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S490 • CID 2005:41 (Suppl 7) • Moss

S U P P L E M E N T A R T I C L E

Epidemiology of Sepsis: Race, Sex, and Chronic

Alcohol Abuse

Marc Moss

Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, Emory University School of Medicine, Atlanta, Georgia

The annual incidences of severe sepsis in several industrialized nations have recently been reported to be 50–

100 cases per 100,000 persons. These numbers exceed the estimated rates for other diseases that hold a

heightened public awareness, including breast cancer and acquired immune deficiency syndrome. There are

also sex and race differences in the incidence of sepsis. Men are more likely than women to develop sepsis,

with a mean annual relative risk of 1.28. Nonwhites are nearly twice as likely to develop sepsis as whites.

These race and sex disparities in the incidence of sepsis are likely explained by differences in a variety of factors, including the presence of comorbid conditions. For example, chronic alcohol abuse is associated with

a persistent fever, delayed resolution of symptoms, increased rates of bacteremia, increased use of intensive

care, prolonged duration of hospital stay, and increased cost of hospitalization for infected patients.

Sepsis remains a major cause of morbidity and mor-

tality in hospitalized patients [1]. Care of patients with

sepsis costs as much as $50,000 per patient, resulting

in an economic impact of nearly $17 billion annual-

ly in the United States alone [2–4]. Between 20% and

50% of patients with sepsis die, and it is the second

leading cause of death among patients in noncoronary

intensive care units. The Centers for Disease Controland Prevention has estimated that sepsis is the tenth

leading cause of death overall in the United States [5].

Furthermore, sepsis is associated with a reduced quality

of life in those who survive their acute illness [6].

Accurate national data on sepsis may be useful for

a variety of reasons, including the establishment of

health care policy and the allocation of health care re-

sources. However, the diagnostic criteria of sepsis need

to be uniformly applied, to accurately compare results

from different studies [2]. By consensus, sepsis is now

defined as the combination of a pathological infection

and physiological changes, known collectively as the

Reprints or correspondence: Dr. Marc Moss, Div. of Pulmonary, Allergy, and

Critical Care, Grady Memorial Hospital, Ste. 2C007, 49 Jesse Hill Junior Dr.,

Atlanta, GA 30303 ([email protected]).

Clinical Infectious Diseases 2005;41:S490–7

2005 by the Infectious Diseases Society of America. All rights reserved.

1058-4838/2005/4108S7-0017$15.00

systemic inflammatory response syndrome [7, 8]. Pa-

tients with coincident acute organ dysfunction are con-

sidered to have severe sepsis. There is a limited but

growing amount of information concerning the epi-

demiology of sepsis in a variety of countries around the

world [2]. Here, I review recent studies examining the

national impact of sepsis in several industrialized coun-

tries and explore some of the disparities in the epide-miology of sepsis due to race, sex, and comorbid con-

ditions, such as chronic alcohol abuse.

GLOBAL EPIDEMIOLOGY OF SEPSIS

AND SEVERE SEPSIS

To date, 5 studies have reported nationalized epide-

miological rates for sepsis. In 2 of these studies, data

were collected with multicenter surveys of patients in

intensive care units for several weeks, and annual ep-

idemiological data were then extrapolated. In the 3

other studies, large national databases were used, andpatients with sepsis were identified on the basis of cod-

ing strategies obtained from hospital records.

The EPISEPSIS group conducted a nationwide, pro-

spective, multicenter survey of patients with severe sep-

sis in 206 French intensive care units over 2 consecutive

weeks [9]. During the study, 3738 critically ill patients

were screened, and a clinical or microbiologically doc-



Epidemiology of Sepsis • CID 2005:41 (Suppl 7) • S491

umented episode of severe sepsis was documented in 546 pa-

tients. The overall attack rate for severe sepsis was 14.6% (546/

3738). When these findings were extrapolated to the entire

population of France (59.6 million), the annual incidence of

severe sepsis in French intensive care units was estimated to

be 95 cases per 100,000 population. The median age of the

patients was 65 years, and 150% had at least one comorbid

condition. The Australian and New Zealand Intensive CareSociety Clinical Trials Groups studied patients in 23 closed

