REVIEW ARTICLE
Cigarette Smoking and Infection
Lidia Arcavi, MD; Neal L. Benowitz, MD
Background: Infectious diseases may rival cancer, heart
disease, and chronic lung disease as sources of morbidity and mortality from smoking. We reviewed mechanisms by which smoking increases the risk of infection
and the epidemiology of smoking-related infection, and
delineated implications of this increased risk of infection among cigarette smokers.
Methods: The MEDLINE database was searched for articles on the mechanisms and epidemiology of smokingrelated infectious diseases. English-language articles and
selected cross-references were included.
Results: Mechanisms by which smoking increases the
risk of infections include structural changes in the respiratory tract and a decrease in immune response. Cigarette smoking is a substantial risk factor for important
bacterial and viral infections. For example, smokers incur a 2- to 4-fold increased risk of invasive pneumococcal disease. Influenza risk is severalfold higher and is much
C
Author Affiliations: Clinical
Pharmacology Unit, Kaplan
Medical Center, Rehovot, Israel
(affiliated with Hadassah and
the Hebrew University School
of Medicine, Jerusalem, Israel)
(Dr Arcavi); Division of Clinical
Pharmacology and
Experimental Therapeutics,
Medical Service, San Francisco
General Hospital Medical
Center, San Francisco, Calif
(Dr Benowitz); and Department
of Medicine, Psychiatry, and
Biopharmaceutical Sciences,
University of California,
San Francisco (Dr Benowitz).
Financial Disclosure: None.
more severe in smokers than nonsmokers. Perhaps the
greatest public health impact of smoking on infection is
the increased risk of tuberculosis, a particular problem
in underdeveloped countries where smoking rates are increasing rapidly.
Conclusions: The clinical implications of our findings
include emphasizing the importance of smoking cessation as part of the therapeutic plan for people with serious infectious diseases or periodontitis, and individuals
who have positive results of tuberculin skin tests. Controlling exposure to secondhand cigarette smoke in children is important to reduce the risks of meningococcal
disease and otitis media, and in adults to reduce the risk
of influenza and meningococcal disease. Other recommendations include pneumococcal and influenza vaccine in all smokers and acyclovir treatment for varicella
in smokers.
Arch Intern Med. 2004;164:2206-2216
METHODS
IGARETTE SMOKING IS A
well-known major risk
factor for premature mortality due to cancer, cardiovascular disease, and
chronic obstructive pulmonary disease.
Cigarette smoking also appears to be a major risk factor for respiratory tract and other
systemic infections. Both active and passive cigarette smoke exposure increase the
risk of infections. The morbidity and mortality of infectious diseases due to smoking are not widely appreciated by physicians.
The mechanism of increased susceptibility to infections in smokers is multifactorial and includes alteration of the
structural and immunologic host defenses. The aims of this article are to review the mechanisms by which smoking
increases the risk of infection, to review
the epidemiology of smoking-related infections, and to discuss implications of
the increased risk of infection among
cigarette smokers.
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2206
The MEDLINE database was searched for articles on the mechanisms and epidemiology of
smoking-related infectious diseases. All relevant English-language articles published between 1978 and 2003 in the MEDLINE database were searched, by using the terms cigarette
smoking and immune system, cellular immunity, humoral immunity, white blood cell, cytokine, and chemotaxis, as well as cigarette
smoking with various specific infectious diseases. Selected references contained in these articles were also reviewed. Studies were included if they appeared to be scientifically valid;
however, no formal quality rating system was
used to screen articles for inclusion.
MECHANISMS BY WHICH SMOKING
MAY PREDISPOSE TO INFECTION
The specific mechanisms by which cigarette smoking increases the risk of systemic infections are incompletely understood. They are multifactorial and probably
interactive in their effects. They include
structural and immunologic mechanisms.
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Mechanical and Structural
Changes Caused by Smoking
Cigarette smoke and many of its components produce structural changes
in the respiratory tract. These changes
include peribronchiolar inflammation and fibrosis, increased mucosal
permeability, impairment of the mucociliary clearance, changes in pathogen adherence, and disruption of
the respiratory epithelium.1 These
changes are thought to predispose to
the development of upper and lower
respiratory tract infections, which
may amplify the cigarette smoke–
induced lung inflammation.
A number of components of cigarette smoke, including acrolein, acetaldehyde, formaldehyde, free radicals produced from chemical
reactions within the cigarette smoke,
and nitric oxide, may contribute to
the observed structural alterations in
the airway epithelial cells.2,3
Immunologic Mechanisms
Cigarette smoking affects both cellmediated and humoral-mediated immune responses in humans and animals.4-6
Cell-Mediated Immune Responses.
Cell Counts and Distribution in Peripheral Blood. Smokers on average
exhibit an elevated peripheral white
blood cell count, about 30% higher
than that of nonsmokers. All major
cell types are increased.6-10 Taylor et
al11 found a significant relationship
between the total white blood cell
count in smokers and the plasma
concentration of nicotine. Friedman et al9 suggested that nicotineinduced catecholamine release might
be the mechanism for this effect.
Other studies support the hypothesis that cigarette smoking
causes bone marrow stimulation.
Van Eeden and Hogg12 found that
polymorphonuclear leukocytes
(PMNs) from long-term smokers
have phenotypic changes indicating bone marrow stimulation, such
as increase in band cell counts,
higher levels of L-selectin, and increased myeloperoxidase content.
The authors suggested that proinflammatory factors released from alveolar macrophages, such as tumor
necrosis factor ␣, interleukin (IL) 1,
IL-8, and granulocyte-macrophage
colony-stimulating factor, are probably responsible for the stimulation of bone marrow by cigarette
smoking. Vanuxem et al13 found that
white blood cell count in smokers
was related to the carboxyhemoglobin concentration reflecting exposure to cigarette smoke. Tell et al14
showed the same relationship between cigarette smoking and increased leukocyte count in adolescents, indicating that there appears
to be a rapid effect of cigarette smoking on white blood cell count that
is unlikely to be due to smokinginduced chronic disease conditions as seen in adult smokers.
Reports of the effects of smoking on the different subsets of lymphocyte T cells are conflicting. The
influence of cigarette smoking on
lymphocyte T-cell subpopulations in
the peripheral blood has been investigated by means of monoclonal
antibodies. Light to moderate smokers (history of less than 50 packyears) were reported to have a significant increase in CD3+ and CD4+
counts and a trend toward increased CD8+ lymphocyte count.
