Update Report 2004
- Version 01 -
Content: Review of publications on epidemiology, incidence and clinical trials in sepsis from 1999 -2004, basic information on sepsis and its history.
Dr. Marc Böhme
2.1. History of Sepsis
2.2. Definition of Sepsis
2.3. Advances in the Epidemiology of Sepsis
2.4. Genetic Polymorphism in Critical Illness
2.5. Epidemiology of Infections and Sepsis in Neonatal
2.6. Meningitis as Source of Sepsis in Neonatal
Sepsis can be defined as the body´s response to an infection. An infection is caused by microorganisms or germs (usually bacteria) invading the body, and can be limited to a particular body region or can be widespread in the bloodstream. Sepsis affects person of all age groups, including healthy and chronical ill persons. Despite improvements in diagnosis and intensive care therapy, sepsis remains an increasing problem. Factors contributing to the increasing incidence of sepsis include an aging population are advance in invasive procedures, increase in the number of patients who are immuncompromised because of intensive therapy for cancer, organ transplantation and autoimmune diseases. Further contributing factors include increases in nosocomial infections and antimicrobial resistance to antibiotic therapy. Although everybody is at potential risk of developing sepsis from minor infections (e.g., flu, urinary tract infections, gastroenteritis, etc.), sepsis is most likely to develop in people who (1) :
are very young (e.g. premature babies) or very old.
have a weakened immune system, often because of treatments such as chemotherapy for cancer, steroids (e.g. cortisone) for inflammatory conditions, etc.
have wounds or injuries, such as those from burns, crash, or a bullet.
are receiving certain treatments or examinations (e.g., intravenous catheters, wound drainage, urinary catheters.
are more prone to develop sepsis than others because of different genetic factors.
Patients who are admitted to the hospital with serious diseases are at the highest risk of developing sepsis because of their underlying disease and previous use of antibiotics. Complications are increasing the risk of developing severe sepsis due to the presence of drug-resistant bacteria in the hospital e.g. multi-resistent staph. aureus (MRSA) or vancomycin-resistent enterococcus (VRE) (2).
The infection leading to sepsis can be acquired outside the hospital known as community-acquired infection or in the hospital known as nosocomial infection. Hospital-acquired infections are generally more difficult to manage than those acquired in the community, because the infecting microorganism is more dangerous to the patient and the patient is often already sick. Furthermore a large increase in the microorganism, that may be resistant to common treatments due to the widespread use of antibiotics in hospitals, was detectable within the past few years. (3).
A blinding spotlight has been placed on sepsis in the past few years. In sheer numbers of peer-reviewed publications, an increasing focus is readily apparent. Our rapidly advancing comprehension of complex pathogenesis and recent successes in therapeutics has contributed much to this ascension. The majority of this focus has rested on clinical trials for hopeful therapies, but this broadening interest in sepsis has similarly led to advances in many areas of understanding, from epidemiology to risk prediction for both occurrence and outcome. (4).
2.1. History of Sepsis
|The Emperor Shen Nung’s treatise is thought to be one of the first scientific papers known in history. It described the antiinfective and antifever capabilities of chang shan, a herbal substance, which has been found to contain antimalarial alkaloids. (5).|
Fig. 2.1-1:Chinese scientific paper
Later in the eighteens century John Pringle, a British physician and Surgeon General of the armed forces, tried to find a remedy for the “putrid diseases” in hospitals that served the army. He reasoned that if there were sepsis, there must be an antiseptic, and he was the first to use the term in his treatise “Observations on the Diseases of the Army”. (6).
| ||In the mid-1800s Ignaz Semmelweis was a Hungarian physician who took a post at the Vienna Lying-In Hospital. He noticed that the incidence of puerperal fever was much higher in the teaching wards for medical students than for midwives. The independent variable, he realized, was that medical students performed autopsies and the midwives did not. He introduced antiseptic practices in the obstetrical wards and reduced the mortality rate of puerperal fever from 13.6% to 1.5%. In 1861, he published his classic work on childbed fever based on his extremely detailed records from his practice. Wilson RF. A brief introduction to sepsis: its importance and some historical notes. (7).|
Fig. 2.1-2: Ignaz Semmelweis
The french chemist Louis Pasteur put forth the “germ theory” of disease in a lecture before the French Academy. Louis Pasteur announced to the French Academy that Streptococcus causes puerperal sepsis. (8)
|In the 19th century, sepsis was regarded as a poisoning of the organism by toxins, toxalbumins, enzymes and other products of bacterial lysis. In the first half of the last century it was assumed that the common cause of gram-negative sepsis is a thermo-stable toxin (endotoxin) which is a component of all gram-negative bacteria. Richard Pfeiffer identified “endotoxin” that caused septic shock in vivo and distinguished it from toxins secreted during bacterial growth in vitro. (9)|
Fig. 2.1-3:Chemical structure of endotoxin.