multidisciplinary intensive care units in 21 hospitals through-

out Australia and New Zealand [10]. Over a 3-month period

in 1999, they identified 3543 intensive care unit admissions for

3338 patients, and 691 met criteria for severe sepsis. The overall

adult populations of these countries were obtained from gov-

ernment censuses in the years 1996 and 2001. Assuming a linear

population growth, they estimated an annual incidence of 77

cases of severe sepsis per 100,000 population. Consistent with

previous studies [2, 11, 12], the mean age of their patients was

61 years, pulmonary and intra-abdominal sources were the

most common sites of infection, and positive cultures were

present in 58% of cases.

Padkin et al. [13] used a database compiled in England,

Wales, and Northern Ireland to determine the incidence of se-

vere sepsis in these countries. A total of 91 adult intensive care

units, or ∼39% of all intensive care units in these countries,

contribute data from the first 24 h of intensive care unit ad-

mission. In 1997, data were available for 56,673 adult intensive

care unit admissions. Overall, 27% of patients (15,362) had

severe sepsis during their first 24 h after admission to the in-

tensive care unit. When the results were modeled for England

and Wales, the annual incidence of severe sepsis was 51 casesper 100,000 population. Angus et al. [14] constructed a similar

patient database from discharge records from hospitals in 7

states in the United States in 1995. To identify patients with

severe sepsis, they selected all acute-care hospitalizations with

a hospital discharge code for a bacterial or fungal infection and

a diagnosis of acute organ dysfunction. In total, they used 1286

distinct infection codes. However, only 225 of these infection

codes were needed to identify 99% of the patients. After ad-

justing for age and sex, they estimated a national incidence for

severe sepsis of 300 cases per 100,000 persons. However, an

editorial expressed concern that this estimate may overstate the

incidence of severe sepsis by 2–4-fold, given that the estimated

deaths would exceed the number of deaths reported in associ-

ation with nosocomial bloodstream infections and septic shock

combined [15]. More recently, our group used the National

Hospital Discharge Survey database and identified 110 mil-

lion cases of patients with sepsis in the United States during

1979–2000 [2]. We have subsequently updated this information

through 2002. When severe sepsis is defined as a diagnosis of

sepsis and acute organ dysfunction, the incidence of severe

sepsis during 1997–2002 was 91 cases per 100,000 population.

The results from these national epidemiological studies illus-

trate that severe sepsis, defined as infection along with systemic

inflammatory response syndrome and acute organ dysfunction,

is a common disorder [16]. For example, the frequency of cases

and deaths related to severe sepsis exceeds the numbers of persons

with other diseases that hold a heightened public awareness,suchas breast cancer and AIDS [17, 18]. It is hoped that the results

of these studies will translate into improvements in health policy,

resource allocation, and the distribution of funding for sepsis

research. In addition, these epidemiological studies demonstrate

that sepsis occurs in elderly patients. Treatment trials for patients

with severe sepsis have sometimes excluded elderly patients be-

cause of concerns that they are less likely to respond to the

therapeutic intervention and are at a higher risk of dying [14].

Future clinical trials must assess the efficacyand cost-effectiveness

of investigational medications in this large group of patients,

which will most likely receive these therapies. With the recent

approval of activated protein C, a treatment is available thatreduces mortality in patients with severe sepsis [19]. The high

cost of caring for patients with sepsis makes comprehensive ep-

idemiological information useful for hospitals to develop accu-

rate fiscal budgets.

On the basis of 4 of these 5 studies, the incidence of severe

sepsis consistently lies between 50 and 100 cases per 100,000

persons in industrialized countries [16] (table 1). Some of the

variability in reported incidence is related to differences in study

design. For example, the diagnostic criteria for severe sepsis

vary between those studies that prospectively identified patients

and those that used hospital records. In addition, variability in

the percentage of intensive care unit admissions related to se-

vere sepsis may reflect differences in national and hospital-

specific bed availability and admissions policies in intensive care

units. Finally, the study of Padkin et al. [13] identified cases

of severe sepsis only during the first 24 h after intensive care

unit admission and, therefore, likely underestimated the true

incidence. However, there may be specific biological reasons

for the different incidences of sepsis in the various countries.

