Sepsis is a leading cause of human mortality and disability worldwide. Biomarkers have been widely used to improve the diagnosis, therapy and prognosis of human sepsis. Despite numerous studies published in PubMed and many biomarkers identified, there is an urgent need for a comprehensive database to collect, annotate and display the biomedical information on sepsis biomarkers. Therefore, MetaSepsisBase was updated to MetaSepsisKnowHub, which is the first sepsis biomarker knowledge-enhanced platform integrating RAG architecture. This knowledge platform includes biomedical information on 427 sepsis biomarkers with 644 records, which were collected from the PubMed and annotated by NCBI Gene database (Nhttps://www.ncbi.nlm.nih.gov/gene) and HGNC database (https://www.genenames.org).

1)Adult sepsis(Age>18 years old)

1.1 The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)[1]

1.1.1 SIRS (Systemic Inflammatory Response Syndrome)
Two or more of:
  Temperature >38°C or <36°C
  Heart rate >90/min
  Respiratory rate >20/min or PaCO2 <32 mm Hg (4.3 kPa)
  White blood cell count >12,000/mm3 or <4,000/mm3 or >10% immature bands

1.1.2 Sepsis
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Organ dysfunction can be identified as an acute change in total SOFA score ≥2 points consequent to the infection.

1.1.3 Septic shock
Septic shock is defined as a subset of sepsis in which underlying circulatory and cellular metabolism abnormalities are profound enough to substantially increase mortality
Patients with septic shock can be identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain MAP ≥65 mm Hg and having a serum lactate level >2 mmol/L (18mg/dL) despite adequate volume resuscitation.

1.2 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference (Sepsis-2)[2]

1.2.1 SIRS (Systemic Inflammatory Response Syndrome)
Two or more of:
  Temperature >38°C or <36°C
  Heart rate >90/min
  Respiratory rate >20/min or PaCO2 <32 mm Hg (4.3 kPa)
  White blood cell count >12,000/mm3 or <4,000/mm3 or >10% immature bands

1.2.2 Sepsis
Sepsis to be the clinical syndrome defined by the presence of both infection and a systemic inflammatory response. We defined infection as a pathologic process caused by the invasion of normally sterile tissue or fluid or body cavity by pathogenic or potentially pathogenic microorganisms. Because of the limitations of SIRS discussed above, we included a list of possible signs of systemic inflammation in response to infection (Table 1).

1.2.3 Severe sepsis
Severe sepsis is defined as sepsis combined with organ dysfunctions.

1.2.4 Septic shock
Septic shock in adults refers to a state of acute circulatory failure characterized by persistent arterial hypotension unexplained by other causes.
Hypotension is defined by a systolic arterial pressure below 90 mm Hg (or, in children, <2SD below normal for their age), a MAP <60, or a reduction in systolic blood pressure of >40 mmHg from baseline, despite adequate volume resuscitation, in the absence of other causes for hypotension.

2)Neonatal sepsis (0-28 days after birth)Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children[3]

2.1 Age classification
Early on-set (EOS): Within 3 days of birth
Late on-set (LOS): 3 days after birth
Hybrid: Unclear relationship between the diagnosis time of neonatal sepsis and the date of birth

2.2 SIRS (Systemic Inflammatory Response Syndrome)
Two or more of:
  Temperature >38°C or <36°C
  Heart rate >90/min
  Respiratory rate >20/min or PaCO2 <32 mm Hg (4.3 kPa)
  White blood cell count >12 000/mm3 or <4000/mm3 or >10% immature bands

2.3 Sepsis
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.

2.4 Severe sepsis
Severe sepsis is defined as sepsis combined with organ dysfunctions. Organ dysfunction can be identified as an acute change in total SOFA score ≥2 points consequent to the infection.

2.5 Septic shock
Fever, tachycardia, and vasodilation are a common inflammatory response triad during infection. When the child presents with both a mental change and a triad of inflammatory reactions, septic shock should be suspected. The mental change manifests as irritability, abnormal crying, fatigue, blurred consciousness, reluctance to communicate with parents, drowsiness, or inability to awaken.

3)Children sepsis (1 month-18 years old): Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children[3]

3.1 SIRS (Systemic Inflammatory Response Syndrome)
Two or more of:
  Temperature >38°C or <36°C
  Heart rate >90/min
  Respiratory rate >20/min or PaCO2 <32 mm Hg (4.3 kPa)
  White blood cell count >12 000/mm3 or <4000/mm3 or >10% immature bands

3.2 Sepsis
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.

3.3 Severe sepsis
Severe sepsis is defined as sepsis combined with organ dysfunctions. Organ dysfunction can be identified as an acute change in total SOFA score ≥2 points consequent to the infection.

3.4 Septic shock

(1) Sepsis shock compensation period (early phase):
  The clinical manifestations meet 3 of the following 6 criteria:
  1.Change of consciousness, restlessness or lethargy, indifferent expression, blurred consciousness, and even coma or convulsion (commonly seen in decompensated shock)
  2.Skin changes, pale and gray complexion, cyanosis around the lips and fingers, skin patterns, and cool limbs. If there is a flushed complexion, warm limbs, and dry skin, it is considered warm shock
  3.Heart rate, pulse, peripheral arterial pulsation is weak, and heart rate and pulse increase rapidly
  4.Capillary refilling time ≥ 3s (excluding environmental temperature effects)
  5.Urinary volume<1 mL/(kgh)
  6.Metabolic acidosis (excluding other ischemic hypoxia and metabolic factors)

(2) Septic shock decompensated period: clinical manifestations worsen with decreased blood pressure during the compensatory period.
  Systolic blood pressure<5th percentile of the same age group or<2 standard deviations from the normal value of that age group. (<70 mm Hg at 1-12 months, < [70 mm Hg +2*age (years old)] at 1-10 years old, <90 mm Hg at>10 years old.)