Sir Alexander Fleming, Howard Florey, and Ernst Chain were joint recipients of the 1945 Nobel Prize for Physiology or Medicine for their work in developing penicillin. (10)
2.2. Definition of Sepsis
Even Hippokrates realised the relationship between a focal injury and the onset of fever which he made ”material which is rotting” responsible for.
The term sepsis has long been used interchangeably with bacteraemia, severe sepsis or even septic shock, undoubtedly a source of some confusion and difficulty in putting together results from published studies. In 1992 the US expert panel from the American College of Chest Physicians and the Society of Critical Care Medicine Members of the American College of Chest Physician/Society of Critical Care Medicine Consensus Conference Committee (1992). American College of Chest Physician/Society of Critical Care Medicine Consensus Conference Committee. Crit. Care Med. 20: 864-874 produced a consensus statement on the suggested definitions to characterise the various stages of the associated inflammatory response and help in differentiating infectious from non-infectious processes. While the recent definitions are centred on the documentation of infection, they aim at encompassing all potential clinical presentations of infection and its consequences. The principles followed in elaborating the definitions were that (1) infectious (and some non-infectious) processes, whatever their cause, elicit a common systemic response which, although of variable intensity, is the expression of common pathophysiologic pathways resulting from the expression and interaction of various humoral and cellular mediators and cytokines and that (2) sepsis and related terms should be reserved for infectious processes; (3) there is a continuum between the various stages of this response to infection (Fig. 2.2-1) which are defined as: (12)
|Infection: Inflammatory response to the presence of micro-organisms or invasion of normally sterile tissue by these organisms.
Bacteremia: Presence of viable micro-organisms in the blood.
Systemic inflammatory response syndrome (SIRS): Two or more of the following:
- Temperature > 38 C° or < 36 C°
- Heart rate > 90 beats/min;
- Respiratory rate > 20 beats/min, or PaCO2 < 32 mmHg;
- White blood cell count > 12,000/mm3, or < 4,000/mm3, or > 10%band forms
Sepsis was defined as the inflammatory reaction (SIRS) to a bacterial infection
Severe Sepsis was defined as Sepsis and organ dysfunction (e.g. cardiovascular, renal, respiratory or hepatic failure), hypoperfusion or hypotension. Manifestations of hypoperfusion may include, but are not limited to lactic acidosis, oliguria, acute alteration in mental status.
Septic shock is defined as a persistent hypotension despite adequate fluid resuscitation, accompanied by signs of hypoperfusion or organ dysfunction.
Fig. 2.2-1:Interferance between Infection, Inflammation and Sepsis.(13)
Although the definitions do provide a framework for classifying patients - a useful achievement for enrolling patients into clinical trials - a persisting and unresolved problem facing clinicians in clinical practice is that the definitions are in part retrospective (based on the documentation of infection) and do not actually help them solve the major clinical issue when faced with a septic patient, which is to differentiate infectious from non-infectious processes. Another critique of this classification has been that its broad-based approach, intended to identify patients early in the course of the infectious process, did not in fact help physicians, and especially intensivists, to better characterise patients exhibiting the least severe presentations of the septic syndromes. In other words, the high sensitivity of the definition is counterbalanced by a rather low specificity. Finally, even the sensitivity of the definitions has been questioned, as there are unquestionably infected patients that do not meet sepsis criteria.(14)
Sepsis can be caused by an infection in virtually any part of the body, although the following regions are most common:
The lungs are the major source of infection in severe sepsis (especially with hospital-acquired infections), with sepsis usually associated with pneumonia. Sepsis patients often have serious respiratory problems (breathing difficulties) and these can sometimes lead to lung injury. Many patients require oxygen therapy, some may require tracheostomy or an endotracheal tube and some may even need mechanical ventilation.
There are numerous possible sources of infection in the abdomen, e.g., appendicitis, bowel problems, gallbladder infections. When the outer surface of the abdominal organs is involved in the infection, it is called “Peritonitis”
The urinary tract
The urinary tract is another common source of infection, particularly in patients needing a urinary catheter. Diabetic patients are also at increased risk of urinary infections leading to sepsis
Bacteria enter the skin through wounds and skin inflammations; they also enter the skin and blood through an opening provided by intravenous catheters, which are required for the administration of fluids and/or medicines
Sepsis can be associated with inflammation and infections of the bone, the bone marrow, the sinuses.
The central nervous system
Sepsis can be associated with inflammation and infections in the brain (e.g., meningitis or encephalitis) or spinal cord. In some cases (around 20%), the source of the sepsis can never be found.
Fig. 2.2-2: Most common sources of primary infection in sepsis.
Nevertheless, several large epidemiological studies improved our understanding and characterisation of the epidemiology and relationships to infection of the various stages of the inflammatory response, and of their outcome.