For example, there may be disparities in distribution of specific

comorbid conditions or genetic polymorphisms between the

patients enrolled into the studies that, when present, alter the

probability of developing severe sepsis.

RACE AND SEX DIFFERENCES IN SEPSIS

There are clearly discrepancies in the incidence and severity of

several medical conditions on the basis of race and sex. With

regard to race, African Americans have a higher prevalence of

essential hypertension [20]. There have been several well-pub-

licized differences in cardiovascular care and outcome according



S492 • CID 2005:41 (Suppl 7) • Moss

Table 1. Incidence of sepsis, as determined in 5 studies.

Authors [reference] Countr y or countries Study period Study design

Incidence,

no. of cases/

100,000

population

Mortality,

%

Mean

age,

years

Angus et. al. [14] United States 1995 Examination of state databases 300 29 63.8

Martin et. al. [2] United States 1997–2002 Examination of national database 91 34 65.9

Padkin et. al. [13] England and Wales 1997 Examination of national database 51 47 65.0EPISEPSIS group [9] France 2001 Multicenter cohort study 95 38 60.7

Finfer et. al. [10] Australia and New Zealand 1999 Multicenter cohort study 77 35 65.0

Figure 1. Incidence of sepsis in the United States from 1979 to 2000,

stratified by sex.

to race [21]. In the oncology literature, African American women

have a higher risk of developing ovarian cancer and a worse

outcome from breast cancer [22, 23]. With regard to pulmonary

diseases, sarcoidosis has been estimated to be 110 times more

prevalent in African Americans than in whites in the Unites States

[24, 25]. In addition, African American men consistently had a

higher incidence of and mortality due to lung cancer than did

white men during the 1970s and 1980s [26].Relatively few clinical studies have investigated race and sex

differences in patients in intensive care units, and almost none

have directly studied patients with sepsis [27–30]. In the study

of Padkin et al. [13], there was a predominance of men (58.8%)

in their cohort of patients with severe sepsis. Similarly, there

were 59.6% men in the Australian and New Zealand study and

twice as many men as women in the French EPISEPSIS study

[9, 10]. In the study of Martin et al. [2], after adjustment for

sex in the population of the United States, men were more

likely to have sepsis than women in every year of their 22-year

study, with a mean annual relative risk of 1.28 [2] (figure 1).

Racial disparities in the incidence of sepsis were even morestriking. Both African Americans and other nonwhites had a

similarly elevated risk of sepsis, compared with whites (mean

annual relative risk of 1.89 and 1.90, respectively). Most con-

cerning was the risk among African American men: they had

the highest rate of sepsis during the study period (330.9 cases

per 100,000 population), the youngest age at onset (mean age,

47.4 years), and the highest mortality (23.3%) [2]. Race and

sex disparities in sepsis related to the source of infection have

also been examined [31, 32]. Overall, 32% of the cases of sep-

sis were from a respiratory source, 32% from a genitourinary

source, and 22% from a gastrointestinal source. With regard

to race, African Americans and other nonwhites had higher

incidences of sepsis for all sources of sepsis. Similar, men had

higher incidences than did women for all sources of sepsis

expect genitourinary sources (figure 2).

Although the disparities in the incidence of sepsis are likely

explained by a variety of factors, including genetic polymor-

phisms, exposure to resistant organisms, and access to health

care, there are race and sex differences in specific comorbid

conditions in patients with sepsis. In our cohort of 10 million

cases of sepsis, race and sex differences were present in the

distribution of several common comorbid conditions, includ-

ing alcohol abuse, diabetes, HIV, end-stage renal failure, and

cancer. For example, African Americans and nonwhite patients

with sepsis were more likely to have several concurrent diag-

noses that are associated with an increased risk of infection,

including diabetes, end-stage renal disease, HIV, and alcohol

abuse. Similarly, male patients with sepsis were more likely tohave chronic obstructive pulmonary disease, cancer, alcohol

abuse, or HIV than were female patients with sepsis.

