives of Internal Medicine · 2009 · 500 citations
• Systemic Immune Inflammation Index (SII), System Inflammation Response Index (SIRI) and Risk of All-Cause Mortality and Cardiovascular Mortality: A 20-Year Follow-Up Cohort Study of 42,875 US Adults · Journal of Clinical Medicine · 2023 · 451 citations
• Red Blood Cell Distribution Width and Mortality Risk in a Community-Based Prospective Cohort · Archives of Internal Medicine · 2009 · 402 citations
• Serum Albumin Level on Admission as a Predictor of Death, Length of Stay, and Readmission · Archives of Internal Medicine · 1992 · 362 citations
• The clinical value of neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), platelet-to-lymphocyte ratio (PLR) and systemic inflammation response index (SIRI) for predicting the occurrence and severity of pneumonia in patients with intracerebral hemorrhage · Frontiers in Immunology · 2023 · 360 citations
• A systematic review of the association between circulating concentrations of C reactive protein and cancer · Journal of Epidemiology & Community Health · 2007 · 322 citations
• Peripheral Blood Markers of Inflammation Predict Mortality and Functional Decline in High‐Functioning Community‐Dwelling Older Persons · Journal of the American Geriatrics Society · 2002 · 248 citations
• Neutrophil extracellular traps promote metastasis in gastric cancer patients with postoperative abdominal infectious complications · Nature Communications · 2022 · 206 citations

Most recent work

• Neutrophil percentage-to-albumin ratio is an independent risk factor for MACEs in patients with acute coronary syndrome undergoing percutaneous coronary intervention · Frontiers in Cardiovascular Medicine · 2026
• Association Between Systemic Immune-Inflammatory Index (SII) and Cancer Grading and Staging: Evidence from the Current Scientific Literature · Biology · 2026
• Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as prognostic factors in patients with colorectal cancer: a retrospective study · Frontiers in Medicine · 2026
• Persistent Systemic Inflammation Mediates the Impact of Postoperative Complications on Survival After Gastric Cancer Surgery · Annals of Surgical Oncology · 2026
• Neutrophil-to-lymphocyte Ratio as a Prognostic Indicator in Patients with Nursing and Healthcare-associated Pneumonia: A Retrospective Study · Internal Medicine · 2026
• Comparative value of novel inflammatory indices in predicting incident carotid atherosclerosis: SIRI outperforms other markers in a general population · Frontiers in Cardiovascular Medicine · 2026
• Prognostic value of the monocyte-to-albumin ratio in nasopharyngeal carcinoma: A retrospective cohort study · Annals of the Academy of Medicine Singapore · 2026
• The association between platelet-to-albumin ratio and diabetic peripheral neuropathy: A cross-sectional study in the Chinese population · PLoS ONE · 2026
• Association of systemic inflammatory indicators with incident valvular heart disease: a prospective analysis of the UK Biobank · European Journal of Preventive Cardiology · 2026
• Manual, digital, and AI tumour-infiltrating lymphocyte scoring: a secondary analysis of the APHINITY randomised trial · The Lancet Oncology · 2026

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