SUPPLEMENT ARTICLE

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

Sepsis remains a major cause of morbidity and mortality 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 annually in the United States alone [24]. 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 Control
and 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 resources. 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 (marc_moss@emory.org).
Clinical Infectious Diseases 2005; 41:S4907
 2005 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2005/4108S7-0017$15.00

S490 CID 2005:41 (Suppl 7) Moss

systemic inflammatory response syndrome [7, 8]. Patients with coincident acute organ dysfunction are considered to have severe sepsis. There is a limited but
growing amount of information concerning the epidemiology 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 countries and explore some of the disparities in the epidemiology of sepsis due to race, sex, and comorbid conditions, such as chronic alcohol abuse.
GLOBAL EPIDEMIOLOGY OF SEPSIS
AND SEVERE SEPSIS
To date, 5 studies have reported nationalized epidemiological 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 epidemiological data were then extrapolated. In the 3
other studies, large national databases were used, and
patients with sepsis were identified on the basis of coding strategies obtained from hospital records.
The EPISEPSIS group conducted a nationwide, prospective, multicenter survey of patients with severe sepsis 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-

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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 and acute organ dysfunction, the incidence of severe

sepsis during 19972002 was 91 cases per 100,000 population.
The results from these national epidemiological studies illustrate 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, such
as 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 because 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 efficacy and 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 that
reduces mortality in patients with severe sepsis [19]. The high
cost of caring for patients with sepsis makes comprehensive epidemiological information useful for hospitals to develop accurate 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 severe sepsis may reflect differences in national and hospitalspecific 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-publicized differences in cardiovascular care and outcome according

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umented episode of severe sepsis was documented in 546 patients. 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 Care
Society Clinical Trials Groups studied patients in 23 closed
multidisciplinary intensive care units in 21 hospitals throughout 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 government 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 severe 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 admission. 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 intensive care unit. When the results were modeled for England
and Wales, the annual incidence of severe sepsis was 51 cases
per 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 adjusting 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 24-fold, given that the estimated
deaths would exceed the number of deaths reported in association with nosocomial bloodstream infections and septic shock
combined [15]. More recently, our group used the National
Hospital Discharge Survey database and identified 110 million cases of patients with sepsis in the United States during
19792000 [2]. We have subsequently updated this information
through 2002. When severe sepsis is defined as a diagnosis of

Table 1.

Incidence of sepsis, as determined in 5 studies.

Authors [reference]

Country or countries

Angus et. al. [14]

Martin et. al. [2]

United States
United States

Padkin et. al. [13]

EPISEPSIS group [9]
Finfer et. al. [10]

England and Wales

France
Australia and New Zealand

Study period

Mortality,
%

Mean
age,
years

1995
19972002

Examination of state databases

Examination of national database

300
91

29
34

63.8
65.9

1997
2001
1999

Examination of national database

Multicenter cohort study
Multicenter cohort study

51
95
77

47
38
35

65.0
60.7
65.0

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

distribution of several common comorbid conditions, including 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 diagnoses 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 to
have 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 1520 million persons 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 1. Incidence of sepsis in the United States from 1979 to 2000,

stratified by sex.

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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 [2730]. 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 more
striking. 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 concerning 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 sepsis 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 polymorphisms, 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
S492 CID 2005:41 (Suppl 7) Moss

Study design

Incidence,
no. of cases/
100,000
population

cost was directly related to medical services [3537]. In addition, 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 decreasing [33]. However, alcohol consumption is increasing in developing 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 for
the development of bacterial pneumonia. Usually, 25%50%
of patients with bacterial pneumonia have a prior history of
alcohol abuse [4043]. In 1965, Nolan [44] reviewed 900 consecutive admissions over a 5-month period and classified 124
patients as being alcoholic when defined by psychological criteria [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 enlisted 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 followed 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 admission diagnosis of pneumonia as were persons who were not

alcohol abusers [47]. In a European study, 50 patients with

community-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 hospitalization and had used alcohol chronically for a longer period of
time. After adjustment for the presence of cirrhosis and cigarette smoking, excessive alcohol intake was the only independent 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 358
cases of pneumococcal pneumonia, prolonged fever, slower resolution, 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 normal activity at 8 weeks after hospital admission [50]. In 1985,
312 patients admitted because of community-acquired pneumonia were followed at a public municipal hospital over a 12month 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 radiography at 1 week.
Recently, the effect of alcohol abuse on the development of
nosocomial pneumonia has been studied. Bercault and Boulain
Epidemiology of Sepsis CID 2005:41 (Suppl 7) S493

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

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.

Alcohol and immune function. There are many potential

mechanisms by which alcohol abuse can increase susceptibility
to infection, bacterial pneumonia, and sepsis, including an increased 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 ciliary 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 sepsisinduced TNF response in alveolar macrophages occurs at a
posttranscriptional level [64]. In addition, acute alcohol exposure suppresses the release of several chemokines, including
IL-8, macrophage inflammatory protein2, and cytokine-induced neutrophil chemoattractant. In addition, diminished hydrogen 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 recruitment, impaired bacterial clearance, increased dissemination of bacteria outside of the lung, and increased mortality in
animal models of sepsis [66]. Some of the intracellular mechanisms responsible for the acute effects of alcohol have been
elucidated. Human monocytes exposed to alcohol in vitro express inhibited lipopolysaccharide-induced nuclear factorkB
activation by decreasing DNA binding of the p65/p50 heterodimer [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 nonalcohol-exposed
lung followed a logarithmic curve, with 87% of the bacteria
removed within 4 h and only 1% of the bacteria remaining at

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[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 pneumonia
was 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 independent risk factor for the development of acute respiratory
distress syndrome (ARDS). Initially, surgeons from the University of Washington examined the effects of acute and chronic 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 alcohol 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 postoperative 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] examined a statewide database over a 1-year period. Only 4% of
the 23,198 cases of pneumonia were classified as alcohol related, 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.

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 diseases
or 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 patients 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 elucidated. 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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Epidemiology of Sepsis CID 2005:41 (Suppl 7) S497