The observed increase in the ratio of
CD4+ to CD8+ lymphocytes in light
smokers was due to the increase of
CD4+ cells.6,10,15-17 Two to 4 years after smoking cessation, the increase
in CD4+ cells disappeared.15,18 By
contrast, studies of heavy smokers
(ⱖ50 pack-years) reported a decrease in CD4+ and a significant increase in CD8+ cell counts. Thus, the
decrease observed in the ratio of
CD4+ to CD8+ lymphocytes in heavy
smokers was due predominantly to
an increase of CD8+ cells.16 These effects appeared to be reversible as
soon as 6 weeks after smoking cessation,17 although in one study6 it
took 2 to 4 years for these effects to
disappear. Other studies have reported no difference in the CD4+ and
CD8+ lymphocyte counts among
moderate smokers.19
Since CD4+ cells facilitate B-cell
proliferation and differentiation and
immunoglobulin synthesis, the decrease in this subset observed in
heavy smokers might contribute to
the increased susceptibility to infections in this population. An increase in CD8+ cells, such as that observed in heavy smokers, has been
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2207
associated with both neoplasia and
infection.20
Studies on Lung Fluids. The results of studies of bronchoalveolar
fluid from smokers differ from findings in the peripheral blood. Bronchoalveolar lavage studies19,21,22 have
demonstrated a marked decrease in
the percentage and absolute number of CD4+ cells, and an increase in
CD8+ cells with a lower CD4+/CD8+
cell ratio in moderate smokers (average, 14 pack-years) vs nonsmokers. No significant changes in these
variables in the peripheral blood
were found in this population of
moderate smokers, in contrast with
the findings in heavy smokers discussed previously. Thus, changes in
lymphocyte population in the bronchoalveolar lavage in smokers may
disclose pathologic changes earlier
than in blood. Moreover, these findings suggest that smokers have a
deficit in cell-mediated immunity in
the lung alveolus, a site critical in the
first-line defense against infection.
Smoking is also associated with significant increases in the percentage
of macrophages22 in bronchoalveolar lavage fluid.
Effects on PMN Function. Several
studies have shown that cigarette
smoking affects the function of white
blood cells.23,24 Polymorphonuclear
leukocytes from the peripheral blood
of smokers exhibit depressed migration and chemotaxis compared with
PMNs from nonsmokers.24,25 The motility and chemotaxis of PMNs are depressed in the oral cavity of smokers compared with nonsmokers.24,26
Which constituents of smoke are responsible for these effects remains
unclear.
Bridges et al27 demonstrated that
whole cigarette smoke, its gas phase,
and the water-soluble fraction were
potent inhibitors of PMN chemotaxis. Of the water-soluble fraction of
cigarette smoking, the unsaturated aldehydes (acrolein and crotonaldehyde) were the major contributors to
the inhibitor properties. Bridges and
Hsieh28 showed that the nonvolatile
components of cigarette smoking also
inhibit chemotaxis by a mechanism
that differs from that of the unsaturated aldehydes present in the vapor
phase of smoke. The nonvolatile component did not inhibit migration. A
relationship was observed between
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the polarity of a fraction and its inhibitory potency; thus, the inhibition of PMN chemotaxis could not be
attributed to either nicotine or the
polycyclic hydrocarbons. Sasagawa et
al29 found that nicotine had no effect
on PMN migration and chemotaxis.
Macrophages from the lungs of
smokers have a greater inhibitory
effect on lymphocyte proliferation
than macrophages from the lungs of
nonsmokers. Thus, the immunosuppressive effects of the macrophages on cell-mediated immune response are increased in smokers.30
The release of cytokines from macrophages may also be altered in
smokers.31 Twigg and coworkers32
showed that cigarette smoking decreases the secretion of the proinflammatory cytokines such as IL-1
and IL-6. Wewers et al22 showed decreased production of tumor necrosis factor ␣. Ouyang et al33 and Hagiwara et al34 reported that cigarette
smoking also suppresses IL-2 and interferon ␥ production. Hydroquinone, the phenolic compound in
cigarette tar, had the most potent inhibitory effect of these cytokines,
whereas nicotine had little effect. On
the other hand, IL-10 production by
human mononuclear cells was inhibited by treatment with nicotine
patches in patients with inflammatory bowel disease.35 Recently, Matsunaga et al36 reported that nicotinic acetylcholine receptors are
involved in the cytokine responses
of alveolar macrophages to Legionella pneumophila infection.
The cytokines IL-1 and IL-6 are
important in the host defense against
infection.37,38 Animal studies have
shown that depletion of these cytokines increases susceptibility to bacterial pneumonia. Since PMNs play
a significant role in host defense
against acute bacterial infections, an
impairment of PMN functions by
smoke may contribute to the increased susceptibility of smokers to
systemic infections, including bacterial pneumonia.
Effects on Lymphocyte Functions.
Natural killer (NK) cell activity in
peripheral blood has been reported
to be reduced in smokers compared with nonsmokers.6,15,39-41 Using a cytotoxicity assay, Ginns et al16
found that smokers had 47% of the
NK activity of nonsmokers. These al-
terations appear to be reversible,
since NK activity in ex-smokers was
similar to that of a never-smoking
group compared with smokers.18,42
The recovery period was relatively
short, as little as 6 weeks.15,17
Since NK cells are important in
the early surveillance response
against viral infections and resistance against microbial infections,43,44 impairment of NK cell activity by cigarette smoking is a
potential mechanism for the increased incidence of infections
among smokers.
The molecular mechanisms by
which cigarette smoking alters lymphocyte function, as described previously, are still poorly defined. Animal studies have shown that nicotine
inhibits the antibody-forming cell response through impairment of antigen-mediated signaling in T cells
and suppression of intracellular calcium response.5,45,46 Kalra et al47 exposed rats to mainstream cigarette
smoke or to nicotine via constantrelease osmotic pumps for up to 30
months and concluded that nicotine was the major immunosuppressive component in cigarette smoking. One suggested mechanism was
through activation of protein tyrosine kinases and the depletion of inositol-1,4,5-trisphosphate–sensitive
calcium stores in T cells.47
Humoral Immune System. Peripheral Blood. The effects of cigarette
smoking on humoral immunity have
been studied extensively.4,5 Several
studies have found that smokers had
serum immunoglobulin levels (IgA,
IgG, and IgM) 10% to 20% lower
than those of nonsmokers.39,48-51 Mili
et al10 found that IgA, IgG, and IgM
levels were higher among former
smokers than current smokers and
increased with duration of smoking cessation. This suggests that the
effect was reversible, with a return
toward the immunoglobulin levels
of nonsmokers. Hersey et al18 found
that 3 months after subjects stopped
smoking, IgG and IgM but not IgA
levels had increased compared with
levels during smoking.
Lung Fluids. The IgG content of
bronchial fluids was found to be
twice as high in smokers than nonsmokers.18,52 A selective increase in
immunoglobulin levels could be ex-
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2208
plained either by stimulation of local immunoglobulin production or
by exudation of plasma immunoglobulin into alveolar spaces in response to inhaled cigarette smoke.53
The availability of opsonic antimicrobial antibodies is essential for
optimal function of phagocytes to
take up and contain bacteria.54 The
antibody response to a variety of antigens, such as influenza virus infection and vaccination55 and Aspergillus fumigatus,56 is depressed in
cigarette smokers.
Summary of Immunologic Effects
of Cigarette Smoking. In summary, cigarette smoking is associated with a variety of alterations in
cellular and humoral immune system function. These alterations include a decreased level of circulating immunoglobulins, a depression
of antibody responses to certain antigens, a decrease in CD4+ lymphocyte counts, an increase in CD8+
lymphocyte counts, depressed
phagocyte activity, and decreased release of proinflammatory cytokines.
The pathogenesis of smoking
effects on the immune system is
not well understood. Some investigatorshavedemonstratedanantigenic
role of substances in cigarette smoking, resulting in the development of
antigen-antibody complexes. These
complexes are capable of causing pulmonary and peripheral changes in
responses of the humoral and cellmediated system. Hersey et al18 and
Costabel et al19 suggested that the
antigen-antibody complexes may induce localized alterations of the
immune status of the saliva and the
bronchoalveolar fluid and predispose
to respiratory tract infections.
