M.C. Reade, E.B. Milbrandt, and D.C. Angus
Introduction
Most patients with sepsis have underlying co-morbidities. Co-existing disease is typ- ically thought to influence the pathophysiology and outcome of sepsis by reducing physiological reserve. Certainly this is true: A patient with chronic obstructive pul- monary disease (COPD) will tolerate pneumonia less well than a patient with previ- ously healthy lungs. Additionally, many chronic disease states (or their treatments) alter the pre-existing inflammatory and immune milieu. This effect ranges from the obvious (as in the case of patients taking immunosuppressant therapy) to the under- appreciated (as in the inflammatory dysregulation associated with obesity). In seek- ing explanations for differences in the host response to infection, much has been made of the possible effects of genetic variability. However, subtle variations in the underlying state of the immune and inflammatory systems have received little atten- tion.
In this chapter, we begin by presenting evidence that pre-existing inflammation influences the risk of developing infection. Mechanisms of acute and chronic inflam- mation will be briefly reviewed. Known risk factors and the distinction between altered susceptibility and clinical course will then be described. Knowledge of dysre- gulated inflammation inherent in many chronic disease states will be summarized.
What knowledge there is of the effect of underlying abnormalities of immunity and inflammation on the pathogenesis of sepsis will be presented. The reverse situation, the lingering effect of sepsis on chronic disease, will also be discussed. We suggest that in future, it may be wise to tailor treatments that target inflammation not only to mediators implicated in the ‘generic’ sepsis patient, but also to abnormalities associated with their co-morbid disease.
Pre-existing Inflammation Influences Risk of Developing Infection
The Health Aging and Body Composition study [1] is an illustrative example of the link between pre-existing inflammation and the development of severe infection.
This study identified 3075 ‘well functioning’ patients aged 70 – 79 years, defined as
those who had no difficulty walking one quarter mile, climbing 10 steps, or per-
forming activities of daily living. Levels of tumor necrosis factor (TNF) and interleu-
kin (IL)-6 were measured on entry to the study, and each patient was followed for
6.5 years. Over this period, 161 participants (5.2 %) were hospitalized for community
acquired pneumonia (CAP). Levels of TNF and IL-6 at baseline were significant pre-
dictors of the development of CAP, with odds ratios for the highest tertiles of 1.6
(1.02 – 2.7) and 1.7 (1.1 – 2.8), respectively, whereas smoking, coronary heart disease, congestive heart failure, chronic renal failure, and diabetes were not independent predictors for CAP. While this study can be practically applied to identify groups at higher risk of pneumonia, it also suggests an important relationship between chronic inflammation and susceptibility to severe infection.
Distinguishing Acute and Chronic Inflammation
Acute and chronic inflammation are pathologically distinct processes. At a tissue level, inflammation is the response to local injury. When of sufficient magnitude, inflammation has systemic as well as local effects. At the site of injury, acute inflam- mation involves vasodilation, margination, and extravasation of neutrophils, and increased vascular permeability with the formation of exudates. These effects are coordinated by a variety of soluble mediators, including inflammatory lipid metabo- lites (platelet activating factor [PAF], prostaglandins and leukotrienes), cascades of soluble proteases and substrates (complement, coagulation, and kinins), nitric oxide (NO), and polypeptide cytokines. Systemically, various acute inflammatory cyto- kines cause fever, vasodilation, and a shift from anabolic to catabolic metabolism.
Acute inflammation usually leads to healing at the site of damage, but if the damag- ing stimulus persists there can be a shift to chronic inflammation, which is a differ- ent pathological process. Chronic inflammation can also develop in the absence of antecedent acute inflammation, as classically occurs in rheumatoid arthritis or ‘low toxicity’ infections such as tuberculosis, as well as in many of the conditions listed in the next section.
Chronic inflammation is characterized by activation of macrophages, lympho- cytes, and plasma cells rather than neutrophils, destruction of tissue, formation of granulation tissue, and fibrosis. Cytokines controlling these processes include IL-1, IL-6, and TNF, which are also involved in acute inflammation. However, in chronic inflammation different cytokines such as IL-10 and transforming growth factor (TGF)- q , which control humoral responses, and IL-2 and interferon (IFN) gamma, which control the cellular response, predominate. Acute and chronic inflammation induce different tissue responses. For example, mice exposed to an inflammatory stimulus for 14 days switch to a different inflammatory mRNA profile in the liver, suggesting different regulatory factors are involved in gene expression when inflam- mation becomes chronic [2]. Anti-inflammatory cytokines are prominent in both the resolution phase of acute inflammation and in chronic inflammation. Indeed, in the subacute phase of sepsis this may lead to profound immunosuppression [3].