Sepsis is a clinical syndrome whose pathophysiology reflects the activation of an innate host response to infection. The apparent simplicity of this definition belies in the complex process whose rational therapy is frustrating in the past. More than 70 randomised clinical trials have been performed to test different hypothesis that manipulation of one of the more than 200 mediators of systemic inflammation can improve survival. Only one therapeutic approach so far found his way to approval (activated protein C) (15) and a second one (Corticosteroids)(16) has found a new clinical indication, sepsis.
Bacterial toxins are based on the excessive cascade-like induction of highly active endogenous mediators (17) as a result of the activation of various cell systems (18) such as monocytes/macrophages, endothelial cells, lymphocytes, granulocytes, fibroblasts and smooth muscle cells and the activation of humoral cascade systems such as the coagulation and the complement system (19). The initial binding to the CD14 receptor of the macrophages/monocytes and following signal transduction mediated by different receptor systems primarily leads to release of tumor necrosis factor alpha (TNF-) and interleukins such as IL-1, IL-6 and IL-8 (20). These in turn induce the release of a large number of secondary mediators such as histamine, prostaglandins, leucotrienes, platelet activating factor, reactive oxygen intermediates, nitric oxide, and probably others as yet undetermined (21). Pharmacol Rev 39: 97-112. This inflammatory cascade combines to induce septic shock and multiorgan failure (MOF) in the presence of systemic gram-negative bacterial infection and endotoxemia.
Fig. 2.2-2: Bacterial toxin induced pathogenesis of sepsis.
2.3. Advances in the Epidemiology of Sepsis
The epidemiology of sepsis has made major strides in the past five years. However, the basis for these successes stems from investigations over the past two decades.
In 1990, the Centre for Disease Control (CDC) estimated that there were 450,000 cases of sepsis per year in the United States, with 100,000 deaths (22). The CDC warned that the incidence was increasing, citing the aging of the U.S. population and the increased prevalence of human immunodeficiency virus (HIV) infection as contributing factors. However, the CDC study counted cases of septicemia, not severe sepsis, which often occurs in patients without positive blood cultures (23). Furthermore, this study was based on data from the National Hospital Discharge Survey that are > 10 years old. In 1992, the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference arrived at the current definition of sepsis as a systemic inflammatory syndrome in response to infection which, when associated with acute organ dysfunction such as acute renal failure, is said to be severe (24). However, there have only been two epidemiologic studies in the United States that used these criteria. One was a single-center study, and the other included only eight academic medical centers. Neither study included children or provided information on population incidence or costs of care.
Rangel-Frausto et al. (25) examined the utility of the newly created sepsis consensus conference definition with respect to progression of illness and relative mortality. This definition, created under the auspices of the American College of Chest Physicians and Society for Critical Care Medicine, established sepsis as the "host response to infection." The clinical utility of this definition rests on its use of readily identifiable systemic inflammatory response syndrome (SIRS) criteria in the setting of infection. As part of this broad definition, subgroups for patients with acute organ dysfunction (severe sepsis) and refractory hypotension (septic shock) were brought forth. The incidence of sepsis using this new definition, and additionally confirmed the stepwise progression in mortality as sepsis progresses into severe sepsis or septic shock on their hospital wards and in their intensive care units (ICUs) was studied. During the study period 3.708 patients were admitted to the survey units, and 2.527 (68%) met the criteria for SIRS. The incidence rates for SIRS in the surgical, medical, and cardiovascular intensive care units were 857, 804, and 542 episodes per 1000 patient-days, respectively, and 671, 495, and 320 per 1000 patient-days for the medical, cardiothoracic, and general surgery wards, respectively. Among patients with SIRS, 26% developed sepsis, 18% developed severe sepsis, and 4% developed septic shock. As the population of patients progressed from SIRS to septic shock, increasing proportions had adult respiratory distress syndrome, disseminated intravascular coagulation, acute renal failure, and shock. Positive blood cultures were found in 17% of patients with sepsis, in 25% with severe sepsis, and in 69% with septic shock. There were also stepwise increases in mortality rates in the hierarchy from SIRS with 7%, sepsis with 16%, severe sepsis with 20%, and septic shock with 46%.
Sands and coworkers (26) performed a prospective cohort study using the same definitions in a broader survey from 8 academic medical centers. 12.759 patients were monitored and 1.342 episodes of sepsis syndrome were documented. The extrapolated, weighted estimate of hospital-wide incidence of sepsis syndrome was 2.0 cases per 100 admissions to the hospital. Patients in ICUs accounted for 59% of the total extrapolated cases, non-ICU patients with positive blood cultures for 11%, and non-ICU patients with negative blood cultures for 30%. Septic shock was present at onset of sepsis syndrome in 25% of patients. The bloodstream infection was documented in only 28% of patients, with gram-positive organisms being the most frequent isolates. The mortality of Sepsis syndrome was 34% at 28 days. In addition to examining incidence and mortality, Sands observed sepsis to be the leading cause of death among patients in noncoronary ICUs.