Smoking, via the effects of nicotine, can stimulate catecholamine
and corticosteroid release. These mediators might increase CD8+ lymphocytes in the cellular-mediated
system17 and suppress the host defense against infections. It is important to recognize that many of the immunologic abnormalities in smokers
resolve within 6 weeks after smoking cessation, supporting the idea that
smokingcessationiseffectiveinarelatively short time in the prevention of
infections.
The results of several studies suggest that nicotine is an important im-
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6
Nuorti et al, 2000
58
Almirall et al, 199959
Smoking Status
Odds Ratio* (95% CI)
Attributable Risk, %
Current smoker
⬎25 Cigarettes/d
30 Pack-years
Passive smoker
Never smoked
Current smoker
⬎20 Cigarettes/d
⬎38 Pack-years
Never smoked
4.1 (2.4-7.3)
5.5 (2.5-12.9)
3.2 (1.6-6.9)
2.5 (1.2-5.1)
1.0
1.88 (1.11-3.19)
2.97 (1.52-5.81)
3.15 (1.52-6.51)
1.00
51
17
SMOKING AND CLINICAL
INFECTIOUS DISEASES
General Considerations With
Respect to Epidemiologic Studies
In evaluating epidemiologic studies
reportinganassociationbetweencigarette smoking and infectious diseases,
one must consider the possibility of
confounding. Compared with nonsmokers, cigarette smoking is associated with lower socioeconomic status, different diet, greater alcohol and
drug use, lower levels of physical activity, and more risk-taking behaviors, including risky sexual behaviors.
Most studies have controlled for factors such as age, sex, race/ethnicity,
alcohol consumption, sexual habits,
etc, although not every study has controlled for every possible confounder.
Because of space limitations, we are
unable to describe which factors were
controlled for every study, but we
have selectively commented on controls for particular studies where it
seemed relevant.
Bacterial Infections
Pneumococcal Pneumonia. Cigarette smoking is a substantial risk factor for pneumococcal pneumonia, especially in patients with chronic
obstructive pulmonary disease. However, even without chronic obstructive pulmonary disease, smoking is a
major risk factor. In a populationbased surveillance study conducted in
Dallas County, Texas, in 1995,57
smoking was strongly associated with
1-14
>24
Figure 1. Cigarette consumption and the risk of
pneumococcal disease (data from Nuorti et al58).
4
3
2
1
0
<5
5-9
≥10
No. of Years Since Quitting Smoking
Figure 2. Decline in the risk of pneumococcal
disease (data from Nuorti et al58).
In vitro adherence of Streptococcus pneumoniae to buccal epithelial
cells has been shown to be increased
in cigarette smokers.60 This increased
adherence may persist for up to 3
years after smoking cessation. Since
increasedadherenceofbacteriatosurface cells is an established pathogenic
step for bacterial colonization and infection in both lung and other organs,
this may contribute to the increased
risk of respiratory infection that exists in cigarette smokers.
Legionnaires Disease. Legionnaires disease is a life-threatening
bronchopneumonia responsible for
1% to 3% of community-acquired
pneumonia. Diverse environmental factors have been identified, and
cigarette smoking appears to be an
independent risk factor.61
Straus et al62 reported that the risk
of legionnaires disease was increased 121% per cigarette pack consumed daily, with an OR of 3.48
(95% CI, 2.09-5.79) for smoking.
For persons without an underlying
disease, the OR for smokers compared with nonsmokers was 7.49
(95% CI, 3.27-17.17).
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15-24
No. of Cigarettes Smoked Daily
invasive pneumococcal disease in otherwise healthy young and middleaged adults (30 to 64 years of age),
for whom pneumococcal vaccination is not currently recommended.
Among such individuals with invasive pneumococcal disease, 47% were
current smokers. The odds ratio (OR)
for invasive pneumococcal disease
was 2.6 (95% confidence interval
[CI], 1.9-3.5) for smokers in the 24to 64-year age group and 2.2 (95% CI,
1.4-3.4) for smokers 65 years or older.
The attributable risk from smoking
was 31% and 13% in these 2 groups,
respectively. A recent populationbased case-control study58 showed
that smoking was the strongest independent risk factor for invasive pneumococcal disease among immunocompetent adults. The OR was 4.1
(95% CI, 2.4-7.3) for active smoking and 2.5 (95% CI, 1.2-5.1) for passive smoke exposure in nonsmokers
compared with nonexposed nonsmokers (Table 1). The attributable risk in this population was 51%
for cigarette smoking and 17% for
passive smoking. This effect showed
a strong dose-response relationship
(Figure 1). The risk of pneumococcal disease declined to nonsmoker levels 10 years after cessation (Figure 2).
In another case-control study,
Almirall et al59 found that current
smoking was associated with a nearly
2-fold risk of community-acquired
pneumonia (OR,1.88; 95% CI, 1.113.19), where 32% of the risk was attributable to cigarette smoking. In this
study, there was a trend toward a
dose-response relationship. A 50% reductionintheORwasreported5years
after cessation of smoking. Table 1
summarizes these results.
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2
0
Abbreviation: CI, confidence interval.
*Adjusted for multiple variables (age, sex, race, chronic illness, level of education, and residence).
munosuppressive component of
cigarette smoke, but other components also appear to have a role.
4
32
Odds Ratio
Source
Odds Ratio
Table 1. Cigarette Smoking and Risk of Pneumococcal Infections
Meningococcal Disease
Active Smokers. In a case-control
study by Fischer et al,63 36% of patients with meningococcal disease
were current smokers, while 14%
were nonsmokers (OR, 2.4; 95% CI,
0.9-6.6). During an outbreak of serogroup C meningococcal disease
among college students, 4 of 6 cases
were in cigarette smokers, a prevalence much higher than that of exposed controls (OR, 7.8; 95% CI,
1.3-64.4).64
Cigarette smoking is associated
with meningococcal colonization of
the nasopharynx. Stuart et al65 found
that 55% of active smokers were carriers compared with 36% of nonsmokers and 76% of those exposed
to secondhand tobacco smoke. The
risk of carriage associated with active smoking increased with the daily
number of cigarettes smoked. The
OR for all smokers was 2.3 (95% CI,
1.2-4.6), with a greater risk for
smokers of more than 20 cigarettes
per day. Caugant et al66 performed
a survey among a Norwegian population and found that active smoking was independently associated
with meningococcal carriage (OR,
2.79; 95% CI, 1.67-4.64). There was
no association between the number of cigarettes smoked daily and
carriage. A similar pattern was found
in a study conducted among recruits in Greece.67
Exposure to Secondhand Tobacco
Smoke. Secondhand tobacco smoke
exposure has also been associated
with an increased risk of meningococcal disease. In a case-control study,
Fischer et al63 established a strong epidemiologic link between smoking and
meningococcal disease in children.
For children younger than 18 years,
having a mother who smoked was the
strongest independent risk factor for
invasive meningococcal infection
compared with other risk factors such
as maternal education, no primary
physician, or humidifier use (OR, 3.8;
95% CI, 1.6-8.9). Thirty-seven percent of the infections could be attributed to maternal smoking. The number of smokers living in the home and
the number of packs smoked per day
had a significant linear relationship
with the risk of meningococcal disease. No such association was ob-
served for paternal smoking in this
study. Among adult patients with meningococcal disease, 50% were passive smokers compared with 29%
controls (OR, 2.5; 95% CI, 0.9-6.9).