CHRONIC ALCOHOL ABUSE AND INFECTION

OR PNEUMONIA

Alcohol abuse is a common behavioral condition that has been

reported to alter immune function and increase susceptibility

to infection [33]. Alcohol is the most frequently abused drug

in the world [34]. In the United States, ∼50% of the adult

population regularly consumes alcohol, and 15–20 million per-

sons carry the diagnosis of alcohol abuse or dependence [34].

Alcohol is the third leading cause of preventable mortality and

is associated with an estimated 100,000 deaths per year in the

United States. The annual economic cost of alcohol abuse in

1990 was $100 billion in the United States, and 110% of this




Figure 2. Incidence of sepsis according to the source of infection, stratified by sex. CV, cardiovascular; GI, gastrointestinal; GU, genitourinary; Resp,

respiratory.

cost was directly related to medical services [35–37]. In addi-tion, 20%–40% of patients admitted to general hospitals have

alcohol-related disorders, and hospitalizations resulting from

alcohol abuse are as common among elderly patients as are

hospitalizations resulting from myocardial infarctions [35]. In

some industrialized countries, alcohol consumption is decreas-

ing [33]. However, alcohol consumption is increasing in de-

veloping nations and is a problem of special concern in areas

of central and eastern Europe [33].

Since the late 1700s, clinicians have postulated that excessive

use of alcohol is associated with an increase risk of infection

[38]. In 1905, Sir William Osler [39] postulated that alcohol

abuse was the single most potent predisposing condition forthe development of bacterial pneumonia. Usually, 25%–50%

of patients with bacterial pneumonia have a prior history of

alcohol abuse [40–43]. In 1965, Nolan [44] reviewed 900 con-

secutive admissions over a 5-month period and classified 124

patients as being alcoholic when defined by psychological cri-

teria [45]. The incidence of acute bacterial pneumonia was

significantly higher among alcoholic patients (17.0%) than

among patients who were not alcoholics (6.5%). More recently,

2 longitudinal studies have examined the association between

alcohol abuse and subsequent hospital admissions in enlist-

ed men [46, 47]. Persons with a primary diagnosis of alcohol

psychosis or alcoholism were matched with a control group of

persons who were not alcoholics and were chronologically fol-

lowed for both the quantity and etiology of their subsequent

hospital admissions. During the first year of service, younger

enlisted men who were alcohol abusers had a higher incidence

of respiratory system diseases than did controls subjects who

were not alcohol abusers [46]. For older personnel, alcohol

abusers were twice as likely to be hospitalized with the admis-

sion diagnosis of pneumonia as were persons who were not

alcohol abusers [47]. In a European study, 50 patients withcommunity-acquired pneumonia were matched by age and sex

with control subjects [48]. The patients with pneumonia had

a significantly higher daily alcohol intake prior to hospitali-

zation and had used alcohol chronically for a longer period of

time. After adjustment for the presence of cirrhosis and ciga-

rette smoking, excessive alcohol intake was the only indepen-

dent risk factor positively associated with the development of

community-acquired pneumonia.

Severity studies. The effects of alcohol abuse on a variety

of outcome measures for patients with bacterial pneumonia

have been examined, including duration of stay, recurrence,

intensive care unit stay, and hospital cost. In a study of 358cases of pneumococcal pneumonia, prolonged fever, slower res-

olution, and a higher rate of empyemas were noted in patients

with chronic alcoholism [49]. In a Scandinavian study of 277

patients with community-acquired pneumonia, alcoholism was

associated with delayed recovery, defined as the return to nor-

mal activity at 8 weeks after hospital admission [50]. In 1985,

312 patients admitted because of community-acquired pneu-

monia were followed at a public municipal hospital over a 12-

month period [51]. In this study, a higher incidence of positive

results of blood cultures was present in the 118 patients with

a history of alcohol abuse than in patients without a history

of alcohol abuse. In the case-control study discussed above, the

authors followed the 50 patients with pneumonia during their

hospital stay [48]. The durations of fever (4.3 vs. 2.1 days) and

hospital stay (10.3 vs. 6.9 days) were significantly longer in the

alcoholic patients. In addition, alcoholic patients had a higher

frequency of persistent pulmonary infiltrates on chest radiog-

raphy at 1 week.