Most importantly, whereas acute inflammation is a constantly changing process, chronic inflammation can become a new steady state.
Known Risk Factors for Altered Prognosis in Sepsis
If chronic disease alters the response to acute infection in a deleterious way, then
chronic diseases should be risk factors for susceptibility to infection and the clinical
course of sepsis. When chronic diseases are taken together, they do indeed increase
mortality [4] (Fig. 1). Unfortunately, it can be difficult to separate the contribution
of altered immune and inflammatory function from the effect of decreased physio-
logical reserve. For example, many studies have found a variety of chronic condi-
tions increase risk of CAP: heart disease, lung disease, asthma, immunosuppressive medication, and alcoholism [5]; male gender, congestive cardiac failure, stroke, can- cer, and diabetes [6]; smoking and body mass index [7]. These epidemiological asso- ciation studies have rarely explored the biological mechanisms for this increased susceptibility.
Before proceeding to explore these associations, it is essential to draw a distinc- tion between ‘susceptibility to infection’ and ‘influence on the clinical course once infected’. To effectively defend against infection, a host must mount a pro-inflamma- tory response. Immunosuppression, and those conditions discussed in the following sections where chronic inflammation blunts the acute pro-inflammatory response, leave the host more prone to developing infection. However, once an infection has become established, effective host defense can be impaired in either of two ways.
First, an overwhelming pro-inflammatory response can become detrimental to ulti- mate survival, worsening hypotension and compromising function in a variety of body systems. Alternatively, a blunted inflammatory response can allow the organ- ism to proliferate to the point of causing organ dysfunction even without robust inflammation. In addition, the immunosuppression that often follows a strong pro- inflammatory response may leave growth of residual initial organisms, or a subse- quent superinfection, unchecked. Successful defense against acute infection once it has become established probably relies on a fine balance between pro and anti- inflammatory mediators. Most studies, especially in the clinical context, do not make the distinction between incidence and clinical course. Patients with a putative risk factor either die of pneumonia (for example), or do not. Such studies make it difficult to tease out the likely effects of underlying pro- or anti- inflammatory bias.
Fig. 1. National age-specific mortality rates for all cases of severe sepsis and for those with and without
underlying comorbidity. Comorbidity is defined as a Charlson-Deyo score
80. National estimates are gener-
ated from the seven-state cohort using state and national age- and gender-specific population estimates
from the National Center for Health Statistics and the U.S. Census. Error bars represent 95 % confidence
intervals. From [4] with permission
Dysregulated Immunity and Inflammation in a Variety of Chronic Disease States
If chronic disease modulates response to infection by causing abnormal immune and inflammatory function, such abnormal function should be easy to demonstrate in these disease states. Altered susceptibility of such patients to infection may also be seen. This question will be addressed by considering patients with, as examples, autoimmune disease, chronic infection, and chronic morbidities not typically associ- ated with immune function but that appear to influence the susceptibility to and course of sepsis. The effects of treatments that modulate inflammation will also be examined.
Systemic Lupus Erythematosis as an Example of Autoimmune Disease
Patients with systemic lupus erythematosis (SLE) develop and die of infection at an abnormally high rate. While abnormal host immune response is likely to play a part, the effect is often difficult to separate from the immunosuppressant effects of medi- cations (such as steroids) used to treat the disease. However, even before steroids were commonly used for SLE, an abnormally high incidence of infection was observed [8]. Numerous studies (reviewed in [9]) have found increased SLE severity related to increased susceptibility to infection. This effect was independent of treat- ment. The clinical manifestations of infections are atypical in SLE, and salmonella, pneumococcus, tuberculosis, and viral infections are more common than would be expected. The immune pathogenesis of SLE along with its associated chronic inflam- mation are presumably at least in part responsible for this abnormal response to infection, although evidence for this is lacking. Abnormal control of inflammation is also likely to be responsible for the most common cause of death in SLE, thrombo- embolic disease.
Periodontitis as an Example of Chronic Infection
Periodontitis is an archetypal model of chronic inflammation. Elevations of white cell counts, acute phase proteins, and cytokines, along with abnormal coagulation, have all been described, and these markers normalize when periodontitis is treated [10]. The association between periodontitis and cardiovascular disease, atheroscle- rosis, and diabetes is well established, and this is thought to have an immunological basis [11]. Treatment of periodontitis results in improved endothelial function, evi- denced by better flow-mediated arterial dilatation [12]. Monocytes from patients with periodontitis produced more IL-6 in response to lipopolysaccharide (LPS) than did cells from healthy controls [13]. It would be surprising if chronic periodontitis did not cause an abnormal response in sepsis, but to date this has not been studied.