Further extending these observations to a more generalized cohort, Brun-Buisson and coworkers (28) investigated the incidence of infection and sepsis among ICU patients throughout France. The prevalence of SIRS was detected as very high, affecting one-third of all in-hospital patients, and > 50 % of all ICU patients; in surgical ICU patients, SIRS occurs in > 80 % patients. The trauma patients are at particularly high risk of SIRS, and most these patients do not have infection documented. The prevalence of infection and bacteraemia increases with the number of SIRS criteria met, and with increasing severity of the septic syndromes. About one-third of patients with SIRS evolve to sepsis. Sepsis may occur in approximately 25 % of ICU patients, and bacteraemic sepsis in 10 %. In such patients, sepsis evolves to severe sepsis in > 50 % of cases, whereas evolution to severe sepsis in non-ICU patients is about 25 %. Severe sepsis and septic shock occur in 2 % - 3 % of ward patients and 10 % -15 % ICU patients. There is a graded severity from SIRS to sepsis, severe sepsis and septic shock, with an associated 28-day mortality of approximately 10 %, 20 %, 20 % - 40 %, and 40 % - 60 %, respectively. The mortality rates are similar within each stage, whether infection is documented or not, and microbiological characteristics of infection do not substantially influence outcome, although the source of infection does. While about three of four deaths occur during the first months after sepsis, the septic syndromes significantly impact on long-term outcome, with an estimated 50 % reduction of life expectancy over the following five years. The major determinants of outcome, both short-term and long-term, of patients with sepsis are the severity of underlying diseases and co-morbidities, the presence of shock and organ failures at onset of sepsis or evolving thereafter.
Table.2.3-1: Source of infection for Sepsis and Severe Sepsis.
|Survey by Brun-Buisson et. al||Sepsis (%)||Severe|
|1996 (N=842) Brun Buisson C, Am J Respir Crit Care Med, 1996; 154: 617-624|
Recent epidemiological reports on the incidence of sepsis and its related mortality confirmed the increasing numbers of sepsis cases per year in the US. Therefore, Angus et. al (29) conducted a study of a large, nationally representative sample to determine estimates of the incidence, associated costs, and outcome of severe sepsis in the United States. Sepsis was defined as documented infection and acute organ dysfunction. Of the 6.621.559 hospitalizations recorded, 192.980 cases of severe sepsis were identified, yielding national estimates of 751.000 cases (3.0 cases per 1,000 population and 2.26 cases per 100 hospital discharges), of which 55.5% had underlying co-morbidity and 160,700 (21.4%) were surgical. Overall, 383.000 (51.1%) patients were transferred to the ICU. The incidence increased >100-fold with age (0.2 per 1.000 in children to 26.2 per1.000 in those >85 yrs old).
Fig.2.3-1: National age-specific incidence and mortality rate for all cases of severe sepsis by gender.
|The mortality was 28.6%, or 215,000 deaths nationally, and also increased with age, from 10% in children to 38.4% in those >85 yrs old.|
The mortality was lower in women but this was explained by differences in age, co-morbidity, and site of infection. The deaths were estimated to 9.3% of all deaths in the United States in 1995 and equaled the number of deaths after acute myocardial infarction.
The adult costs were generally stable around $21.000– 25.000. Infants were the most expensive, with an average cost of $54.300, whereas the average cost for patients aged 1–19 years was $28.000. The average length of stay (LOS) and cost per case were 19.6 days and $22.100. Interestingly the non-survivors had a similar LOS with 19.9 vs. 19.4 days, but the costs were significantly more with $25.900 vs. $20.600, (p < .0001) than in survivors. The total national hospital cost associated with the care of patients who incurred severe sepsis was $16.7 billion. The costs of care for patients aged < 1 and 1 –19 years were $1.1 billion and $622 million, representing 6.6% and 3.7% of the total costs. The costs of care for patients aged 65 and 75 years were $8.7 billion and $5.1 billion, representing 52.3% and 30.8% of the total costs.
|The identification of Gram-positive organisms as suspected infectious culprits in cases of sepsis has become more common (Fig. 2.3-2) A recent review of clinical trials in sepsis has suggested that subgroups of patients with sepsis and Gram-positive infection were less likely to benefit from anti-inflammatory therapy than were patients with Gram-negative sepsis (30). Thus, the increase in Gram-positive infection in septic patients may explain why mortality rates have only modestly decreased over time.|
Fig. 2.3-2: Distribution of organisms causing infection in sepsis patients.
Questions about temporal changes in incidence, mortality, and common pathogens were still unanswered. This complex problem was tackled by Martin et al. (31) reviewed discharge data on approximately 750 million hospitalizations in the United States over the 22-year period and identified 10.319.418 cases of sepsis. Cases were identified from discharge records in the National Health Discharge Survey (NHDS) that included a code for sepsis.
Fig. 2.3-3. Numbers of Cases of Sepsis in the United States, According to the Causative Organism, 1979–2000.