In the Norwegian population survey, Caugant et al66 found a doubling of carriage rate for passive smokers (OR, 2.30; 95% CI, 1.21-4.37). In
a prospective study, Haneberg et al68
found that passive smoking in children younger than 12 years was significantly more frequent in meningococcal patients (62%) than the
population controls (32%) (P⬍.001).
There are several potential
mechanisms by which tobacco might
increase the risk of meningococcal
disease. One is that tobacco smoke
is a risk factor for meningococcal nasopharyngeal carriage, so that persons living with smokers have a
greater chance to be exposed to meningococci. A second possible
mechanism is that a preceding viral
infection, which is more frequent in
smokers, can act as a cofactor for meningococcal disease. During an outbreak of meningococcal disease in
Los Angeles County, California, patients with meningococcal disease
were more likely than matched
neighborhood controls to have had
an upper respiratory tract infection
(OR, 3.2; 95% CI, 1.4-7.1) or to be
exposed to a household visitor with
an upper respiratory tract infection
(OR, 2.6; 95% CI, 1.02-6.6).69 Third,
ineffective humoral immunity
against the Neisseria meningitidis
polysaccharide capsule is a wellrecognized risk factor for invasive
meningococcal disease.
Otitis Media and Exposure to Secondhand Tobacco Smoke. Longterm tobacco smoke exposure is a
risk factor for otitis media and bronchitis in children.3 In a prospective
study, 175 children with recurrent
otitis media were compared with an
age-matched group of 175 children
to determine the role of passive cigarette smoking on the incidence of
this disease. The case group more
commonly had exposure to secondhand smoke, with an OR of 1.88
(95% CI, 1.02-3.49) (P=.04). Prospective follow-up of the case group
showed no significant difference in
the clinical course of the children
who were exposed to secondhand
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2210
smoke and those who were not.70
Ilicali et al71 examined the development of otitis media with effusion
and recurrent otitis media in 166
children 3 to 7 years old, compared
with an age-matched control group
of 166 children. Passive smoking was
a significant risk factor for otitis media with effusion and recurrent otitis media. The case group was exposed to smoke from a mean of 19.6
cigarettes per day vs 14.4 cigarettes
per day for the control group
(P⬍.004). Only maternal smoking
was a significant factor (P⬍.001).
Moreover, in utero exposure to cigarette smoke was associated with an
increased risk of otitis media. In a
study carried out by Stathis et al,72
acute ear infections were associated with the mother’s consumption of 1 to 9 cigarettes (OR, 1.6; 95%
CI, 1.1-2.5), 10 to 19 cigarettes (OR,
2.6, 95% CI, 1.6-4.2), and 20 or more
cigarettes (OR, 3.3; 95% CI, 1.95.9) per day during pregnancy. For
subacute ear infections, an association was present with the mother’s
consumption of 10 to 19 cigarettes
(OR, 2.6; 95% CI, 1.4-5.0) and 20
or more cigarettes (OR, 2.8; 95% CI,
1.3-6.0). In utero exposure to 20 or
more cigarettes per day was also associated with an increased risk of ear
surgery by 5 years after delivery (OR,
2.9; 95% CI, 1.3-6.6).
Periodontal Disease. Tobacco use is
a substantial risk factor for periodontal disease.73,74 Smokers are 2.5
to 6 times more likely to develop
periodontal disease than nonsmokers, and there is a direct relationship between the number of cigarettes smoked and the risk of
developing periodontal disease.
Among current smokers, the odds of
periodontitis range from 2.79 (95%
CI, 1.90-4.10) for 9 or fewer cigarettes per day to 5.88 (95% CI, 4.038.58) for 31 or more cigarettes per
day. Among former smokers, the
odds of periodontitis declined with
the number of years since quitting,
from 3.22 (95% CI, 2.18-4.76) for
0 to 2 years to 1.15 (95% CI, 0.831.60) for 11 or more years since
quitting.75
The severity of periodontal disease is also increased in smokers and
the postoperative results are poorer
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than those achieved in nonsmokers.76 There is a direct relationship
between tobacco use and increased
attachment loss, pocket depth, and
reduced bone crest height.77,78 Smokers have a greater extent of subgingival bacterial colonization than
never-smokers.79,80
Helicobacter pylori Infection. The
pathogenesis of peptic ulcer disease
is multifactorial. Helicobacter pylori infection and smoking are wellestablished risk factors. More than
95% of duodenal ulcers are associated with H pylori infection, and treatment of H pylori markedly reduces ulcer recurrence rates. Smokers are
more likely to develop ulcers.81 Ulcers in smokers take longer to heal82
and relapse more often in smokers
compared with nonsmokers.83-85
Moshkowitz et al86 found that
gastric and duodenal ulcers were
more prevalent in smokers than nonsmokers (gastric, 4.1% vs 1.8%; duodenal, 50% vs 39.8%, respectively;
P⬍.05). Bateson,87 in a prospective
study, reported that 51.8% of patients with duodenal ulcers and
48.8% of those with gastric ulcers
were smokers, compared with 31.8%
of the controls. This study reported
an association between current
smoking and H pylori infection in patients with normal results of endoscopy. Current cigarette smokers had
a higher rate (49.6%) of H pylori
infection than nonsmokers and
ex-smokers (35.5%) (P⬍.01). In another study, 73% of H pylori–
positive smokers had a duodenal
or gastric ulcer, whereas only 27%
of seropositive nonsmokers had
ulcers.88
Recently, Nakamura et al89 reported an increased risk of severe
atrophic gastritis and intestinal metaplasia associated with smoking (OR,
9.31; 95% CI, 3.85-22.50; and OR,
4.91; 95% CI, 1.90-12.68) within
H pylori–positive subjects.
Nicotine potentiates the vacuolating toxin activity of H pylori. This
toxin may be an important determinant of the virulence of H pylori. In
an in vitro model, Cover et al 90
showed that treatment of cells with
nicotine after exposure to H pylori
toxin induces formation of vacuoles within eukaryotic cells and incites mucosal damage. While ciga-
rette smoking is a strong predictor
of recurrent ulcer in the presence of
H pylori treatment, cigarette smoking appears to have little effect on ulcer healing after eradication of H pylori.91 Borody et al92 showed that, in
197 patients with eradicated H pylori and cured duodenal ulcer by endoscopy examination, there was no
recurrence of ulcer, regardless of
smoking status during a follow-up
period of 6 years. These observations support the idea that a major
mechanism by which smoking increases ulcer disease is by increasing the rate of infection and/or the
virulence of H pylori.
Viral Infections
Common Cold. Large epidemiologic studies support the association between smoking and the prevalence of colds and lower respiratory
tract symptoms. In a prospective cohort study, Blake et al93 examined a
large group of US Army recruits
(1230 soldiers) and found that
22.7% of smokers had upper respiratory infection compared with 16%
of nonsmokers; a relative risk of 1.5
(95% CI, 1.1-1.8).
