Sepsis: The Most Dangerous Inflammatory Disease

Sepsis is one of the oldest and most complex inflammatory diseases. The term “sepsis” is derived from the Greek word sepsin, which means “to make putrid” (Singh & Evans, 2006). Even though it has been reported since ancient times, this condition still represents an economic burden and it is considered a serious disease with high mortality rates (Angus & van der Poll, 2013). Recent epidemiological studies indicate that sepsis affects more than 48.9 million people worldwide each year, potentially leading to 11 million deaths (Rudd et al., 2020). Furthermore, it is estimated that 3 million newborns (neonatal sepsis) and 1.2 million children worldwide are affected by sepsis every year (Fleischmann-Struzek et al., 2018). Despite advances in the medical field in recent decades, epidemiological data on the disease are still scarce and underestimated, as the number of septic patients may be much higher than has been recorded (Adhikari et al., 2010). This article will describe the main definitions, symptoms, treatments, and challenges associated with sepsis and septic shock.

Definitions, Development, and Symptoms

Sepsis is defined as a life-threatening syndrome resulting from a systemic inflammatory response to an infection that leads to multiple organ dysfunction (organ failure) (Singer et al., 2016). In the most unfavorable cases, sepsis can progress to septic shock, in which the underlying abnormalities are profound enough to substantially increase mortality (Singer et al., 2016). The mechanisms of sepsis development are not fully understood, but two main phases have been characterized: an initial stage defined by a massive production of pro-inflammatory cytokines and a second stage marked by the process of immunosuppression. The initial phase of sepsis, known as SIRS—Systemic Inflammatory Response Syndrome—of a massive release of inflammatory mediators in response to the pathogenic organism's presence. SIRS is counterregulated by a phase of immunosuppression called CARS— Compensatory Anti-inflammatory Response Syndrome—marked by the release of anti-inflammatory cytokines with the aim of controlling exacerbated inflammation and restoring normal organ and tissue function (van der Poll et al., 2017; Ward et al., 2008). However, clinical and experimental studies suggest that the CARS sepsis phase makes patients more susceptible to secondary and opportunistic infections, which can be caused by various pathogens, increasing the risk of death (Sundar & Sires, 2013; van Vught et al., 2016).

Figure 1: Timeline of sepsis progression (Faix, 2013).

The inflammatory response in sepsis is mainly triggered by the activation of the body’s defense system (immune system), where inflammatory cells do recognize specific components of microorganisms, such as peptidoglycans, lipoteichoic acid (LTA), and lipopolysaccharide (LPS) (Bhan et al., 2016). This recognition will lead to the production and release of inflammatory mediators, or fundamental molecules for inflammatory cell recruitment, such as macrophages and neutrophils, which will migrate to the affected tissue in order to contain the infection by promoting bacterial death. However, through mechanisms that are not yet well understood, the inflammatory response in sepsis can be deregulated and progress from a local reaction to a systemic reaction, causing tissue and organ damage (Bhan et al., 2016). Sepsis can arise from infections caused by bacteria (most prevalent), viruses, fungi, or protozoa. More in detail, the main sources of infections that can lead to sepsis are typically classified as follows: lung (pneumonia), genitourinary (kidney or bladder infections), gastrointestinal (intestinal, liver, pancreas, or other infections), skin, and soft tissue (muscle or connective tissue infections) (Gauer et al., 2020).

Sepsis can affect individuals of all ages, but certain groups look more susceptible, including people over the age of 65 and infants. Some risk factors encompass long-term health conditions (chronic diseases), hospitalization, use of immunosuppressants (medications that suppress the immune system), and recent surgery or invasive medical procedures (Hunt, 2019).

Figure 2: Groups at risk for the development of sepsis (BioMérieux Connection, 2021).

The symptoms of sepsis show high variability and it may depend on several factors, which include: the primary site of infection (bladder, lungs, skin, etc.), the type of microorganism (fungus, bacteria, virus, etc.—and their varieties), the patient’s body response to the infection (overall patient’s health condition), and the interval before starting treatment (duration of the infection) (Caraballo & Jaimes, 2019). The main symptoms observed—lethargy, low blood pressure, shortness of breath, and confusion—are directly related to changes in the cardiovascular, respiratory, and central nervous systems. Alterations in these systems' functionality are referable to an exacerbated and systemic inflammatory response, resulting in a clinical condition called “Acute Organ Dysfunction”.