Chronic Conditions not Typically Associated with Abnormal Inflammation Alcohol dependence
The well known clinical association between chronic alcoholism and sepsis can be explained in multiple ways. Alcoholics tend to be malnourished, are more prone to aspiration, have generally poorer health, and, in acute illness, access health care late.
That this association is partly attributable to the immunosuppressant effect of
chronic alcoholism was suggested by the observation that alcoholic patients with
septic shock had lower pro-inflammatory cytokine and IL-6 levels than non-alcohol- ics [14]. Similarly, alcoholic patients had increased anti-inflammatory IL-10 levels, a reduced IL-6/IL-10 ratio, and three times more postoperative wound infections than did non-alcoholic controls [15]. In vitro and animal studies support the immuno- suppressant effects of alcohol (reviewed by [14]).
Hypertension
Chronic hypertension appears to alter the function of immune cells. For instance, more monocytes from hypertensive patients bound to an endothelial cell layer in vitro than did cells from normotensive controls, suggesting hypertension had ‘acti- vated’ them in vivo [16]. The secretion of IL-1 q and TNF in response to LPS was greater in mononuclear cells from hypertensive patients [17]. Whether this associa- tion between chronic inflammation and hypertension is cause or effect or both is less clear, as recently reviewed [18]. In any case, patients with chronic hypertension might be expected to respond to systemic infection differently than controls. This hypothesis remains untested.
Obesity
Obese patients have a worse prognosis in sepsis [19]. While this is undoubtedly mul- tifactorial, altered inflammation may play a part. Obese experimental animals and humans have higher levels of circulating TNF, angiotensinogen, TGF q and IL-6, which it now seems are secreted by the adipocytes themselves [20]. In addition, lep- tin, adiponectin, and resistin, proteins, secreted principally by adipocytes, have immunomodulatory activity [21]. At the other extreme, malnourishment is also associated with increased baseline and stimulated TNF production [22], and malno- urishment also predisposes to worse outcome in sepsis.
Smoking and COPD
Smoking worsens mortality in sepsis [7]. The acute effects of cigarette smoke are pro-inflammatory, in part due to oxidative stress and lipid peroxidation. Neutrophils and macrophages are rapidly recruited to the lung, where there is increased expres- sion of TNF and macrophage inflammatory proteins [23]. The effects of chronic smoking, however, are more complex. Chronic smoking causes immunosuppression, which allows the normally sterile lower airways to become chronically colonized with potential respiratory pathogens. Human bronchial epithelial cells exposed to cigarette smoke had reduced granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-8 production in response to LPS and TNF, at least in part explained by reduced activator protein (AP)-1 activation [24]. Smokers also have a shift from effector to suppressor T cells [25]. COPD eventually develops in 15 – 20 % of smokers. This is characterized by both chronic inflammation in the lung tissue and cytokine mediated systemic effects such as muscle wasting and weight loss [26].
An interesting observation is the protective effect of cigarette smoking on ulcerative colitis, which may in part be due to the chronic immunosuppression smoking causes [27]. The explanation is probably more complex than this, however, as Crohn’s dis- ease appears to be worsened by smoking.
Gender differences
It appears that males may be at increased risk for developing sepsis [4] (Fig. 2).
However, the differential effects of susceptibility to infection and clinical course
once infection is established make this gender effect less clear. Males could either be
Fig. 2. National age-specific incidence and mortality rates for all cases of severe sepsis by gender, exclud-
ing those with human immunodeficiency virus (HIV) disease. National estimates are generated from a seven-state cohort (Florida, Maryland, Massachusetts, New Jersey, New York, Virginia, and Washington) using state and national age-specific population estimates from the National Center for Health Statistics and the U.S. Census. The incidence among women was equivalent to that of men 5 years younger. A simi- lar age-based difference was seen in mortality but, in multivariate regression, this difference was explained by underlying comorbidity and site of infection. Pop: population. From [4] with permission
at greater risk of infection, or at greater risk of developing sepsis once they have an infection. Mortality from sepsis also appears to be influenced by gender. While the above study found age- and comorbidity- adjusted sepsis mortality was the same in men and women [4], another found women with pneumonia were almost twice as likely to die as men [28]. If indeed females are more likely to die once they have pneumonia, this could be explained by hypothesizing that females have a greater acute inflammatory response (and so die of septic shock), or alternatively that they have a lesser inflammatory and immune response which prevents them from effec- tively clearing the infecting organism. In support of the first hypothesis, cell medi- ated immunity appears to be more active in females, reflected in stronger responses to immunization and higher rates of autoimmune disease (as reviewed [29]). Sup- porting the contrary hypothesis, however, are in vitro studies, such as that which found that LPS applied to male macrophages stimulated release of more pro-inflam- matory cytokines and higher cell surface expression of TLR4 and CD14 than in cells from females [30].