Cohen et al94 showed that smoking status was predictive of the development of clinical colds when
they exposed 400 healthy volunteers intranasally to a low dose of 1
of 5 respiratory viruses. Viral suspensions were installed into the
nares and infections were diagnosed on the basis of viral isolation, virus-specific antibody, and
clinical findings. Smokers had a significantly higher incidence of acute
infection (clinical cold) than nonsmokers, with an OR of 2.23 (95%
CI, 1.03-4.82). Among virologically confirmed infected individuals, smoking was associated with a
higher likelihood of symptoms leading to a clinical diagnosis (OR, 1.83;
95% CI, 1.00-3.36). This risk for
smokers was independent of alcohol consumption, as well as of demographic, environmental, immunologic, and psychological variables.
Cohen et al94 suggested that the relationship between smoking and increased symptoms from viral respiratory infections could be explained
by impairment of immune processes that limit viral replication or
(REPRINTED) ARCH INTERN MED/ VOL 164, NOV 8, 2004
2211
enhancement of inflammatory processes involved in the production of
symptoms. When Vitalis et al95 exposed guinea pigs with latent adenoviral infection to a single dose
of cigarette smoke, they developed
a more aggressive inflammatory response. An important feature of
adenovirus infection is that portions of its viral DNA persist in
host cells after viral replication has
stopped. This may be important in
the pathogenesis of permanent airway obstruction, bronchiectasis,
chronic obstructive pulmonary disease, and emphysema. The probable mechanism is through a protein expressed by the latent viral
DNA. This protein amplifies the expression of genes that are activated
in cigarette smoke–induced airway
inflammation.96
Influenza. Several studies have confirmed the relationship between cigarette smoking and the risk of influenza infections.97 Influenza infections
are more severe, with more cough,
acute and chronic phlegm production, breathlessness, and wheezing
in smokers. Female smokers in the
Israeli Army had a 60% risk of influenza compared with 41.6% in
nonsmokers (OR, 1.44; 95% CI,
1.03-2.01). They also had a 44% increase in complications (visited the
clinic more frequently) during an
epidemic influenza illness caused by
the A(H1N1) subtype.98 In another
study of 336 healthy young male recruits in the Israeli military unit conducted by Kark et al, 99 the incidence of influenza was 68.5% among
smokers and 47.2% among nonsmokers (P⬍.001). The OR was 2.42
(95% CI, 1.53-3.83). Influenza was
more severe among smokers, with
a dose-related increase in rate: 30%
in nonsmokers, 43% in light smokers, and 54% in heavy smokers
(P ⬍.001). Work loss occurred in
50.6% of smokers and 30.1% of nonsmokers. Overall, 31.2% (95% CI,
16.5-43.1) of influenza cases were
attributed to cigarette smoking.
Enhanced bacterial adherence has
been documented for respiratory cells
infected, with influenza A virus being
responsible for viral-bacterial combination pneumonia.100 Studies have
suggested that inflammatory activation of platelet-activating factor is an
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important factor in the attachment
and invasion of cells by pneumococcal strains. Cigarette smoking alters
platelet-activating factor metabolism and may contribute to the increased incidence of bacterial superinfection in people who develop
influenza.101,102
Although influenza was more severe in smokers, smokers’ antibody
levels to A(H1N1) antigen were not
significantly higher than those of
nonsmokers. Only 50% of those
with severe disease achieved titers
greater than 20. Moreover, influenza antibodies wane more rapidly
in smokers than in nonsmokers.55
This finding suggests that smokers
are not only at a high risk of influenza, but have an increased susceptibility to new attacks afterward.99 Influenza rates are similar
in vaccinated smokers and nonsmokers. However, influenza vaccination can be considered to be
moreefficacious in smokers than nonsmokers because the infection rates
arehigherinunvaccinatedsmokers.103
Varicella. In adults, varicella infection is associated with a substantial
incidence of complications. One of
these complications is varicella pneumonitis, for which smokers appear to
be at greater risk. Ellis et al104 showed
that among 29 adults with varicella
infection, 7 of the 19 smokers were
hospitalized with pneumonitis, but
none of the 10 nonsmokers developed pneumonia. Later, Grayson and
Newton-John105 reported a 15-fold
risk of varicella pneumonitis in smokers compared with nonsmokers and
varicella (P⬍.001).
Human Papillomavirus Infections.
Human papillomavirus (HPV) infection of the lower genital tract is
one of the most common sexually
transmitted diseases and is the cause
of cervical intraepithelial neoplasia. Although the human papillomavirus is the infectious agent, the clinical manifestations of HPV are a
function of the interaction of the virus and other factors such as the patient’s cell-mediated and humoral
immune system, as well as patient
characteristics such as smoking.106
The incidence of HPV infection is
difficult to establish, since most of
the infections are transient and, un-
til the advent of polymerase chain reaction–based diagnostic techniques, the serologic measurements
did not have good sensitivity or
specificity. Between 7% and 50% of
teenage patients are infected with
HPV,107,108 depending on their sexual
behavior. The association of cigarette smoking, both active and passive, with HPV expression and cervical intraepithelial neoplasia is
strong. A relative risk of 2.7 (95% CI,
1.7-4.3) for smoking has been
reported.109
Nicotine and other constituents of
smoke have been found in the cervical mucus of active and passive
smokers.110 These constituents have
been associated with decreased numbers of Langerhans cells in the cervix in a cytologic examination.106 The
Langerhans cells are part of the antigen–T-lymphocyte cell-mediated
immune response system and are responsible for recruiting CD4+ lymphocytes, which are necessary for the
local immune response. Patients who
did not respond to interferon treatment for HPV had low levels of CD4+
lymphocytes and a low CD4+/CD8+
ratio. This ratio was nearly normal in
patients who responded to interferon treatment.111 The at-risk profile of low CD4+/CD8+ ratio is similar to that due to smoking described
earlier in this article. In addition,
some studies have shown that vitamin A and beta carotene protect
against cervical intraepithelial neoplasia.112 Cigarette smokers have decreased serum beta carotene levels.
Most likely, cigarette smoke acts as
a cofactor facilitating HPV infection
and as an immune suppressant. However, the virus and smoking are independent and additive in their effects on the immune system.
Human Immunodeficiency Virus
Infection. A few studies have investigated cigarette smoking as a cofactor for AIDS in individuals infected
with human immunodeficiency virus (HIV). The first association between smoking and AIDS was observed by Newell et al. 113 Later,
Royce and Winkelstein114 reported
an elevated risk of AIDS and a more
rapid progression in seropositive
smokers compared with nonsmokers. In 1990, Boulos et al 115 reported an association between smok-
(REPRINTED) ARCH INTERN MED/ VOL 164, NOV 8, 2004
2212
ing and HIV infection in pregnant
Haitian women. Women who
smoked 4 or more cigarettes per day
had a 25% HIV-1 seropositive rate,
compared with 9.6% for women who
smoked fewer than 4 cigarettes per
day. The association between HIV
infection and smoking was confounded by an association between
cigarette smoking and high-risk
sexual behavior, but cigarette smoking was found to be an independent risk factor after controlling for
both high-risk sexual behavior and
HIV infection in this population. The
OR for smoking and HIV infection
was significant (OR, 3.4; 95% CI,
1.6-7.5). On the other hand, Burns
et al116 observed a higher HIV seroconversion rate in persons who were
homosexual who smoked than in
nonsmokers, but found no effect of
smoking on clinical outcome in their
cohort. Similar results were also reported by Craib et al,117 who failed to
find a significant association between cigarette smoking and the development of Pneumocystis carinii
pneumonia.