This data reported a strong increase from 164.072 in 1979 to 659.953 in 2000 with an annually increase of about 13.8% of all hospitalisations. Interestingly the most common causative micro-organism changed from Gram-negative bacteria in 1979 to Gram-positive bacteria since 1989. Among the reported organism caused for sepsis in 2000, Gram-positive bacteria accounted for 52.1% per case with Gram-negative bacteria for 37.6% per case, polymicrobials for 4.7 percent, anaerobes for 1.0 percent and fungi for 4.6%.
The greatest relative change were observed in the incidence of Gram-positive infection, which increased by an average of 26.3% per year. However Gram-negative infection becomes the second common infection side in sepsis. The mortality rates for the entire cohort declined over the 22-year period, averaging 27.8% during the first six years to 17.9% during the last six years. Despite the improved mortality rate the increasing incidence of sepsis resulted in a tripling of death by sepsis in the hospitals. The proportion of patients with sepsis and organ failure increased from 19.1 percent to 33.6% today Organ failure had a cumulative effect on mortality: approximately 15 percent of patients without organ failure died, whereas 70 % of patients with three or more failing organs (classified
Figure 2.3-4. Overall Hospital Mortality Rate among Fig.:2.3-5. Population-Adjusted Incidence of
Patients Hospitalized for Sepsis, 1979–2000. Sepsis, According to Sex, 1979–2000.
as having severe sepsis and septic shock) died. The additive effect of organ failure on mortality was consistent over time, with improvements in survival being most evident among patients with fewer than three failing organs. The proportion of patients with sepsis who had any organ failure, a marker of the severity of illness, increased over time, from 19.1 % in the first 11 years to 30.2 % in later years. Organ failure occurred in 33.6 % of patients during the most recent sub-period, resulting in the identification of 184,060 cases of severe sepsis in 1995 and 256,033 in 2000. Organ failure had a cumulative effect on mortality: approximately 15 % of patients without organ failure died, whereas 70 percent of patients with three or more failing organs (classified as having severe sepsis and septic shock) died. The additive effect of organ failure on mortality was consistent over time, with improvements in survival being most evident among patients with fewer than three failing organs. The organs that failed most frequently in patients with sepsis were the lungs (in 18 % of patients) and the kidneys (in 15 % of patients); less frequent were cardiovascular failure (7 %), hematologic failure (6 %), metabolic failure (4 %), and neurologic failure (2 %).
Similar epidemiological studies were still missing within the last decades for the European Community. Recent advance in the development of new therapeutic options and the successful clinical trials in the treatment of sepsis were stimulating the lack of incidence in this disease.
Alberti et al (32) (European Sepsis group) conducted a large cohort study in 14.364 unselected consecutive adult patients admitted to 28 ICUs in Europe, Canada and Israel. The principal goal of this study was to determine the incidence and characteristics of infection in ICU patients, contrasting the “infection approach” with the “sepsis approach”. A clearcut distinction was made to distinguish three groups of ICU infections: (a) community-acquired infections, (b) hospital-acquired infections, i.e. infections occurring in a patient hospitalised (or institutionalised) before being transferred to the ICU, and (c) ICU-acquired infections.
The study showed that about 21.1% of all patients had infection on ICU admission, reaching one-third (32.3%) of patients in the long-stay group. In this long-stay group the crude incidence of ICU-acquired infections was 18.9%, but varied with infection status at ICU admission. It was 1.5 times higher (26.4%) in patients infected on admission than in non-infected patients (15.3%). In other words, about one-half of ICU-acquired infections occurred in patients infected previous to ICU admission. These high figures point out that infection remains a major problem in ICUs, although the incidence varied between ICUs according to unit type or case-mix. The inflammatory response to infection was present in almost 80% of patients, but obviously it results in a mixture of patients with different infectious problems (Table 2.3-5). Of the infected patients 30% had no microbiological documentation, a rate increasing to 46.1% in the short-stay group. While 85.8% of ICU-acquired infections were microbiologically documented, only 54.8% community-acquired infection had such documentation.
Table 2.3-6: Long-stay group: incidence of sepsis and sepsis-related conditions to infection characteristics.
A total of 3.034 infectious episodes were recorded at ICU admission (338 in the short-stay group and 2696 in the long-stay group) and 1.581 during ICU stay. About one-half of ICU-acquired infections occurred in patients previously infected at ICU admission. Of the 4.277 episodes of infection recorded in the long-stay group, 3.946 (92.3%) could be classified into one of the categories of the ACCP/SCCM classification. The severity of infectious episode did not markedly depend on the source or site of infection or on its microbiological documentation. However, abdominal infections were more likely to be associated with septic shock (46% vs. 28.4% in the remainders), as well as bloodstream infections (41.2% vs. 18.8%), and Candida or fungal infections (38.9% vs. 31.8%).
The overall incidence of infection at ICU admission in the entire cohort was 21.1%, with similar incidences of community-acquired infections (11.9%) and hospital-acquired infections (9.2%).