Changes in the Respiratory and Cardiovascular Systems

One of the most common manifestations of sepsis is increased respiratory rate (i.e., shortness of breath), which can occur when fluids accumulate in the lungs, blocking gas exchange and consequently leading to low oxygen levels in the tissues (hypoxemia). To restore the oxygen levels, the body responds by increasing the heart and respiratory rates. In addition to the increase in heart rate, another cardiovascular change is a decrease in blood pressure (hypotension). This is a consequence of blood vessel dilatation, typically observed in sepsis, which allows fluid to leak from the blood vessels into the tissues, causing generalized tissue edema. The coagulation system is also highly activated during sepsis. On the one hand, the formation of small clots is beneficial, helping to retain bacteria and prevent the systemic spread of infection (Lipinska-Gediga, 2016); on the other hand, the strong activation of this system can lead to a process known as “Disseminated Intravascular Coagulation”, a condition associated with thrombosis and hemorrhage, the latter being due to reduced coagulation factors and platelets (van der Poll et al., 2017).

Changes in the Central Nervous System and Others

Here, sepsis manifestations can be particularly linked to lethargy, confusion, or delirium. These symptoms may arise due to multiple factors that affect brain function, such as systemic inflammation, increased cytokine levels, blood vessel damage with loss of blood-brain barrier integrity, neuroinflammation, altered brain metabolism, and impaired brain blood flow (Piva et al., 2023). The renal system is also commonly affected by sepsis, which increases the patient's risk of death (Gotts & Matthay, 2016). Septic acute kidney injury is a syndrome diagnosed by low urine output and elevated blood creatinine in which renal tubular cells are damaged and blood flow to the kidney is reduced (Alobaidi et al., 2015). In the liver, sepsis impairs the transport and processing of lipids and affects the removal of metabolites by liver cells (Gotts & Matthay, 2016). Sepsis-induced liver damage is evidenced by elevated blood levels of alanine aminotransferase (an important liver enzyme) and bilirubin (a molecule metabolized by the liver).

Figure 3: Sepsis Symptoms (Cleveland Clinic. n.d.).

Diagnosis

Sepsis is a potentially dangerous infection that requires prompt identification and treatment. Diagnosing this condition can be challenging due to its complexity and numerous symptoms that overlap with other conditions, such as infection or trauma. To facilitate the practice of healthcare professionals and to ensure effective and timely treatment for patients, the first International Consensus for the Definition of Sepsis and Septic Shock (Sepsis-1) was established in 1991 to formulate principles for rapid diagnosis of the disease to allow early therapeutic intervention (Bone et al., 1992). The criteria were organized as follows:

• Body temperature > 38°C or < 36°C;

• Heart rate > 90/min;

• Respiratory rate > 20/minute (or PaCO2< 32mmHg);

• Global blood leukocyte count > 12,000 cells/µL or < 4,000 cells/µL (or > 10% immature forms) (Bone et al., 1992).

Since these principles are sensitive, but non-specific—as other diseases can display similar outcomes—there was a need to develop a more complex list of signs and symptoms to reflect the clinical picture of sepsis better. Thus, in 2001, the second International Consensus for the Definition of Sepsis and Septic Shock (Sepsis-2) refined the general signs and symptoms of the disease as well as incorporated thresholds for organ damage (Levy et al., 2003).

As research on sepsis has advanced significantly in recent years, both the scientific and medical communities have proposed a revision of the previous definition postulated in 2001. Thus, according to the latest International Consensus for the Definition of Sepsis and Septic Shock (Sepsis-3) of 2015, sepsis is characterized by the initial activation of both pro-inflammatory and anti-inflammatory responses, associated with important modifications in non-immunological systems such as cardiovascular, and neuronal, hormonal, bioenergetic, metabolic, and coagulation. As its definition was centered on “organ dysfunction," an organ dysfunction score, called SOFA (Sequential Organ Failure Assessment), was then established as a diagnostic criterion (Table 1). According to this score, the patient who presents a SOFA classification ≥ 2 points would have sepsis (Singer et al., 2016).

Table 1: Sequential [Sepsis-Related] Organ Failure Assessment Score (Singer et al., 2016).

Given the limitations of using SOFA, especially outside intensive care units, quickSOFA was developed for rapid diagnosis consisting of at least 2 of the following easily obtained clinical parameters: 

• Respiratory rate ≥ 22/min;

• Systolic blood pressure ≤ 100mmHg;

• Changes in the state of consciousness.

