Bacterial Sepsis

Hippocrates, in the fourth century BCE, used the term sepsis denoting decomposition. Avicenna, in the eleventh century, called diseases causing purulence as blood rot. In the nineteenth century, the term sepsis was widely used to describe severe systemic toxicity. A closely derived term of septicemia was used for bacterial infection in the blood, which has been replaced by the term bacteremia. In the last 2 centuries, the processes underlying infections have been better studied and elucidated. The role of microorganisms in causing infections and the intricate mechanisms of various intrinsic and extrinsic toxins in damaging body tissues that result in fever and shock has been discovered with painstaking research. At the beginning of the twentieth century, the term endotoxin was devised by Pfeiffer to explain the causative agent in infection with cholera. It later was linked to other gram-negative bacterial pathogenicity. ^[13]

The initial sepsis clinical practice guidelines were published in 2004 and revised in 2008 and 2012. The October 2021 guidelines are a revision of the 2012 Surviving Sepsis Campaign (SSC) guidelines for the management of severe sepsis and septic shock. See Guidelines for more detail.

The October 2021 update to the global adult sepsis guidelines by the Surviving Sepsis Campaign (SSC) places a stronger focus on the care of sepsis patients after their discharge from the intensive care unit (ICU). ^[3]  These updated guidelines reflect increased geographic and gender diversity compared to previous versions.

Key highlights include the following:

• Long-term recovery: The guidelines recognize the significant long-term effects of sepsis, as patients often endure prolonged ICU stays and face a challenging recovery journey.
• Patient and family involvement: Emphasizing the importance of involving patients and their families in discussions about care goals and discharge planning.
• Ongoing support: Recommendations include ensuring early and continuous follow-up with healthcare providers to address the physical, cognitive, and emotional challenges that may arise post-discharge.

Overall, the updated guidelines aim to enhance the quality of care and support for sepsis survivors, facilitating a smoother transition from ICU to home.

The etiology of sepsis is diverse, and clinical clues to various organ systems aid in appropriate workup and diagnosis. It is pertinent to be able to distinguish between the infectious and noninfectious causes of fever in a septic patient. The following are organ system–specific etiologies of possible sepsis ^[14] :

• Skin/soft tissue: Necrotizing fasciitis, cellulitis, myonecrosis, or gas gangrene, among others, with erythema, edema, lymphangitis and positive skin biopsy result
• Wound infection: Inflammation, edema, erythema, discharge of pus, with positive Gram stain and culture results from incision and drainage or deep cultures
• Upper respiratory tract: Pharyngitis, tonsillitis, or sinusitis, among others, with inflammation, exudate with or without swelling, and lymphadenopathy or positive throat swab culture or rapid test result
• Lower respiratory tract:  Pneumonia, empyema, or lung abscess, among others, with productive cough, pleuritic chest pain, consolidation on auscultation, positive sputum culture result, positive blood culture result, rapid viral testing, urinary antigen testing (eg, Pneumococcus, Legionella), quantitative culture of protected brush, or bronchoalveolar lavage
• Central nervous system: Meningitis, brain abscess, or infected hematoma, among others, with signs of meningeal irritation, elevated CSF cell count and protein level, reduced CSF glucose level, positive Gram stain and culture results
• Cerebrovascular system: Myocardial infarction, acute valvular dysfunction, myocarditis, pericarditis, ruptured aortic aneurysm, aortitis, or septic emboli, among others, with elevated levels of cardiac enzymes, and imaging (ultrasonography, CT scanning, or MRI) of the chest, abdomen, and/or pelvis showing vascular involvement
• Vascular catheters (arterial, venous): Redness or drainage at insertion site, positive blood culture result (from the catheter and a peripheral site), and catheter tip culture after sterile removal
• Gastrointestinal:  Colitis, infectious diarrhea, ischemic bowel, or appendicitis, among others, with abdominal pain, distension, diarrhea, and vomiting; positive stool culture result and testing for toxigenic Escherichia coli, Salmonella, Shigella, Campylobacter, or Clostridium difficile
• Intra-abdominal: Renal abscess, pyelonephritis, pancreatitis, cholecystitis, liver abscess, intra-abdominal abscesses, or perforation, compromise, or rupture of an intra-abdominal or pelvic structure, among others, with specific symptoms and signs4; aerobic and anaerobic culture of drained abdominal fluid collections; peritoneal dialysis (PD) catheter infection with cloudy PD fluid, abdominal pain, deranged cell count, and positive PD fluid culture result
• Urinary tract:  Cystitis, pyelonephritis, urethritis, or renal abscess, among others, with urgency, dysuria, pelvic, suprapubic, or back pain; urine microscopy showing pyuria or a positive urine culture result; urosepsis has been reported after prostatic biopsy ^[15]
• Female genital tract: Pelvic inflammatory disease, cervicitis, or salpingitis, among others, with lower abdominal pain, vaginal discharge, positive results on endocervical and high vaginal swabs
• Male genital tract: Orchitis, epididymitis, acute prostatitis, balanitis, or prostatic abscess, among others, with dysuria, frequency, urgency, urge incontinence, cloudy urine, prostatic tenderness, and positive urine Gram stain and culture results
• Bone: Osteomyelitis presenting with pain, warmth, swelling, decreased range of motion, positive blood and/or bone culture results, and MRI changes
• Joint: Septic arthritis presenting with pain, warmth, swelling, decreased range of motion, positive arthrocentesis with cell counts, and positive Gram stain and culture results
• Nonspecific systemic febrile syndromes: Babesiosis, rickettsial diseases, lyme disease, typhus, or typhoid fever, among others, with multiorgan involvement, specific travel and epidemiologic exposures, and associated rashes or other symptoms