Although the association between smoking and HIV infection
could be due to a confounding factor such as participation in highrisk behaviors, a biological effect of
cigarette smoking must be considered. Nicotine and cotinine are concentrated in the cervical secretions
of women who smoke 118,119 and
could alter local immune factors and
increase susceptibility to viral infections of the genital tract. In patients infected with HIV, smoking is
also associated with an increased incidence of bacterial pneumonia. In
a multicenter study done by the Pulmonary Complications of HIV Infection Study Group, this smoking
effect was strongest in the most lymphopenic subgroup of patients.120
As discussed previously, cigarette smoking is associated with an
increase in the percentage of CD4+
in blood in seronegative populations. Several studies112,114,116,117,121,122
have shown that these effects are attenuated in the HIV-infected smoking population during the first 2
years of infection. Analysis of the
data suggested that an effect of
smoking is present within the first
few years of HIV infection but then
disappears, and these patients ex-
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perience a marked decrease in CD4+
counts. In other words, when smokers become infected with HIV, it
takes up to 2 years for viral-related
depletion of CD4 cells to overwhelm the smoking effect. In contrast, a significant decrease in CD4
and CD8 cells is seen in their bronchoalveolar lavage fluid, suggesting that cigarette smoking has a significant impact on lung defenses
in HIV-infected individuals.22 In
HIV-infected patients, cigarette
smoking increases the risk of oral
candidiasis (relative risk, 1.32; 95%
CI, 1.02-1.70), hairy leukoplakia
(associated with Epstein-Barr virus
infection; relative risk, 1.51; 95%
CI, 1.15-1.99), and communityacquired pneumonia (relative risk,
2.62; 95% CI, 1.30-5.27).116,122
Tuberculosis
Persons at special risk for tuberculosis include immune-suppressed individuals and persons of low socioeconomic status. Several studies have
shown that smoking is a risk factor
for tuberculin skin test reactivity, skin
test conversion, and the development
of active tuberculosis. Yu et al123 reported that the relative risk of development of tuberculosis for heavy
smokers compared with nonsmokers was 2.17 (95% CI, 1.29-3.63). Buskin et al124 found that, after adjusting for age and heavy drinking, smokers of 20 years’ or greater duration had
2.6 times (95% CI, 1.1-5.9) the risk
of nonsmokers for tuberculosis.
Alcaide et al125 also found a strong
association between active smoking and the risk of pulmonary tuberculosis. Both studies showed a
dose-response relationship with the
number of cigarettes consumed
daily. McCurdy et al126 reported an
incidence of 16.6% in tuberculin reactivity (⬎10 mm in duration at 48
to 72 hours) among Hispanic migrant farm worker residents in California. This prevalence was higher
for former smokers than for neversmokers (OR, 3.11 [95% CI, 1.28.09] vs 1.00). Current smokers had
a nearly 2-fold increased risk compared with never-smokers (OR, 1.87;
95% CI, 0.73-4.80).
In a case-control study among incarcerated adults, Anderson et al127
reportedan81%rateoftuberculinskin
Table 2. Cigarette Smoking and Risk of Tuberculosis
OR (95% CI)
Smoking Status
Observed Tuberculin
Reactivity*
Skin Test
Conversion†
Smoking history
Never
Former
Current
1.00
3.11 (1.20-8.09)
1.87 (0.73-4.80)
1.00
1.00
1.78 (0.98-3.21)
Current or former
Duration of smoking
⬍15 y
ⱖ15 y
Cigarettes/d
⬍20
ⱖ20
⬍10
ⱖ10
Cigarettes/y
ⱕ199
200-399
ⱖ400
1.00
1.4 (0.8-2.3)‡
1.3 (0.8-2.1)‡
2.17 (1.29-3.63)§
3.8 (1.5-9.8)储
2.4 (1.9-3.0)¶
1.60 (0.81-3.16)
2.12 (1.03-4.36)
3.0 (1.3-7.9)储
13.0 (2.3-73.8)储
1.7 (1.4-2.2)¶
2.6 (2.2-3.1)¶
0.96 (0.59-1.55)§
1.16 (0.66-2.04)§
2.17 (1.29-3.63)§
Abbreviations: CI, confidence interval; OR, odds ratio; TB, tuberculosis.
*From McCurdy et al.126
†From Anderson et al.127
‡From Buskin et al.124
§From Yu et al.123
储From Alcaide et al.125
¶From Gajalakshmi et al.128
test conversion in smokers compared
with 10.3% in nonsmokers. An interesting finding of this study was that
the duration of smoking was more important than the number of cigarettes
smoked daily. Table 2 summarizes
the results of these studies.
A large case-control study in India examined smoking and tuberculosis in men between 35 and 69 years
of age.128 The tuberculosis prevalence risk ratio was 2.9 (95% CI, 2.63.3) for ever-smokers compared with
never-smokers, and the prevalence
was higher with a higher level of cigarette consumption (Table 2). The
mortality from tuberculosis among
men 25 to 69 years of age, based on
4072 tuberculosis deaths, showed a
risk ratio of 4.5 (95% CI, 4.0-5.0)
and 4.2 (95% CI, 3.7-4.8) for urban
and rural residents, respectively. The
authors found that the smokingattributable fraction of deaths from tuberculosis was 61%, greater than the
fractionofsmoking-attributabledeaths
from vascular disease or cancer.
In a study among children living with a patient with active pulmonary tuberculosis, passive smoking was a strong risk factor for the
(REPRINTED) ARCH INTERN MED/ VOL 164, NOV 8, 2004
2213
development of active tuberculosis
(OR, 5.39; 95% CI, 2.44-11.91). Passive smoke exposure was confirmed by measurement of urinary
cotinine levels, which were higher
in children who developed the disease.129 The biological basis by which
tobacco smoking increases tuberculosis risk may be through a decrease in immune response, mechanical disruption of cilia function,
defects in macrophage immune
responses, and/or CD4+ lymphopenia, increasing the susceptibility
to pulmonary tuberculosis.130,131
Of historical interest is the relationship between tuberculosis and
the rise of cigarette smoking in the
early 20th century. Before that time,
chewing tobacco was the preferred
type of tobacco. Public fears that users of chewing tobacco who spit in
public places might be spreading tuberculosis is one of the factors that
led to the increase in cigarette sales
in the United States. This is nicely
described by Kluger132 as follows:
“Chewing tobacco was no longer
merely messy but socially disagreeable in more crowded urban America,
and its inevitable by-product, spit-
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Risk of TB
ting, was now identified as a spreader
of tuberculosis and other contagions and, thus, an official health
menace. The leisurely pipe all at once
seemed a remnant of a slower-temp
age, and cigar fumes were newly offensive amid thronged city life. The
cigarette, by contrast, could be
quickly consumed and easily snuffed
out on the job as well as to and from
work.”
SUMMARY AND
IMPLICATIONS
Cigarette smoking remains an enormous health problem and is the principal cause of several preventable
diseases and much premature death.
Generally, physicians think of cancer, atherosclerotic cardiovascular
disease, and chronic obstructive pulmonary disease as the major health
problems caused by smoking. Our
review summarizes research on another significant adverse health effect
due to active and passive smoking:
the development of infections. Infectious diseases may rival cancer,
heart disease, and chronic lung disease as sources of morbidity and
mortality from smoking.