Of the 8.353 patients in the long-stay group 1.581 (crude incidence: 18.9%) developed at least one ICU-acquired infection. First, only about 80% of clinically documented infections were classified in sepsis categories, of which about one-half had manifestations of either severe sepsis or septic shock. Second, one-fifth of infections did not fulfil criteria for any sepsis category. Therefore, in addition to sepsis categorisation, it appears important to focus epidemiological studies on infection itself for a better understanding of the associated conditions, risks and outcomes of septic patients.
A further aim of our study was to examine outcome in infected patients. The origin of infection, and especially ICU-acquired infection, appeared markedly to affect ICU and hospital outcomes (Fig. 6). The rates were similar to those previously reported in the literature (33). However, the impact of ICU-acquired infections on hospital mortality differed depending on the infected status at ICU admission. The difference in hospital mortality was higher in the non-infected group (22.7%) than in the community-infected group (18.5%) and the hospital-infected group (7.9%).
Fig 2.3-6: Survival according to the infection status at ICU admission; N patients number of patients in each category; N event number of death in each category.
2.4. Genetic Polymorphism in Critical Illness
The first complete genomic sequence of a free-living organism (the bacteria Haemophilus influenzae) was published in 1995 (34). Since then, more than 100 bacterial genomes have been fully sequenced, and the genomes of multi-cellular organisms have also recently been completed (35) . Although it has been known for many years that genetic variations encode characteristics such as eye and hair color, there have only recently come to realize that variations within genes have important implications for all biological traits: they might cause illness, change the clinical presentation of diseases, and affect our response to drugs. Variations in DNA sequence that occur in more than 1% of the population are termed polymorphisms. Although insertions and deletions of DNA sequences exist, much of the genetic variation between individuals is known as single nucleotide polymorphisms (SNPs). SNPs are changes in a single nucleotide (ie, A, C, G, or T, including insertions and deletions) with a mutation frequency of more than 1% of the population. SNPs are present for a given gene in 5% to 25% of the population in many cases, and their association with medical illnesses is increasingly recognized. Mutations in proteins for bacterial identification (CD14, TLR4) and inflammatory responses (interleukin-1, tumor necrosis factor) have been associated with differential susceptibility or survival, including the onset of and outcome from sepsis. Whether these genetic variations are truly responsible for the observed differences remains to be determined. Linkage disequilibrium, where genes migrate together because of their relative proximity on a given chromosome, means identified mutations may
Table 2.4-1: Review on methodology characteristics of selected studies examining gene polymorphism in sepsis.
simply represent a marker for a nearby gene that truly confers the risk. Furthermore, in complex critical illnesses such as sepsis, it is likely that susceptibility and outcome are mediated by a number of genes and do not display the simple characteristics of being "good" genes or "bad" genes. Many genetic polymorphisms have been identified in genes coding for key inflammatory molecules. A number of investigators have examined the contribution of genetic predisposition to the incidence and the severity of sepsis (Table 2.4-1) (36). In particular, the presence of the TNF2 polymorphism in the promoter region of the gene for TNF was associated with a greater risk of death in septic populations (37). In the future, investigators may attempt to refine predictive models by adding genetic variables. However, if genetics influence physiologic variables already accounted for by existing models, the addition of genotype to the system may not provide additional useful information. The importance of gender in genetic predisposition to sepsis has been emphasized recently. Experimentally, gender differences in the inflammatory response to hemorrhagic shock (38), including responses to immunomodulation therapy (39), were noted. Both the incidence of sepsis requiring ICU admission and the incidence of septic shock appear to be lower in females (40). Schroeder et al. (41) demonstrated that mortality was higher in septic male patients homozygous for the TNFB2 single nucleotide polymorphism compared with male patients with TNFB1. However, female patients did not demonstrate any difference in mortality with regard to TNFB2 status. This study demonstrates an interaction between gender and factors that predispose to poor outcome. There is a need for research to determine the importance of gender as a risk factor in sepsis. Genetic medicine will shortly be arriving in critical care medicine and clinical trials. Combining total genome analysis to include both human cells and pathogens simultaneously may lead to the identification of factors that contribute to he development of infectious diseases. There will be increasing use of genetic information to tailor drug selection and dosage and to predict the risk of severe sepsis. The era of one-drug-fits-all treatments is about to give way to individualized therapies that match the patient’s unique genetic makeup with an optimally effective drug.
2.5. Epidemiology of Infections and Sepsis in Neonatal
Neonatal sepsis is uncommon in developed countries, but the rate increases dramatically in premature newborns and those born to mothers with infections or prolonged rupture of the fetal membranes. While infections caused by organisms contracted from the mother at birth have decreased in the past two decades, there has been an increase in nosocomial infections. Today, most infants with sepsis have been hospitalized in neonatal intensive care units for weeks or months because of a congenital malformation or surgical conditions. Antimicrobial therapy is usually begun prior to the isolation. The number of antimicrobial agents that can be safely used in neonates is relatively small, and dose administration usually needs to be adjusted based on the birthweight. However bacterial resistance has become a major problem where there has been indiscriminate use of broad-spectrum antimicrobiotic drugs.
