Sepsis

Sepsis is a potentially life-threatening condition that arises when the body's dysregulated response to infection causes injury to its own tissues and organs.
This initial stage of sepsis is followed by dysregulation of the immune system. Common signs and symptoms include fever, increased heart rate, increased breathing rate, and confusion. There may also be symptoms related to a specific infection, such as a cough with pneumonia, or painful urination with a kidney infection. The very young, old, and people with a weakened immune system may not have any symptoms specific to their infection, and their body temperature may be low or normal instead of constituting a fever. Severe sepsis may cause organ dysfunction and significantly reduced blood flow. The presence of low blood pressure, high blood lactate, or low urine output may suggest poor blood flow. Septic shock is low blood pressure due to sepsis that does not improve after fluid replacement or requires medications to raise the blood pressure.
Sepsis is caused by many organisms including bacteria, viruses, and fungi. Gram negative and gram positive bacteria are the most common causes of sepsis. Viral pathogens and diarrheal illnesses are common causes in children. In 60–70% of cases an infectious pathogen is found. Common locations for the primary infection include the lungs, brain, urinary tract, skin, and abdominal organs. Risk factors include being very young or old, a weakened immune system from conditions such as cancer or diabetes, major trauma, and burns. A shortened sequential organ failure assessment score, known as the quick SOFA score, has replaced the SIRS system of diagnosis. qSOFA criteria for sepsis include at least two of the following three: increased breathing rate, change in the level of consciousness, and low blood pressure. Sepsis guidelines recommend obtaining blood cultures before starting antibiotics; however, the diagnosis does not require the blood to be infected. Medical imaging is helpful when looking for the possible location of the infection. Other potential causes of similar signs and symptoms include anaphylaxis, adrenal insufficiency, low blood volume, heart failure, and pulmonary embolism.
Sepsis requires immediate treatment with intravenous fluids and antimicrobial medications. Ongoing care and stabilization often continues in an intensive care unit. If an adequate trial of fluid replacement is not enough to maintain blood pressure, then the use of medications that raise blood pressure becomes necessary. Mechanical ventilation and dialysis may be needed to support the function of the lungs and kidneys, respectively. A central venous catheter and arterial line may be placed for access to the bloodstream and to guide treatment. Other helpful measurements include cardiac output and superior vena cava oxygen saturation. People with sepsis need preventive measures for deep vein thrombosis, stress ulcers, and pressure ulcers unless other conditions prevent such interventions. Some people might benefit from tight control of blood sugar levels with insulin. The use of corticosteroids is controversial, with some reviews finding benefit, others not.
A person's age, immune system function, the virulence of the pathogen causing infection, the amount of microorganisms in the body causing infection all affect the incidence, severity and prognosis of sepsis. The risk of death from sepsis is as high as 30%, while for severe sepsis it is as high as 50%, and the risk of death from septic shock is 80%. Sepsis affected about 49 million people in 2017, with 11 million deaths. In the developed world, approximately 0.2 to 3 people per 1000 are affected by sepsis yearly. Rates of disease have been increasing. 85% of cases occurred in low or middle income countries with 40% of cases worldwide occurring in Sub-Saharan Africa. Some data indicate that sepsis is more common among men than women; however, other data show a greater prevalence of the disease among women.

Signs and symptoms

In addition to symptoms related to the actual cause, people with sepsis may have a fever, low body temperature, rapid breathing, a fast heart rate, confusion, and edema. Early signs include a rapid heart rate, decreased urination, and high blood sugar. Signs of established sepsis include confusion, metabolic acidosis, low blood pressure due to decreased systemic vascular resistance, higher cardiac output, and disorders in blood-clotting that may lead to organ failure. Fever is the most common presenting symptom in sepsis, but fever may be absent in some people, such as the elderly or those who are immunocompromised.
The drop in blood pressure seen in sepsis can cause lightheadedness and is part of the criteria for septic shock.
Oxidative stress is observed in septic shock, with circulating levels of copper and vitamin C being decreased.
Diastolic blood pressure falls during the early stages of sepsis, causing a widening/increasing of pulse pressure, which is the difference between the systolic and diastolic blood pressures. If sepsis becomes severe and hemodynamic compromise advances, the systolic pressure also decreases, causing a narrowing/decreasing of pulse pressure. A pulse pressure of over 70 mmHg in patients with sepsis is correlated with an increased chance of survival. A widened pulse pressure is also correlated with an increased chance that someone with sepsis will benefit from and respond to IV fluids.