There are numerous noninfectious causes of fever and organ dysfunction that can mimic sepsis ^[16] :

• Alcohol/drug withdrawal
• Postoperative fever (48 hours postoperatively)
• Transfusion reaction
• Drug fever
• Allergic reaction
• Cerebral infarction/hemorrhage
• Adrenal insufficiency/adrenal hemorrhage
• Myocardial infarction
• Pancreatitis
• Acalculous cholecystitis
• Ischemic bowel
• Aspiration pneumonitis
• ARDS (both acute and late fibroproliferative phase)
• Subarachnoid hemorrhage
• Fat emboli
• Transplant rejection
• Deep venous thrombosis
• Pulmonary emboli
• Gout/pseudogout
• Hematoma
• Cirrhosis (without primary peritonitis)
• Gastrointestinal hemorrhage
• Phlebitis/thrombophlebitis
• IV contrast reaction
• Neoplastic fevers
• Decubitus ulcers

Table 1. Infectious and Noninfectious Causes of Fever ^[17] (Open Table in a new window)

An abdominal wall abscess is depicted on the CT scan below.

A right lower quadrant abdominal wall abscess and enteric fistula are observed and confirmed by the presence of enteral contrast in the abdominal wall.

Organisms can be introduced via various mechanisms, including direct inoculation of microbes into the body or body site, such as in skin or soft tissue infections or bloodstream infections associated with indwelling venous catheters. Inhalational acquisition is a mode of infection in the setting of respiratory infection, as is aspiration of oral/gastric content. Ascending urinary tract infection can cause systemic infection. The gastrointestinal tract also can be a source of infection if contents macroscopically rupture or seed the intra-abdominal compartment or if organisms translocate through the mucosal barrier. Other mucosal surfaces can serve as entry points, including the conjunctiva, the upper respiratory tract, and the genitourinary tract. External disease-transmitting vectors, such as arthropods, also can cause infection. ^{[8, 18]}

The pathophysiology of sepsis is complex and results from the effects of circulating bacterial products, mediated by cytokine release, caused by sustained bacteremia. Cytokines are responsible for the clinically observable effects of bacteremia in the host. ^{[18, 19, 20, 21]} Impaired pulmonary, hepatic, or renal function may result from excessive cytokine release during the septic process.

Sepsis is a common cause of mortality and morbidity worldwide. The prognosis depends on underlying health status and host defenses, prompt and adequate surgical drainage of abscesses, relief of any obstruction of the intestinal or urinary tract, and appropriate and early empiric antimicrobial therapy. ^[22]

The prognosis of sepsis treated in a timely manner and with appropriate therapy is usually good, except in those with intra-abdominal or pelvic abscesses due to organ perforation. When timely and appropriate therapy has been delivered, the underlying physiologic condition of the patient determines outcome.

A systematic review by Winters et al suggested that beyond the standard 28-day in-hospital mortality endpoint, ongoing mortality in patients with sepsis remains elevated up to 2 years and beyond. ^[23] In addition, survivors consistently demonstrate impaired quality of life. ^[24]

Clinical characteristics that affect the severity of sepsis and, therefore, the outcome include the host's response to infection, the site and type of infection, and the timing and type of antimicrobial therapy.

Host-related

Abnormal host immune responses may increase susceptibility to severe disease and mortality. For example, extremes of temperature and the presence of leukopenia and/or thrombocytopenia, advanced age, presence of co-morbid conditions, hyperglycemia, bleeding diatheses, and failure of procalcitonin levels to fall are associated with worsened outcome. ^[25]

Important risk factors for mortality include the patient's comorbidities, functional health status, newly onset atrial fibrillation, hypercoagulability state, hyperglycemia on admission, AIDS, liver disease, cancer, alcohol dependence, and immune suppression.