The rate of sepsis in infants born at any hospital varies according to the economic standards, availability of prenatal care, and variations in perinatal risk factors. The rate of neonatal sepsis has been 2-4 per 1000 live births since 1980 in the US, with a worldwide range of 1-8 per 1000 live births. Low birthweight and male gender are associated with higher rate of sepsis. Today, in developed countries most neonatal sepsis occurs in premature infants (42).
Table 2.5-1: Birthweight specific sepsis rate within the first 30 days of life for infants born at Yale New Haven Hospital, 1978-1988.
Neonatal infections are usually classified according to time and mode of onset. They are grouped into three categories: i) congenital infection, acquired in utero by vertical transmission with onset before birth; ii) early-onset neonatal infections, acquired by vertical transmission in the perinatal period, either shortly before or during the process of birth; and iii) late-onset neonatal infections, acquired by horizontal transmission in the nursery. Opinions differ as to what is the appropriate age for differentiating between early- and late-onset infections; the range varies between 2-7 days of age. The exact time is not very important, as 80-90% of infections in the first week of life have their onset in the first two days of life.
Since the early 1970s when group B streptococcus emerged as a major cause of neonatal sepsis and meningitis, group B streptococci and Escherichia coli have accounted for approximately 60-80% of cases of early-onset neonatal sepsis and meningitis. Since perinatal prophylaxis has been encouraged, the rate of group B streptococcus infections has fallen; the Center for Disease Control and Prevention (CDC) has predicted that an 80% drop is possible. All of the major types of group B streptococci may colonize women and may cause early-onset sepsis in the neonatal manifested, with or without meningitis, or pneumonia. (43)
The numbers of both community-acquired and hospital-acquired staphylococcal infections have increased in the past 20 years. This trend parallels the increased use of intravascular devices. During the period from 1990 through 1992, S. aureus was the most common cause of nosocomial cases of pneumonia and surgical-wound infections and the second most common cause (after coagulase-negative staphylococci) of nosocomial bloodstream infections, according to data from the National Nosocomial Infections Surveillance system of the CDC. A second trend, resulting in part from selective antibiotic pressure, has been the dramatic worldwide increase in the proportion of infections caused methicillin-resistant S. aureus. In tertiary care hospitals, methicillin-resistant strains are increasingly found in the community. Data from the National Nosocomial Infections Surveillance system for the period from 1987 to 1997 show that the number of methicillin-resistant S. aureus infections in intensive care units has continued to increase (Fig. 2.5-3) (44). Methicillin-resistant strains have also become resistant to other antimicrobial agents. The same 10-year CDC survey showed that the proportion of methicillin-resistant isolates with sensitivity only to vancomycin increased from 22.8 percent to 56.2 percent in 1997. These isolates constitute the subgroup of strains from which the S. aureus strains with intermediate sensitivity to vancomycin (glycopeptide-intermediate S. aureus) have recently emerged. New molecular typing techniques have clearly documented the ability of epidemic, disease-producing clones of methicillin-resistant S. aureus to populate hospitals and spread to diverse geographic regions rapidly. The rapid spread and pathogenicity of these clones suggest that they possess unique, as yet undefined, determinants of virulence creating a nonbacterial thrombus on the cardiac valve that facilitates subsequent bacterial adherence.(45)
Fig. 2.5-2: Incidence early- and late-onset invasive groub B streptococcus in selected active core with AAP= American Academy of Pediatrics, ACOG=American Colege of Obstetrischen and Gynecology .
Fig. 2.5-3: NNIS data of methicillin-resistant S. aureus infections for a period from 1987 to 1997.
2.6. Meningitis as Source of Sepsis in Neonatal
Meningitis is one of the most serious infections you can have. It is also one of the scariest - since untreated some forms of meningitis can cause death or lasting impairment.
Meningitis, strictly speaking, is an inflammation of the meninges. There are many causes for inflammation of tissue, and the meninges are no exception. However, the most common cause of meningeal inflammation is irritation caused by infection with bacteria or viruses. These organisms usually enter the meninges through the bloodstream from other parts of the body. As a matter of fact, many meningitis-causing bacteria are carried in the nose and throat, often without the carrier having symptoms.
Viral meningeal infections are usually (but not always) less severe than bacterial infections. This is quite fortunate, since there are no antibiotic treatments available for most viruses and we must therefore let viral meningitis run its course by itself. Bacterial meningitis, on the other hand, must be treated with antibiotics in most cases to avoid severe consequences. Unfortunately the only way to confirm that meningitis is not bacterial is to culture the spinal fluid (actually the cerebrospinal fluid, since it bathes both the spinal cord and the brain) and see if there are bacteria in it. This can take 3-5 days. Since a bacterial meningitis can do a lot of damage in 3-5 days, common practice is to start antibiotics immediately after doing the spinal tap and keep giving the antibiotics until the culture has shown no bacteria for 3-5 days.
