MetaSepsisCDSS:
Knowledge-Guide Clinical Decision Support System

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, the MetaSepsisBase, which is the first sepsis biomarker knowledge platform, was constructed. 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 MetaSepsisBase 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 MetaSepsisBase 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.