Recently, the effect of alcohol abuse on the development of

nosocomial pneumonia has been studied. Bercault and Boulain



S494 • CID 2005:41 (Suppl 7) • Moss

Figure 3. Incidence of acute respiratory distress syndrome (ARDS) in

351 critically ill patients, stratified by a prior history of alcohol abuse.

[52] studied 135 patients who developed ventilator-associated

pneumonia and 135 matched control subjects. The matching

process was extremely well done and was based on a variety of

criteria, including cause of hospital admission, indication for

ventilatory support, immunologic status, cardiac status, age,

Glasgow coma score, and probability of death, as determined

by an admission severity-of-illness score. The primary goal of

this study was to determine whether nosocomial pneumoniawas independently associated with death in the intensive care

unit. However, in the multivariate analysis, chronic alcohol

abuse was also independently associated with mortality in the

patients with nosocomial pneumonia.

Chronic alcohol abuse has also been reported to be an in-

dependent risk factor for the development of acute respiratory

distress syndrome (ARDS). Initially, surgeons from the Uni-

versity of Washington examined the effects of acute and chron-

ic alcohol abuse on the morbidity and mortality of trauma, a

known at-risk diagnosis for the development of ARDS [53].

The risk of respiratory failure, defined as the requirement of

mechanical ventilation, was higher among trauma patients with

evidence of chronic alcohol abuse. Hudson et al. [54] identified

695 critically ill patients with 1 of 7 at-risk diagnoses for the

development of ARDS. ARDS occurred in 179 patients (26%).

In patients with both prior alcohol-related disease and a low

arterial pH, the risk of developing ARDS (71.4%) was twice

that observed in patients with a normal pH and no history of

alcohol-related disease (38.7%). Subsequently, 351 medical and

surgical intensive care unit patients with 1 of 7 at-risk diagnoses

were followed for the development of ARDS [55]. Patients with

a prior diagnosis of chronic alcohol abuse were nearly twice as

likely to develop ARDS as were patients without a history of alcohol abuse (figure 3). The association between chronic al-

cohol abuse and ARDS has been confirmed in a prospective

trial of 220 patients with septic shock [56]. In addition, the

effects of chronic alcohol abuse on the incidence of postop-

erative ARDS have been studied in patients undergoing lung

resection surgery [57]. A total of 21% of patients with a history

of alcohol abuse developed ARDS after their surgery, compared

with only 2% of postoperative patients without a history of

alcohol abuse [57, 58].

In an attempt to determine the economic impact of alcohol

abuse on hospitalizations for pneumonia, Saitz et al. [59] ex-

amined a statewide database over a 1-year period. Only 4% of the 23,198 cases of pneumonia were classified as alcohol relat-

ed, on the basis of appropriate hospital discharge codes. The

overall hospital mortality for pneumonia was 10%, and 12%

of all admissions included a requirement for intensive care. In

a risk-adjusted analysis, the hospital charges ($11,179 vs.

$9886), the total duration of hospital stay (increased by 0.6

days), and the requirement for intensive care (18% vs. 12%)

were higher for the patients with a history of alcohol abuse.

Alcohol and immune function. There are many potential

mechanisms by which alcohol abuse can increase susceptibility

to infection, bacterial pneumonia, and sepsis, including an in-

creased risk of aspiration, poor dental hygiene, suppression of

a normal cough reflex, malnutrition, and physical proximity to

other infected people [60]. However, both acute and chronic

exposure to alcohol have direct effects on the immune system[61]. Alcohol abuse has been reported to cause alterations in

neutrophil and macrophage function and abnormalities in cil-

iary and surfactant function in the lung [61].

After exposure to bacterial toxins, macrophages normally

secrete TNF, other inflammatory cytokines, and reactive oxygen

intermediates. Acute alcohol administration has a suppressive

effect on release of proinflammatory cytokines, such as TNF,

IL-1, and IL-6, from monocytes and macrophages [62, 63].

This suppressive effect of acute alcohol exposure on the sepsis-

induced TNF response in alveolar macrophages occurs at a

posttranscriptional level [64]. In addition, acute alcohol ex-

posure suppresses the release of several chemokines, includingIL-8, macrophage inflammatory protein–2, and cytokine-in-

duced neutrophil chemoattractant. In addition, diminished hy-

drogen peroxide production by alveolar macrophages has been

demonstrated in a septic rat model of acute alcohol abuse [65].