Reconciling these conflicting arguments will require further study. Perhaps men have an ‘anti-inflammatory’ disposition, making them more susceptible to infection, but with comparatively less risk of the sepsis syndrome if infection occurs because they mount a less robust acute inflammatory response. Just as feasible in the light of the above epidemiological studies is to suggest that men have a ‘pro-inflammatory’
disposition, and so are less susceptible to infection and have a greater ability to clear
infection if it occurs, but that this greater clearance comes at the cost of developing
the acute inflammatory symptoms of sepsis. Further complicating this analysis is the possibility that the ability to mount an inflammatory response has a differential effect on susceptibility to, and clearance of, infection. In any case, the effect of gen- der (whatever it is) could well have much the same effect on the response to acute infection as the chronic inflammatory conditions discussed here.
Age and frailty
Increasing age is associated with higher levels of circulating inflammatory mediators and acute phase proteins. Contributing factors may include reduced anti-inflamma- tory estrogen in females, increased fat tissue, and subclinical infections. Many stud- ies suffer from the difficulty of separating co-morbidities from the effects of age alone. However, inflammatory cells from elderly patients produce more pro-inflam- matory cytokines than do cells from young subjects (as reviewed [31]). Only a pro- portion of elderly subjects become ‘frail’, and the ‘frailty syndrome’ is associated with increased inflammation and markers of activated coagulation [32]. Inflamma- tory mediators are strong predictors of mortality in the elderly, independent of other known risk factors [31].
Extreme exercise and chronic sleep deprivation
It is not only pathological conditions that can alter the inflammatory and immune response. Exercise leads to the production and systemic release of acute phase cyto- kines such as TNF, IL-1, and in particular the counter-regulatory, IL-6, from muscle cells. While the physiological role of cytokines in exercise may be to regulate metab- olism, prolonged and exhausting exercise increases susceptibility to acute infection and allergies (reviewed in [33]). Prolonged work shifts in ICU medical personnel also cause a pro-inflammatory state, which correlates with worse endothelial func- tion [34] and, one could speculate, reduced resistance to infection.
Therapy that Might Modulate Inflammation
Therapeutic immunosuppression, such as after organ transplantation, is a well rec- ognized risk factor for severe infection [35]. Chemotherapy for malignancy is simi- larly immunosuppressant [36]. Red blood cell transfusion depresses immune func- tion, increasing risk of bacterial infection and cancer recurrence, while improving survival of transplanted organs [37]. Immunosuppression associated with therapy is clearly not beneficial for the host response to infection. In contrast, reduction of inflammation appears to confer some benefit. A number of medications not typi- cally associated with inflammation have recently been suggested to improve progno- sis in sepsis, such as statins [38] and possibly heparin, which at least in part appears due to an anti-inflammatory effect [39].
Mechanisms Whereby Dysregulated Inflammation Influences Response to Sterile and Infectious Inflammatory Stimuli
Implicit in the above discussion is the sense that many chronic conditions reduce the
acute inflammatory response. This effect can be direct, as with alcoholism or after
blood transfusion, or indirect, via the immunosuppression associated with the chronic
inflammatory state (as with the other conditions listed). The effect of these alterations
appears to be different, depending on whether the insult is infectious or sterile.
Attenuation of acute inflammation appears to have a beneficial effect in the face of a sterile insult. Analogous to clinical chronic inflammation is ‘endotoxin toler- ance’ observed in animals and in vitro. Prior exposure to a small dose of endotoxin reduces inflammation in response to subsequent exposures. For example, pretreat- ment of rabbits with endotoxin reduced fever in response to subsequent endotoxin challenge, and reduced mortality [40]. The effect appears to be dependent on IL-10 and TGF q , as blocking antibodies to these cytokines prevented tolerance [41]. Endo- toxin tolerance appears to confer a beneficial effect on the host response to burns, hepatic, renal and cardiac ischemia/reperfusion, and hemorrhagic shock (as reviewed [42]), all of which begin as a sterile inflammatory response.