We have reviewed the strength of
the association between smoking
and infections as measured by relative risk and the presence of a doseresponse effect. The possible mechanisms by which smoking increases
the risk of infections include structural changes in the respiratory tract
and a decrease in immune response, both systemically and locally within the lungs.
Cigarette smoking is a substantial risk factor for important bacterial and viral infections. To highlight some of the more common and
serious links between smoking and
infection, smokers incur a 2- to 4-fold
increased risk of invasive pneumococcal disease, a disease associated
with high mortality. Influenza risk is
severalfold higher and much more severe in smokers compared with nonsmokers. Perhaps the greatest public health impact of smoking on
infection is the increased risk of tuberculosis. The highest rates of tuberculosis and associated mortality are
among the poor and people in underdeveloped countries. The prevalence of smoking is high among the
poor in developed countries and is increasing rapidly in underdeveloped
countries. Thus, it is likely that smoking contributes substantially to the
worldwide disease burden of tuberculosis.
The findings of our review further emphasize the potential health
benefits of smoking cessation and
have specific clinical implications:
1. Smoking cessation should be
part of the therapeutic plan for
people with any serious infectious
disease, periodontitis, or positive results of tuberculin skin tests.
2. Secondhand smoke exposure
should be controlled in children to reduce the risks of meningococcal disease and otitis media and in adults to
reduce the risks of influenza and meningococcal disease.
3. We have 3 recommendations
for prevention of specific diseases:
• Pneumococcal and influenza
vaccine in all smokers
• Acyclovir treatment for varicella in smokers
• Yearly Papanicolaou smears in
women who smoke.
Accepted for Publication: November 28, 2003.
Correspondence: Neal L. Benowitz, MD, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San
Francisco, Box 1220, San Francisco, CA 94143-1220 (nbeno@itsa
.ucsf.edu).
Funding/Support: This study was
supported in part by Public Health
Service grants DA02277 and
DA12393 from the National Institutes of Health, Bethesda, Md, and
the Flight Attendants’ Medical Research Institute, Miami, Fla.
Acknowledgment: We thank Joel
Ernst, MD, for his critical review of
the manuscript and Kaye Welch for
editorial assistance.
REFERENCES
1. Dye JA, Adler KB. Effects of cigarette smoke on
epithelial cells of the respiratory tract. Thorax.
1994;49:825-834.
2. Marcy TW, Merrill WW. Cigarette smoking and
respiratory tract infection. Clin Chest Med. 1987;
8:381-391.
3. Richardson MA. Upper airway complications of
cigarette smoking. J Allergy Clin Immunol. 1988;
81:1032-1035.
(REPRINTED) ARCH INTERN MED/ VOL 164, NOV 8, 2004
2214
4. Sopori ML, Goud NS, Kaplan AM. Effect of tobacco smoke on the immune system. In: Dean
JH, Luster AE, Kimer M, eds. Immunotoxicology and Immunopharmacology. New York, NY:
Raven Press; 1994:413-432.
5. Sopori ML, Kozak W, Savage SM, et al. Effect of
nicotine on the immune system: possible regulation of immune responses by central and peripheral mechanisms. Psychoneuroendocrinology. 1998;23:189-204.
6. Tollerud DJ, Clark JW, Brown LM, et al. The effects of cigarette smoking on T cell subsets: a
population-based survey of healthy caucasians.
Am Rev Respir Dis. 1989;139:1446-1451.
7. Yeung MC, Buncio AD. Leukocyte count, smoking, and lung function. Am J Med. 1984;76:
31-37.
8. Corre F, Lellouch J, Schwartz D. Smoking and
leucocyte-counts: results of an epidemiological
survey. Lancet. 1971;2:632-634.
9. Friedman GD, Siegelaub AB, Seltzer CC, Feldman R, Collen MF. Smoking habits and the leukocyte count. Arch Environ Health. 1973;
26:137-143.
10. Mili F, Flanders WD, Boring JR, Annest JL,
Destefano F. The associations of race, cigarette
smoking, and smoking cessation to measures
of the immune system in middle-aged men. Clin
Immunol Immunopathol. 1991;59:187-200.
11. Taylor RG, Woodman G, Clarke SW. Plasma nicotine concentration and the white blood cell count
in smokers. Thorax. 1986;41:407-408.
12. van Eeden SF, Hogg JC. The response of human bone marrow to chronic cigarette smoking.
Eur Respir J. 2000;15:915-921.
13. Vanuxem D, Sampol J, Weiller PJ. M’Barki M,
Grimaud C. Influence of chronic smoking on leukocytes [in French]. Respiration. 1984;46:
258-264.
14. Tell GS, Grimm RH Jr, Vellar OD, Theodorsen L.
The relationship of white cell count, platelet count,
and hematocrit to cigarette smoking in adolescents: the Oslo Youth Study. Circulation. 1985;
72:971-974.
15. Hughes DA, Haslam PL, Townsend PJ, TurnerWarwick M. Numerical and functional alterations
in circulatory lymphocytes in cigarette smokers.
Clin Exp Immunol. 1985;61:459-466.
16. Ginns LC, Goldenheim PD, Miller LG, et al. Tlymphocyte subsets in smoking and lung cancer: analysis of monoclonal antibodies and flow
cytometry. Am Rev Respir Dis. 1982;126:
265-269.
17. Miller LG, Goldstein G, Murphy M, Ginns LC. Reversible alterations in immunoregulatory T cells
in smoking: analysis by monoclonal antibodies
and flow cytometry. Chest. 1982;82:526529.
18. Hersey P, Prendergast D, Edwards A. Effects of
cigarette smoking on the immune system: follow-up studies in normal subjects after cessation
of smoking. Med J Aust. 1983;2:425-429.
19. Costabel U, Bross KJ, Reuter C, Ruhle KH,
Matthys H. Alterations in immunoregulatory Tcell subsets in cigarette smokers: a phenotypic
analysis of bronchoalveolar and blood
lymphocytes. Chest. 1986;90:39-44.
20. Reinherz EL, Rubinstein A, Geha RS, Strelkauskas
AJ, Rosen FS, Schlossman SF. Abnormalities of
immunoregulatory T cells in disorders of immune
function. N Engl J Med. 1979;301:1018-1022.
21. Leatherman JW, Michael AF, Schwartz BA,
Hoidal JR. Lung T cells in hypersensitivity
pneumonitis. Ann Intern Med. 1984;100:390392.
WWW.ARCHINTERNMED.COM
©2004 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 03/10/2022
22. Wewers MD, Diaz PT, Wewers ME, Lowe MP,
Nagaraja HN, Clanton TL. Cigarette smoking in
HIV infection induces a suppressive inflammatory environment in the lung. Am J Respir Crit
Care Med. 1998;158:1543-1549.
23. Fisher GL, McNeill KL, Finch GL, Wilson FD, Golde
DW. Functional evaluation of lung macrophages from cigarette smokers and nonsmokers.
J Reticuloendothel Soc. 1982;32:311-321.
24. Noble RC, Penny BB. Comparison of leukocyte
count and function in smoking and nonsmoking
young men. Infect Immun. 1975;12:550-555.
25. Corberand J, Nguyen F, Do AH, et al. Effect of
tobacco smoking on the functions of polymorphonuclear leukocytes. Infect Immun. 1979;
23:577-581.
26. Eichel B, Shahrik HA. Tobacco smoke toxicity:
loss of human oral leukocyte function and fluidcell metabolism. Science. 1969;166:14241428.