These acute effects of alcohol lead to decreased neutrophil re-

cruitment, impaired bacterial clearance, increased dissemina-

tion of bacteria outside of the lung, and increased mortality in

animal models of sepsis [66]. Some of the intracellular mech-

anisms responsible for the acute effects of alcohol have been

elucidated. Human monocytes exposed to alcohol in vitro ex-

press inhibited lipopolysaccharide-induced nuclear factor–kB

activation by decreasing DNA binding of the p65/p50 heter-

odimer [67]. In addition, alcohol prevents nuclear translocation

of p65 and, to a lesser extent, p50 subunits.

Acute alcohol intoxication also decreases the clearance of

bacteria from the lung or after an intradermal injection [68,

69]. When mice were exposed to aerosolized Staphylococcus

aureus, the clearance of bacteria from the non–alcohol-exposed

lung followed a logarithmic curve, with 87% of the bacteria

removed within 4 h and only 1% of the bacteria remaining at




24 h. In contrast, mice acutely exposed to alcohol intraperi-

toneally 15–30 min before intratracheal administration of bac-

teria cleared !50% of the bacteria at 4 h. This alteration in

clearance is likely due to several factors, including depression

of ciliary function. Laurenzi and Guarneri [70] quantitated

ciliary function by measuring the time required to move carbon

particles a distance of 5 mm in the intact tracheas of kittens.

Normally, carbon particles moved at a fast rate of 3.12 s/mm, yet acute alcohol exposure markedly slowed ciliary function to

10.6 s/mm.

Chronic alcohol ingestion causes different abnormalities in

immune function. In animal models, chronic exposure to alco-

hol has been reported to increase the release of proinflamma-

tory cytokines and chemokines, such as TNF, IL-1b, and IL-8.

This proinflammatory response is likely related to an increased

production of reactive oxygen species [71]. However, isolated

alveolar macrophages from chronic alcoholic patients released

less TNF in response to stimulation than did alveolar macro-

phages from healthy persons [72]. In addition, chronic alcohol

abuse does not impair neutrophil mobilization or adherence[73]. Surfactant has a potent bactericidal activity against in-

vading pulmonary pathogens, which is believed to be secondary

to the detergent-like activity of surfactant long-chain free fatty

acids [74]. Chronic alcohol abuse causes deficiencies in the

amount of these free fatty acids produced by alveolar type II

cells, induces the release of surfactant inhibitors, and leads to

decreased opsonization of microorganisms and impaired bac-

tericidal activity [75, 76].

Chronic alcohol exposure has been reported to enhance in-

testinal permeability, leading to abnormalities in intestinal ep-

ithelial barrier function [77]. Increased intestinal permeability

can facilitate bacterial translocation, a process by which gut

flora or bacterial products traverse the abnormal intestinal bar-

rier and, ultimately, reach mesenteric lymph nodes and the

portal circulation. These translocating bacteria can then dis-

seminate and cause sepsis.

CONCLUSION

In summary, we have identified specific populations that are

at increased susceptibility to develop sepsis and severe sepsis.

Other specific risk factors are associated with a poor prognosis

for patients who have developed sepsis. Some of these persons

are distinguished by race or sex and others by other diseasesor comorbid conditions that they might have acquired. The

recognition of responsive populations in sepsis is important

for several reasons. This information will be helpful to clinicians

in answering questions regarding prognosis in family meetings.

It is also possible that some of these specific populations might

respond differently to the therapies that are now available for

patients with sepsis. Finally, the identification of specific pa-

tients who are predisposed to developing sepsis raises many

questions regarding the reasons for increased susceptibility. By

understanding the mechanisms that cause these alterations in

responsiveness, the pathogenesis of sepsis will be better eluci-

dated. Therefore, physicians will be able to provide better care

for all patients with sepsis.

Acknowledgments

Financial support. National Institutes of Health (grants AA-014435

AA-013757).

Potential conflicts of interest. M.M.: no conflicts.

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