Introduction:
Sepsis is a life-threatening condition that requires emergency treatment, and the patient should be admitted to the intensive care unit (ICU). The most important key to successfully treating sepsis is the early diagnosis of the symptoms. Treatment includes recognizing the source of the infection and draining it, followed by fluids and administering broad-spectrum antibiotics.
What Is Sepsis?
Sepsis is a condition in which the body responds improperly due to an infection. Severe sepsis occurs when there is organ dysfunction. Septic shock occurs when there is decreased blood pressure even after fluid resuscitation. Systemic inflammatory response syndrome (SIRS) is when there are more than two organ failures. Sepsis can occur from any bacterial or viral infection. In the year 2020, virally-mediated sepsis had a devastating impact, followed by SARS-CoV-2 (Severe acute respiratory syndrome Coronavirus 2).
What Are the Novel Diagnostics for Sepsis?
Apart from blood cultures and molecular approaches such as PCR (polymerase chain reaction) and MALDI–TOF (matrix-assisted laser desorption ionization-time of flight), recently identified biomarkers help in diagnosing sepsis, which include:
Novel Innate Response Biomarkers
- PAMPs (Pathogen-Associated Molecular Patterns): With the help of PRRs (pattern-recognition receptors) on host cells, these biomarkers can be identified. PAMPs are derived from pathogens that are harmful and recognized by the immune system. Examples include bacterial lipopolysaccharides (LPS), which are present on the outer layer of the pathogen.
- DAMPs (Damage-Associated Molecular Patterns): These are released when there is damage or injury to the host cell and cause an immune response. These can also be detected using PRRs.
- Calprotectin: These are released from neutrophils which is a white blood cell that helps in the immune response. This protein complex has two subunits which are S100A8 and S100A9. It is increased in cases of gastrointestinal tract inflammation such as IBD (inflammatory bowel disease).
Novel Cytokine/Chemokine Biomarkers
Interleukin 6 (Il-6): This protein helps in measuring the severity of the condition. Its increased levels indicate a worse prognosis. It can be measured with the help of ELISA (enzyme-linked immunosorbent assays), which is a laboratory test to detect any biological samples in the blood.
- Monocyte Chemoattractant Protein 1 (MCP1): It is a type of chemokine, which is a small protein and is associated with the activation of a monocyte, which is a white blood cell. MCP1 helps in measuring the severity of the inflammation. It is also used as a prognostic marker.
- Pentraxin 3 (PTX 3): This protein acts as an acute phase reactant and increases as inflammation increases. It also helps in monitoring the response to the treatment.
- sTNFR1 (Soluble Tumor Necrosis Factor Receptor 1): TNF-α (tumor necrosis factor-alpha) is a type of inflammatory mediator and binds to TNFR1. This shows severe systemic inflammation with organ dysfunction. This also helps in measuring the severity and prognosis of the condition.
Receptor Biomarkers
- Presepsin: This is also called soluble CD14 subtype (sCD14-ST), which is found on the surfaces of monocytes and macrophages. This can help in early detection of sepsis.
- CD64: It is also called Fcγ receptor I (FcγRI). It is a type of surface cell protein that is found in various immune cells. Elevated levels are associated with phagocytic (ingestion of cells) and inflammatory function. It is measured with the help of flow cytometry which quickly analyses particles. Elevated levels suggest a poor prognosis.
Microcirculation-Related Biomarkers
- Angiopoietin-1 (Ang-1) And Angiopoietin-2 (Ang-2): These biomarkers belong to the family of growth factors. Therefore are involved in regulating blood vessels and endothelial function. These levels help in assessing endothelial dysfunction and blood vessel permeability.
- Micro-RNA (miRNA): These are small non-coding RNAs (ribonucleic acid) that regulate gene expression. These can be measured with the help of qPCR (quantitative polymerase chain reaction) or microarray analysis. These can be found in the body fluids. Some miRNAs (micro RNA [ribonucleic acid]) are miR-122, miR-146a, miR-150, and miR-155.
Biomarkers of Organ Dysfunction
- Long Non-coding RNAs (LncRNAs): These contain more than 200 nucleotides, and they do not encode proteins. These are associated with chromatin remodeling, gene regulation, and cellular signaling.
- Matrix Metalloproteinases (MMPs): These are a group of enzymes that play an important role in the remodeling and degradation of the extracellular matrix, which provides support to the organs. These MMPs are associated with the severity of sepsis and organ dysfunction.
- Nanodiagnostics: These include the use of nanotechnology in the detection of biomarkers. It has unique properties because of its large surface area and small size. A type called nanosensors utilize nanomaterials to diagnose the specific molecule.
What Are the Novel Therapeutics in Sepsis?
The main aim in the treatment of sepsis should involve source control and treating the inflammatory response, and protecting the organs. The novel therapeutics in sepsis include:
Pathogen-Directed Therapies
- PAMPs Removal: The main goal is to remove the circulating pathogen molecules (removal of PAMPs). These include the use of extracorporeal therapies (filtration of the blood) such as hemoperfusion and hemodialysis (filtration of the blood with the help of a dialyzer).
- Bacteriophages: Also called phage therapy, which involves the use of bacteriophages which are the viruses that target and kill specific bacteria.
- Intravenous Immunoglobulin (IVIG): It is a type of blood product that is obtained from pooled human plasma and contains a high number of antibodies such as IgG, IgM, and IgA; therefore these improve the immune response.
- Targeted Monoclonal Antibodies: These are the antibodies that specifically bind to the targeted molecules which are involved in the development of sepsis. Examples include anti-tumor necrosis factor (TNF) antibodies, anti-CD14 antibodies, anti-endotoxin antibodies, and anti-interleukin 1 (IL-1) antibodies.
- Liposomes: These are small lipid-based vesicles and can encapsulate substances such as antibodies or drugs. Therefore these can help in drug delivery, with controlled release and target-specific release.
Host-Directed Therapies:
- Angiotensin 2: These hormones are especially used in septic shock. It helps in regulating fluid balance and blood pressure in the body and improves tissue perfusion.
- Selepressin: It is a type of selective vasopressin V1a receptor agonist drug that improves blood pressure and vascular tone and also restores tissue permeability.
- Mesenchymal Stem Cells: These are multipotent cells and can be derived from the umbilical cord, bone marrow, or adipose tissue. They contain regenerative properties and can improve the immune response. Apart from these, they also possess antimicrobial properties and the ability to repair tissue.
- Extracellular Vesicles: These are small membrane-bound vesicles that help in transferring bioactive molecules such as nucleic acid, proteins, or lipids. These improve the immune response, contains anti-inflammatory effects, and have the ability to repair and regenerate tissue.
- Toll-Like Receptor (TLR) Ligand Binders: These are a type of PRR that can initiate an immune response by spotting PAMPs. Some TLR ligand binders are TLR2 and TLR9 modulators, TLR4 inhibitors, and TLR7 and TLR8 agonists.
Conclusion:
Therefore, there are many new diagnostics and therapeutics that have been identified and developed for the treatment of sepsis. These novel diagnostics help in the early recognition of the pathogen and help in understanding the pathway of infection. But using multiple diagnostic biomarkers have more benefits than a single one.