Cause

Infections leading to sepsis are usually bacterial but may be fungal, parasitic, or viral. Gram-positive bacteria were the primary cause of sepsis before the introduction of antibiotics in the 1950s. After the introduction of antibiotics, gram-negative bacteria became the predominant cause of sepsis from the 1960s to the 1980s. After the 1980s, gram-positive bacteria, most commonly staphylococci, are thought to cause more than 50% of cases of sepsis. Other commonly implicated bacteria include Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella species. Fungal sepsis accounts for approximately 5% of severe sepsis and septic shock cases; the most common cause of fungal sepsis is an infection by Candida species of yeast, a frequent hospital-acquired infection. The most common causes for parasitic sepsis are Plasmodium, Schistosoma and Echinococcus.
The most common sites of infection resulting in severe sepsis are the lungs, the abdomen, and the urinary tract. 40–60% of infections causing sepsis originate in the lungs, 15–30% are abdominal infections, and 15–30% are bladder, kidney, skin or soft tissue infections. But the site of infection, as well as the causative infectious pathogen vary depending on geographic location and region.

Pathophysiology

Sepsis is caused by a combination of factors related to the particular invading pathogen and the status of the immune system of the host. The early phase of sepsis, characterized by excessive inflammation, may be followed by a prolonged period of decreased functioning of the immune system. Either of these phases may prove fatal. On the other hand, systemic inflammatory response syndrome occurs in people without the presence of infection, for example, in those with burns, polytrauma, or the initial state in pancreatitis and chemical pneumonitis. However, sepsis also causes a similar response to SIRS.
Platelets have a potentially key role in immune modulation during sepsis. Systemic inflammation, endothelial injury, and dysregulated coagulation activate platelets in the early phases of the condition. These activated platelets interact with leukocytes and endothelial cells, amplifying both inflammatory and thrombotic responses. This interaction contributes to microvascular thrombosis and progression to multiple organ dysfunction syndrome.

Microbial factors

Bacterial virulence factors, such as glycocalyx and various adhesins, allow colonization, immune evasion, and establishment of disease in the host. Sepsis caused by gram-negative bacteria is thought to be largely due to a response by the host to the lipid A component of lipopolysaccharide, also called endotoxin. Sepsis caused by gram-positive bacteria may result from an immunological response to cell wall lipoteichoic acid. Bacterial exotoxins that act as superantigens also may cause sepsis. Superantigens simultaneously bind major histocompatibility complex and T-cell receptors in the absence of antigen presentation. This forced receptor interaction induces the production of pro-inflammatory chemical signals by T-cells.
There are several microbial factors that may cause the typical septic inflammatory cascade. An invading pathogen is recognized by its pathogen-associated molecular patterns. Examples of PAMPs include lipopolysaccharides and flagellin in gram-negative bacteria, muramyl dipeptide in the peptidoglycan of the gram-positive bacterial cell wall, and CpG bacterial DNA. These PAMPs are recognized by the pattern recognition receptors of the innate immune system, which may be membrane-bound or cytosolic. There are four families of PRRs: the toll-like receptors, the C-type lectin receptors, the NOD-like receptors, and the RIG-I-like receptors. Invariably, the association of a PAMP and a PRR will cause a series of intracellular signalling cascades. Consequently, transcription factors such as nuclear factor-kappa B and activator protein-1 will up-regulate the expression of pro-inflammatory and anti-inflammatory cytokines.
Other immunological responses related to microbial infections, such as NETs, can also play a role or be observed in sepsis. NET formation only occurs via neutrophil cell death, which occurs during microbial infections. Neutrophil extracellular traps, called NETs, eliminate bacteria from the blood flow. These compounds are part of the innate immune system, which is activated initially during infections.