Clinically speaking, septic shock is defined as sepsis with increased lactate levels and hypotension (low blood pressure) requiring blood vessel constrictor therapy (vasopressor drugs) (Hotchkiss et al., 2016). Elevated lactate levels are usually caused by impaired tissue oxygenation. To identify septic shock, the following parameters are monitored:

• Hypotension requiring vasopressors to maintain a mean arterial pressure ≥ 65mmHg;

• Lactate level greater than 2 mmol/L (>18mg/dL), despite adequate volume administration of intravenous fluids (Singer et al., 2016).

Treatment

Screening of patients with sepsis and septic shock should be done based on the patient’s signs and symptoms, biomarker measurement, and SOFA assessment to allow for early identification and prompt intervention. Treatment should focus on antimicrobial therapy, restoration of tissue blood flow, and management of organ dysfunction (Cecconi et al., 2018). The management of sepsis is a dynamic process that requires close monitoring, and therapy adjustments may be necessary based on the patient's response.

Early antibiotic treatment is essential and a broad-spectrum antibiotic (one that is effective against a wide range of bacteria) is the first choice until the specific pathogen causing the infection is identified. Once the results of laboratory tests are available, a more effective antibiotic for that specific bacteria should be administered. Intervention with intravenous fluids (fluid resuscitation) should be performed to increase blood pressure within normal levels and ensure adequate tissue blood flow. The administration of vasopressor medications may also be necessary to constrict blood vessels and restore blood pressure. Generally, affected patients do require supportive care to control organ dysfunction and failure, including mechanical ventilation for respiratory support, renal replacement therapy for kidney failure, blood transfusion, and others (Rello et al., 2017). Since sepsis is characterized by exacerbated inflammation, the use of anti-inflammatory drugs such as corticosteroids has also been suggested to treat the disease but is still controversial (Vandewalle & Libert, 2020). Continuous monitoring of vital signs, laboratory biomarkers, and SOFA assessment may be essential as a personalized therapeutic approach is often necessary.

Figure 4: Treatment and monitoring of a septic patient (News in Health, 2014).

Challenges and Perspectives

Despite the recent progress involving sepsis medical care and scientific discoveries, it is still a challenge to define, diagnose, and effectively treat sepsis because of the complexity of the disease. The diagnosis of sepsis involves a combination of clinical assessment, laboratory tests, and imaging tests (Duncan et al., 2021), as a specific biomarker for this disease has not yet been identified (Rudd et al., 2018). The complexity of the diagnostic process may contribute to delays in effective treatment, which may cause long-term hospitalizations and increased mortality rates (Marik, 2014). Moreover, numerous signs and symptoms associated with sepsis often overlap with those of other illnesses, leading to potential misdiagnosis (Duncan et al., 2021). The true prevalence of the disease may be underestimated, as the actual number of septic patients is likely higher than officially reported (Adhikari et al., 2010).

Sepsis is also an economic burden. As a matter of fact, treatments typically involve long-term hospitalization, and often in an intensive care unit. Furthermore, patients who survive sepsis are more likely to be readmitted due to permanent organ damage, which leads to physical disability and cognitive impairment, a condition known as “post-sepsis syndrome” (Hall et al., 2011). In addition, sepsis-related outcomes may be due to antibiotic resistance, as bacterial infections are not cleared after antibiotic treatment, making this disease even more dangerous (Goldstein et al., 2019).

Advancing our understanding of sepsis, improving diagnosis, developing more effective treatments, addressing prevention, and raising public awareness of early symptom recognition can be crucial to reducing the mortality and burden associated with sepsis. Investment in research and innovation is still necessary and may be critical to the development and progression of the disease. The identification of reliable biomarkers for early detection of sepsis would be important to rapidly assess the severity of the disease and initiate timely interventions. Simultaneous advances in both therapies and technology towards individualized treatment by early identification of patients at risk could be critical in both monitoring and reducing sepsis mortality.

Conclusion

Sepsis is a condition that carries high mortality and potentially life-changing effects. The mechanisms of sepsis onset and progression are complex and not yet fully understood. Besides, sepsis poses a health and economic burden, involving long-term hospitalization, intensive care unit stays, and post-sepsis syndrome, affecting the quality of life of a significant number of patients.

Efforts within the medical and research communities to refine diagnostic methods and therapeutic interventions are ongoing, but not yet fully satisfactory. Despite improvements in recent years, further progress is needed as millions of people around the world are still affected by this deadly disease. A multidisciplinary approach involving medical enhancements and technological tools may be essential for an effective and comprehensive sepsis management strategy.

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