Abstract

Sepsis is a life-threatening condition that leads to severe organ failure. It is a growing major concern, disproportionally affecting older adults, who represent 60 to 80% of the cases. Despite improvements in treatment over the years, mortality rates remain around 20%. Many patients require treatment in the intensive care unit for sepsis. There are many causes of this, ranging from bacteria to viruses. It is important to diagnose sepsis early, so effective treatment can be instituted early, increasing the chance for better outcomes. Treatment and diagnosis can be expedited using specific biomarkers such as C-reactive protein, procalcitonin test, and damage-associated molecular patterns. Exploring biomarkers might help the process of sepsis management.

Keywords

Biomarkers, C-reactive protein, Pathogen-Associated Molecular Pattern Molecules, Procalcitonin, Sepsis, 

Introduction

Sepsis is a systemic inflammatory condition that causes life-threatening organ failure, which occurs when the body has an extreme response to an infection.¹ Sepsis is a serious clinical concern; if left untreated, it may progress rapidly, leading to septic shock, which causes organ failure, possibly leading to death.² Early recognition and diagnosis are crucial for improving the likelihood of survival. On average, the mortality rate is around 20% with around 360 cases per 100,000 people per year in the UK.³

Causes

Usually, bacterial infections are the primary cause of sepsis; however, viral and fungal infections can also lead to sepsis.³ An investigation conducted in over 70 countries discovered that in patients in ICUs, the types of infections were as follows: gram-negative(62%), gram-negative bacteria(47%), fungal (19%), and viruses having the lowest proportion.⁴ There can also be non-infectious causes of sepsis, which include sterile inflammatory conditions such as burns, pancreatitis, etc.⁵

Risk factors

Anyone can develop sepsis if infected.⁶ However, young children, older adults, and persons with underlying health

conditions, such as diabetes, have a higher risk of developing sepsis.⁷ Reports suggest that 60% to 80% of septic cases occur in people over 65.^8,9 Older individuals are more vulnerable to developing sepsis due to frailty and a weakened immune system, and these may have serious health outcomes.¹⁰ The risks of sepsis in infants are due to malnutrition and hospital-acquired infections.¹¹

Symptoms

Symptoms of sepsis include rapid heart rate, low blood pressure, fever, and difficulty breathing.⁶ Sepsis may have Postural Orthostatic Tachycardia Syndrome (POTS) and Orthostatic Hypotension.¹² Tests are done to establish the cause of sepsis, which include blood and urine culture, etc.¹³

Management

Management of sepsis requires admission to the hospital, preferably in the intensive care unit. Treatment with appropriate antibiotics is needed. The choice of antibiotics depends on the cause of the infection and other factors such as allergies, the patient’s age, etc.¹

Challenges in diagnosing sepsis

Given the variety of symptoms sepsis has, there may be overlaps with other systemic infections.¹⁴ For example, meningitis and sepsis both have dizziness, confusion, and difficulty breathing as symptoms.^15,16 However, expected symptoms may not always be present. For example, an immunosuppressed patient may not develop a fever, or critically ill patients may experience tachycardia, but this is due to stress and is not an indication of sepsis.¹⁷

Despite the many biomarkers sepsis has, e.g., C-reactive protein (CRP) and procalcitonin (PCT), diagnosis is not based on only one of them.¹⁸ CRP is one of the most common biomarkers of sepsis, increasing in all inflammatory disorders, even in uncomplicated surgeries. PCT is also involved, though it is considered to be more specific than CRP.¹⁷

There is no single definitive test for diagnosing sepsis.¹⁹ To help categorise patients, clinicians use the Sequential Organ Failure Assessment score (SOFA) to help identify the risk of mortality of a patient or groups of patients.^20,21 The SOFA score is based on 6 factors; these include respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems. These are scored from 0 to 4, and the higher the score, the more likely that there is organ failure.²⁰ The SOFA score can be used daily to monitor the patient’s health, as a comparative factor, and overall to see if there is any progress.²¹ However, the SOFA score cannot predict the outcome, specifically whether a patient will die or not, which depends on the care given; the SOFA score was designed for adults and is not available for children.²¹

Role of biomarkers in diagnosis, management, and prognosis of sepsis

Biomarkers play a crucial role in the diagnosis and treatment of sepsis as they further help antibiotic therapy, identify risks, and patient management.^22,23 Many biomarkers have been identified for sepsis, including fluid phase pattern recognition molecules (PRMs), damage-associated molecular patterns (DAMPs), C-reactive protein (CRP), and lactate, being the most commonly used biomarker.^18,22

CRP is an acute reactive protein that is produced by the liver; it rises rapidly in response to inflammation and infection.²⁴ However, it is also affected by other factors such as trauma and surgery.²⁴ Due to this, it cannot be used alone to diagnose sepsis and should be combined with other biomarkers such as the procalcitonin test (PCT). Procalcitonin is the peptide precursor of calcitonin, and it helps maintain calcium levels in the blood.²⁵ During a bacterial infection, the immune system activates macrophages and monocytes. This activation leads to the release of pro-inflammatory cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-α). These cytokines stimulate the production of procalcitonin (PCT) in the liver and various other tissues.²⁶ PCT concentrations increase early and normalise rapidly, with a half-life of 24 hours, compared to CRP, which takes 12 to 24 hours to rise and remains raised for 3 to 7 days.²⁷ PCT levels remain low or only slightly elevated in viral or mild bacterial infections.