In contrast, reducing acute inflammation appears to blunt the initial defensive response to infection – with a worsening of outcome if the infection becomes wide- spread, by which time any benefit from initial anti-inflammatory effects are negated.
While there are conflicting opinions [42], the balance of evidence suggests that pre- existing inflammation alters response to acute infection in a harmful way. For exam- ple, Escherichia coli peritonitis reduced the ability of mice to clear respiratory Sta- phylococcus aureus and pseudomonas infection. This was associated with reduced recruitment of neutrophils into the lungs, and reduced circulating complement lev- els [43]. Similarly, the immunosuppression generated by cecal ligation and puncture (CLP) in mice resulted in reduced clearance of intratracheal pseudomonas, which was mediated by IL-10. CLP mice exposed to pseudomonas had a 10 % survival com- pared to 95 % after sham surgery [44]. It seems that the acute response is impaired in the context of pre-existing inflammation at least in part due to a counter-regula- tory anti-inflammatory effect.
There may be additional mechanisms linking pre-existing inflammation to reduced resistance to infection. A high level of circulating cytokines may promote infection by a direct effect on the host/pathogen interaction. TNF, IL-1, and IL-6 all increased the in vitro growth of S. aureus, acinetobacter, and pseudomonas [45].
Inflammatory cytokines also upregulate bacterial receptors on the host cell surface, increasing the likelihood that bacteria can cause invasive disease. TNF, IL-1, and thrombin increased pneumococcal binding to endothelial cells via the PAF receptor [46].
Long term exposure to TNF uncouples T cell receptor signal transduction path- ways. In a study of autoimmune disease, loss of T cell function predominantly involved loss of suppressor T cells, which predisposed to heightened inflammation and autoimmunity [47]. In the context of acute infection, loss of T cell receptor function might worsen inflammation through an effect on suppressor T cells, or reduce bacterial clearance through an effect on effector T cells.
In summary, chronic infection or inflammation appear to reduce the ability to
mount an acute inflammatory response. This is beneficial if the acute inflammation
is not due to another infection. However, if there is an acute infection, it is more
likely to become invasive, and less likely to be cleared. The negative effect of reduced
clearance outweighs any transient beneficial effect from reduced inflammation, as
the infection overwhelms the host.
The Converse Situation: Resolved Acute Inflammation Accelerates Chronic Disease and Predisposes to Further Infection
While pre-existing chronic inflammation alters the course of acute illness, it also appears that the residual effects of acute inflammation persist long after apparent clin- ical resolution of disease. For example, higher IL-6 and IL-10 levels prior to discharge were associated with increased 90-day mortality in a cohort of 1808 patients hospital- ized with CAP [48]. Mice survivors of intra-abdominal sepsis were at increased risk of subsequent pseudomonas and aspergillus infection [49]. Immune function in patients surviving sepsis is also altered, at least in the short term. These observations may sim- ply reflect a prolongation of the immune system downregulation well described in the later phases of sepsis, as has been reviewed elsewhere [3, 42].
Conclusion
It appears that the impact of pre-existing chronic conditions is much more than to simply reduce physiological reserve. An organism can arrive in a host whose immune system is in a state of normal, suppressed, or heightened activity, and it would be surprising if this host difference did not influence the nature of the response to the insult. While a degree of chronic inflammation may induce a benefi- cial ‘inflammatory tolerance’ to sterile inflammatory insults such as ischemia-reper- fusion, the adverse effect on the host ability to clear infection appears clear. Further- more, the negative effects of acute inflammation appear to persist long after the inflammatory stimulus has cleared and the patient appears to have recovered.
Consideration of these phenomena may have implications for the utility of postu- lated anti-inflammatory therapy in sepsis in various patient sub-populations. Fur- ther suppression of inflammation might be the worst strategy in patients with chronically downregulated inflammatory responses. Presumably patients with or without co-morbidities affecting inflammation would form separate subgroups. Per- haps this underlies the finding that only a subset of sepsis patients appears to bene- fit from suppression of inflammatory cytokines [3].Conversely, this may explain why most studies of immunomodulators fail to find an effect in the overall group. The effect of co-morbidities might be at least as influential in determining host response as are other factors, like genetic variability. At the very least it is important to take into account the effect of pre-existing disease when studying patterns of inflamma- tory mediators in sepsis.
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