Among common bacterial causes of meningitis and sepsis are: Neisseria menigitidis (Meningococcus)
Meningococcus is a bacteria often carried in the nose and throat without symptoms. It can be spread by droplets coughed or sneezed out by an infected person or by a carrier; many outbreaks of meningococcal infection occur in people living in close quarters (like schools, colleges, and military installations). It takes 1-10 days (most often 4 days or less) after exposure to show symptoms; patients are usually contagious until they have been treated for at least 24 hours.
Meningococcal infection can cause meningitis, sepsis, or both. Oddly, someone with meningococcal infection with meningitis may do better than s/he would with sepsis and no meningitis; this does not always happen, though. Signs of meningococcal infection may include fever with chills and a rash; the classic rash of meningococcal infection is "petechial", caused by tiny blood clots just below the skin surface. In severe cases the infection can result in shock and death within a few hours even if treated.
Pneumococci are even more common than meningococcus; in fact pneumococci are the most common cause of ear infections and sinus infections, as well as the most common bacteria found in the blood of children under 2 years old with fevers, many of whom have no obvious site of infection. Again, like meningococcus, many people have pneumococci in their noses and throats but have no symptoms. The bacteria is transmitted from one person to another, usually by droplets. Like viral upper respiratory infections, pneumococcal infections are more common in winter. Infection can begin as little as 1-3 days after exposure.
The signs of pneumococcal meningitis and sepsis can be the same as those of meningococcal meningitis. Often, however, pneumococcal infection can appear first as a high fever with a very high white-blood-cell count (where almost all of the white cells are neutrophils or bacteria-fighting cells) and no obvious site of infection.
Streptococcus pneumoniae, or pneumococcus, is a bacteria that causes many different kinds of infections in people, ranging from ear infections and sinus infections to pneumonia, meningitis, and sepsis.
Although the names (and bacterial genuses) are similar, S. pneumoniae is quite different from group A streptococcus. S. pneumoniae infections are on the average much more serious -- pneumococcus is the most common cause of bacterial meningitis in the United States, and about 8% of children with pneumococcal meningitis die of the infection, while 1 out of 4 surviving children, or more, have neurologic damage including hearing loss after "getting over" the infection. And it's a pretty common bug to be infected with: pneumococci are the most common cause of ear infections and sinus infections, as well as the most common bacteria found in the blood of children under 2 years old with fevers, many of whom have no obvious site of infection. Many people have pneumococci in their noses and throats but have no symptoms. The bacteria are transmitted from one person to another, usually by droplets. Like viral upper respiratory infections, pneumococcal infections are more common in winter. Infection can begin as little as 1-3 days after exposure. Studies of ear fluid cultures suggest that anywhere from 20 to 40% of ear infections are caused by pneumococcus. The signs of pneumococcal meningitis and sepsis can be the same as those of meningococcal meningitis. Often, however, pneumococcal infection can appear first as a high fever with a very high white-blood-cell count (where almost all of the white cells are neutrophils or bacteria-fighting cells) and no obvious site of infection.
Sepsis, severe sepsis and septic shock are the significant cause of morbidity and mortality. In the United States it has been estimated that are approx. 750.000 of new cases of sepsis each year with an associated crude mortality rate between 20-50%. Moreover, among hospitalised patients in non-coronary intensive care units it has been reported that sepsis is the most common cause of death (46).
Fig. 3-1: Incidence and mortality rate in sepsis in the US, Angus et al.
Accurate data on epidemiology of sepsis and its severe forms came first up since the definition of sepsis was accepted and implemented by the American College of Chest Physician/Society of Critical Care Medicine Consensus Conference Committee” in 1991. Several national surveys applying these consensus criteria have been performed to estimate the burden health care and the economical impact by this disease. Within the last few years our rapidly advancing comprehension of complex pathogenesis and recent successes in therapeutics Riedemann NC, Guo RF, Ward PA., Nat Med. 2003 May;9(5):517-24 has contributed much to the improvement in patient outcome. The majority of this focus has rested on clinical trials for hopeful therapies, but this broadening interest in sepsis has similarly led to advances in many areas of understanding, from epidemiology to risk prediction for both occurrence and outcome.
However main driving factor for the higher no. of death today include the increased use of invasive techniques and immunsuppressiv drugs, chemotherapy and transplantation and HIV, the increasing resistance against antibiotics and the increasing nosocomial infections. Recent studies on incidence in sepsis showed a dramatic increase driven by a patient population with more elderly patients treated with modern but invasive techniques.
Septic Shock (%)
|Rangel-Frausto||Surgical and medical ICU|
|Brun-Buisson||Surgical and medical ICU|
N=842, ICU patients
|Albert||Surgical and medical ICU|
N=3.946 infected patients
* 15% of severe Sepsis detected on normal wardsFig: 3-2: Summary of the epidemiological data of several surveys.
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