Age older than 40 years is associated with comorbid illnesses, impaired immunologic responses, malnutrition, increased exposure to potentially resistant pathogens in nursing homes, and increased use of medical devices, such as indwelling catheters and central venous lines. ^{[26, 27, 28, 29]}

Infection site

Sepsis due to urinary tract infection has the lowest mortality rate, whereas mortality rates are higher with unknown sources of infection, gastrointestinal sources (highest in ischemic bowel), and pulmonary sources. ^{[30, 31, 32]}

Infection type

Sepsis due to nosocomial pathogens has a higher mortality rate than sepsis caused by community-acquired pathogens. Increased mortality is associated with bloodstream infections due to Staphylococcus aureus, fungi, and Pseudomonas, as well as polymicrobial infections. When bloodstream infections become severe (ie, septic shock), the outcome may be similar regardless of whether the pathogenic bacteria are gram-negative or gram-positive.

Antimicrobial therapy

Studies have shown that the early administration of appropriate antibiotic therapy (ie, antibiotics to which the pathogen is sensitive) is beneficial in septic patients demonstrating bacteremia. Previous antibiotic therapy (ie, antibiotics within the prior 90 days) may be associated with increased mortality risk, at least among patients with gram-negative sepsis. Patients who have received prior antibiotic therapy are more likely to have higher rates of antibiotic resistance, reducing the likelihood that appropriate antibiotic therapy will be chosen empirically. ^{[33, 34, 35, 36]}

Restoration of perfusion

Failure to attempt aggressive restoration of perfusion early may be associated with an increased mortality risk. A severely elevated lactate level (>4 mmol/L) is associated with a poor prognosis in patients with sepsis.

In 1990, there were an estimated 60.2 million cases of sepsis globally, which decreased to approximately 48.9 million cases by 2017, reflecting an 18.8% reduction. ^[37] In 2017, 33.1 million of these cases were linked to underlying infectious causes, while 15.8 million were associated with injuries or non-communicable diseases. The global age-standardized incidence of sepsis fell from 1,074.7 cases per 100,000 in 1990 to 677.5 cases per 100,000 in 2017, a decline of 37.0%. Diarrheal diseases remained the most common underlying cause of sepsis throughout this period, with significant cases also attributed to road traffic injuries and maternal disorders.

In 2017, there were an estimated 11.0 million sepsis-related deaths worldwide, accounting for 19.7% of all deaths that year. ^[37] The global age-standardized mortality rate for sepsis was 148.1 deaths per 100,000 population. The majority of sepsis-related deaths were associated with lower respiratory infections, with road injuries and neonatal disorders also being significant contributors. Among children under five, neonatal disorders, lower respiratory infections, and diarrheal diseases were the leading causes of sepsis-related deaths.

Sepsis-related mortality patterns varied significantly by location, with the highest rates found in areas with the lowest socio-demographic index (SDI). ^[37] In low SDI regions, most sepsis-related deaths were due to infections, while in high SDI areas, they were often linked to non-communicable diseases. In 2017, an estimated 8.2 million sepsis-related deaths occurred in countries with low, low-middle, or middle SDIs. A sensitivity analysis indicated that when only explicit sepsis ICD codes were considered, there were about 9.2 million sepsis-related deaths, representing 16.5% of all deaths that year.

Pathogens

The predominant infectious organisms that cause sepsis have changed over the years. Gram-positive bacteria are the most common etiologic pathogens, although the incidence of gram-negative sepsis remains substantial. The incidence of fungal sepsis has been rising with more patients on immunosuppressive therapies and more cases of HIV infection. In approximately half of sepsis cases, the organism is not identified (culture-negative sepsis).

Risk factors for sepsis and septic shock include the following ^[38] :

• ICU admission with subsequent nosocomial infection
• Bacteremia
• Advanced age (≥65 years)
• Immunosuppression - Conditions that impair host defenses such as seen with neoplasms, renal failure, hepatic failure, AIDS, asplenism, diabetes, autoimmune diseases, organ transplant, alcoholism, and the use of immunosuppressant medications and immunomodulators
• Community-acquired pneumonia
• Previous hospitalization and antibiotic therapy in the preceding 90 days
• Genetic factors - Defects of cellular and humoral immunity (low or absent antibody production, T cells, phagocytes, natural killer cells, complement)
• ​Urosepsis due to benign prostatic hypertrophy (BPH) in older males or complicated UTI
• Major trauma and burn injuries
• Age younger than 1 year
• Pregnancy or post-partum status
• Individuals who have survived sepsis