Due to this, PCT can contribute to an early diagnosis, lowering the chance of developing sepsis.²⁷ Furthermore, during a bacterial infection, the PCT concentration is usually above 0.1 ng/mL, but at a concentration above 0.5ng/mL, the patient may be at risk of developing sepsis.²⁷ Measuring PCT levels in urine can be valuable in patients with sepsis, particularly in cases involving urinary tract infections or urosepsis. Additionally, cerebrospinal fluid (CSF) PCT levels may help in diagnosing central nervous system infections, such as bacterial meningitis, in septic patients.^23,28 Together, CRP and PCT values can provide a diagnosis of an infection before it develops into sepsis, making them promising biomarkers that may contribute to more effective treatment.^27,29

Sepsis damages various cells, including lymphocytes and gastrointestinal epithelial cells, leading to apoptotic cell death.^7,30 When cells get destroyed, High-MobilityGroupBox1 (HMGB1), a non-histone nuclear protein  involved  in  the regulation  of inflammatory

responses, is released either actively by stimulated macrophages or passively during cellular necrosis and apoptosis. As a late mediator of sepsis, HMGB1 acts as DAMPs, which are released into the systemic circulation, and can help to promote immune defence.^7,31 DAMPs sustain inflammation by activating macrophages through the Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) pathways.³² Many types of DAMPs help with this, such as S100 proteins and HMGB nuclear proteins; S100 proteins are calcium-binding proteins primarily found in phagocytes’ cytoplasm. S100A8/A9 are the S100 family heterodimer, and their levels become high during sepsis.⁷

Increased HMGB1 levels in the later stages of sepsis are associated with worse outcomes, particularly in patients with pre-existing chronic inflammatory conditions, and are linked to higher mortality rates.³³ Due to its role in the progression of sepsis, HMGB1 is being investigated as a potential biomarker for both diagnosis and prognosis.

While DAMPs are endogenous molecules released by dying host cells, pathogen-associated molecular pattern molecules (PAMPs) are exogenous microbial products released by pathogens; they both can increase inflammatory responses by activating signalling pathways through Pattern Recognition Pathways (PRR).^34,35 Examples of PAMPs include lipopolysaccharide (LPS) and lipoproteins.⁷ LPS are found in large quantities in the outer membrane of gram-negative bacteria, and when found in the blood, they may lead to septic shock in large amounts. To overcome this, clinicians have attempted to block LPS associated with gram-negative infections; however, no success was achieved.⁷ One study attempted to use the E5 monoclonal antibody against LPS, administering 2 doses of E5 to 847 patients for 30 days. However, there was no significant improvement.³⁶

Overall, DAMPs can be classed as an advantage and a disadvantage due to their ‘pro-inflammatory and immunosuppressive role’.³⁷ This depends on factors such as their concentration and length of exposure – if the concentration of DAMPs is too high, it may lead to a cytokine storm and cell death.^37,38 Additionally, there is a risk of DAMPs activating Systemic Inflammatory Response Syndrome (SIRS), which in severe circumstances, leads to multi-organ failure.³⁵ PAMPs can help activate antigen-presenting cells by interacting with PRRs, which can contribute to the adaptive immune system.³⁹

Using multiple biomarkers

It is important to investigate multiple biomarkers in sepsis diagnosis and management for the enhanced accuracy of the approach in detecting and evaluating the condition. Since sepsis involves complex and varied pathophysiological processes, relying on a single biomarker may fall short of capturing the full clinical picture. Combining multiple biomarkers that reflect different dimensions of immune response, inflammation, and organ dysfunction would offer a more comprehensive assessment of the clinical status. Employing a multi-Journal of Geriatric Care and Research biomarker approach facilitates early sepsis detection and helps stratify patients according to their risk of progression to severe sepsis or septic shock, ultimately guiding more precise and timely treatment decisions.

Conclusion

In summary, sepsis is a serious medical condition that requires treatment in a hospital and has a risk of death in almost 20%. Symptoms include dizziness, confusion, and breathing difficulties. Older adults are more vulnerable to sepsis and may have a worse prognosis. There are biomarkers that can help to diagnose the condition early. There are many biomarkers that can be used for investigation; the common ones are DAMPs and PAMPs. Use of multiple biomarkers is preferred. There is a need for investigating biomarkers early in patients showing the signs and symptoms of sepsis, which would help in the treatment process.

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