4)SOFA score criteria

5)qSOFA (Quick SOFA) criteria
  Respiratory rate ≥22/min
  Altered mentation
  Systolic blood pressure ≥100 mm Hg

Reference
  1. Singer, M., et al., The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA, 2016. 315(8): p. 801-10.
  2. Levy, M.M., et al., 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med, 2003. 31(4): p. 1250-6.
  3. Weiss, S.L., et al., Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children. Pediatr Crit Care Med, 2020. 21(2): p. e52-e106.

All data included in our MetaSepsisKnowHub were collected from PubMed by manual text-mining.

The following key words were used for searching PubMed:

“(sepsis[tiab] OR septic shock[tiab] OR severe sepsis[tiab]) AND (biomarker[tiab] OR marker[tiab] OR indicator[tiab])”.

The further annotation of biomarkers was obtained via the NCBI Gene database and HGNC database.

The original articles were screened in detail, and irrelevant papers were excluded. From the included papers, we extracted the identified sepsis biomarkers along with their biomedical information. The inclusion criteria were as follows:

1. The article should definitely conclude that the target biomarker can be used as an effective biomarker for sepsis;

2. The design and implementation of the experiments should be scientific and logical;

3. Relevant results should have significant statistical value including diagnostic or prognostic biomarkers’ names, the area under the curve (AUC) on the diagnostic receiver operating characteristic (ROC) curve, sensitivity and specificity. The numerical value above should be >0.6. For prognostic biomarkers, the odds ratio, risk ratio and hazard ratio should be >1.2 or < 0.8, and the p-value should be < 0.01;

4. Articles containing detailed experimental information and biomarker description were considered first;

5. The research should contain an ethics license or a declaration of no ethical issues.

We plan to update the MetaSepsisKnowHub every 12 months with new functions, new data and newly designed interface.

GO was used to annotate genes in biological processes, cellular components, and molecular functions, and pathway enrichment analysis of biomarkers was conducted with KEGG, via String (http://string-db.org). All biomarkers were analyzed for GO and KEGG enrichment analyses, and the following figure displays the top 5 fields with the highest frequency in GO and top 20 pathways in KEGG pathway analysis. Alongside each database update, we will also update the results of the enrichment analyses.


To understand the biomarkers better in the view of systems biology, we conducted analyses of protein-protein interaction (PPI) and miRNA-gene interaction.



Practical Analysis Platform Link

Item Definition
Research Information

ID

ID in the database, A refers to Adult, N refers to Neonatal, C refers to Children

Disease Stratification

The clinical stratifications and severity of disease, including SIRS, sepsis, severe sepsis or septic shock

Application Type

The type of application of biomarkers, including diagnosis or prognosis

Biomarker Category

Category based on the biological effects or clinical use of biomarkers, including acute phase protein, CD molecule, cytokine biomarker, chemokine biomarker, miRNA, lncRNA, neuropeptide, lipocalin, metabolites, clinical assessment tool, etc.

Samples Information

Detailed description of samples used to identify the biomarker (biomarker candidate), including number of samples in each group.

Samples Type

The source of the samples in the study, including whole blood, serum, plasma, urine, saliva, etc.

Research Technique

Main technologies for separating and analyzing biomarkers

Pubmed ID

ID of the literature in the PubMed database

Published Year

Year of the literature published

Region

The country or region where the main research progress is located

Biomarker Information

Biomarker Name

Name of biomarker

Biomarker Description

The brief introduction of biomarkers

NCBI Gene ID

ID of NCBI gene database

Gene type

Category based on the biological effects of genes, including protein-coding, ncRNA, lncRNA, biological-region, etc.

Ensemble ID

ID of ENSEMBL database

HGNC ID

ID of HGNC database

Uniprot ID

ID of UniProt database

OMIM ID

ID of OMIM database

Brief Name

Brief name of biomarkers in NCBI and HGNC database

Level of Effect

Category at different levels based on the genetic central dogma, including gene level, transcription, translation, cell level and organ dysfuction

Cut off Value

A threshold value for a quantity

AUC

The area under the curve

Sensitivity

Sensitivity relates to the test's ability to identify positive results

Specificity

Specificity relates to the test's ability to identify negative results.

Abundance Change in Patients or Non-survivors

If not specified, it refers to the disease versus control ratio of the expression level of biomarkers.

Summary

The overall comments to biomarkers

Cohort or Experimental Validation

The situation where the research results have been validated through basic experiments or cohorts

Potential Drug Target Information

TTD ID

ID of TTD database

PubChem ID

ID of PubChem database

KEGG Pathways

KEGG signaling pathways associated with biomarker

Drug Name

Name of potential drug that can use biomarker as therapeutic target

Indication

Indication of potential drug

Therapeutic Category

Therapeutic effect category of potential drug, including anti-inflammatory agent, anti-cancer agent, anti-viral agent, analgesics, etc.