27. Bridges RB, Kraal JH, Huang LJ, Chancellor BM.
Effects of tobacco smoke on chemotaxis and
glucose metabolism of polymorphonuclear
leukocytes. Infect Immun. 1977;15:115-123.
28. Bridges RB, Hsieh L. Effects of cigarette smoke fractions on the chemotaxis of polymorphonuclear
leukocytes. J Leukoc Biol. 1986;40:73-85.
29. Sasagawa S, Suzuki K, Sakatani T, Fujikura T. Effects of nicotine on the functions of human polymorphonuclear leukocytes in vitro. J Leukoc Biol.
1985;37:493-502.
30. Holt PG. Immune and inflammatory function in
cigarette smokers. Thorax. 1987;42:241-249.
31. McCrea KA, Ensor JE, Nall K, Bleecker ER, Hasday JD. Altered cytokine regulation in the lungs
of cigarette smokers. Am J Respir Crit Care Med.
1994;150:696-703.
32. Twigg HL III, Soliman DM, Spain BA. Impaired
alveolar macrophage accessory cell function and
reduced incidence of lymphocytic alveolitis in
HIV-infected patients who smoke. AIDS. 1994;
8:611-618.
33. Ouyang Y, Virasch N, Hao P, et al. Suppression
of human IL-1␤, IL-2, IFN-␥, and TNF-alpha production by cigarette smoke extracts. J Allergy Clin
Immunol. 2000;106:280-287.
34. Hagiwara E, Takahashi KI, Okubo T, et al. Cigarette smoking depletes cells spontaneously secreting Th(1) cytokines in the human airway.
Cytokine. 2001;14:121-126.
35. Madretsma S, Wolters LM, van Dijk JP, et al. Invivo effect of nicotine on cytokine production by
human non-adherent mononuclear cells. Eur J
Gastroenterol Hepatol. 1996;8:1017-1020.
36. Matsunaga K, Klein TW, Friedman H, Yamamoto Y. Involvement of nicotinic acetylcholine
receptors in suppression of antimicrobial
activity and cytokine responses of alveolar
macrophages to Legionella pneumophila
infection by nicotine. J Immunol. 2001;167:
6518-6524.
37. Smith KA. Interleukin-2: inception, impact, and
implications. Science. 1988;240:1169-1176.
38. Luster MI, Simeonova PP, Gallucci R, Matheson J. Tumor necrosis factor ␣ and toxicology.
Crit Rev Toxicol. 1999;29:491-511.
39. Ferson M, Edwards A, Lind A, Milton GW, Hersey P. Low natural killer–cell activity and immunoglobulin levels associated with smoking in human subjects. Int J Cancer. 1979;23:603609.
40. Nair MP, Kronfol ZA, Schwartz SA. Effects of alcohol and nicotine on cytotoxic functions of human lymphocytes. Clin Immunol Immunopathol.
1990;54:395-409.
41. Tollerud DJ, Clark JW, Brown LM, et al. Association of cigarette smoking with decreased numbers of circulating natural killer cells. Am Rev
Respir Dis. 1989;139:194-198.
42. Silverman NA, Potvin C, Alexander JC Jr, Chretien PB. In vitro lymphocyte reactivity and Tcell levels in chronic cigarette smokers. Clin Exp
Immunol. 1975;22:285-292.
43. Herberman RB, Holden HT. Natural cell–
mediated immunity. Adv Cancer Res. 1978;
27:305-377.
44. Herberman RB. Natural Cell–Mediated Immunity Against Tumors. New York, NY: Academic
Press; 1980.
45. Geng Y, Savage SM, Johnson LJ, Seagrave J,
Sopori ML. Effects of nicotine on the immune
response, I: chronic exposure to nicotine impairs antigen receptor–mediated signal transduction in lymphocytes. Toxicol Appl Pharmacol.
1995;135:268-278.
46. Geng Y, Savage SM, Razani-Boroujerdi S, Sopori
ML. Effects of nicotine on the immune response,
II: chronic nicotine treatment induces T cell anergy.
J Immunol. 1996;156:2384-2390.
47. Kalra R, Singh SP, Savage SM, Finch GL, Sopori ML. Effects of cigarette smoke on immune
response: chronic exposure to cigarette smoke
impairs antigen-mediated signaling in T cells and
depletes IP3-sensitive Ca(2+) stores. J Pharmacol Exp Ther. 2000;293:166-171.
48. Dales LG, Friedman GD, Siegelaub AB, Selzer CC.
Cigarette smoking and serum chemistry tests.
J Chronic Dis. 1974;27:293-307.
49. Gulsvik A, Fagerhoi MK. Smoking and immunoglobulin levels [letter]. Lancet. 1979;1:449.
50. Gerrard JW, Heiner DC, Ko CG, Mink J, Meyers
A, Dosman JA. Immunoglobulin levels in smokers and non-smokers. Ann Allergy. 1980;
44:261-262.
51. Andersen P, Pedersen OF, Bach B, Bonde GJ. Serum antibodies and immunoglobulins in smokers and nonsmokers. Clin Exp Immunol. 1982;
47:467-473.
52. Onari K, Seyama A, Inamizu T, et al. Immunological study on cigarette smokers, part I: serum protein pattern in smokers. Hiroshima J Med
Sci. 1978;27:113-118.
53. Warr GA, Martin RR, Sharp PM, Rossen RD. Normal human bronchial immunoglobulins and proteins: effects of cigarette smoking. Am Rev Respir
Dis. 1977;116:25-30.
54. Reynolds HY. Immunoglobulin G and its function in the human respiratory tract. Mayo Clin
Proc. 1988;63:161-174.
55. Finklea JF, Hasselblad V, Riggan WB, Nelson WC,
Hammer DI, Newill VA. Cigarette smoking and
hemagglutination inhibition response to influenza after natural disease and immunization. Am
Rev Respir Dis. 1971;104:368-376.
56. Gruchow HW, Hoffmann RG, Marx JJ Jr, Emanuel
DA, Rimm AA. Precipitating antibodies to farmer’s
lung antigens in a Wisconsin farming population.
Am Rev Respir Dis. 1981;124:411-415.
57. Pastor P, Medley F, Murphy TV. Invasive pneumococcal disease in Dallas County, Texas: results from population-based surveillance in 1995.
Clin Infect Dis. 1998;26:590-595.
58. Nuorti JP, Butler JC, Farley MM, et al; Active Bacterial Core Surveillance Team. Cigarette smoking and invasive pneumococcal disease. N Engl
J Med. 2000;342:681-689.
59. Almirall J, Gonzalez CA, Balanzo X, Bolibar I. Proportion of community-acquired pneumonia cases
attributable to tobacco smoking. Chest. 1999;
116:375-379.
(REPRINTED) ARCH INTERN MED/ VOL 164, NOV 8, 2004
2215
60. Raman AS, Swinburne AJ, Fedullo AJ. Pneumococcal adherence to the buccal epithelial cells of
cigarette smokers. Chest. 1983;83:23-27.
61. Doebbeling BN, Wenzel RP. The epidemiology
of Legionella pneumophila infections. Semin
Respir Infect. 1987;2:206-221.
62. Straus WL, Plouffe JF, File TM Jr, et al; Ohio Legionnaires Disease Group. Risk factors for domestic acquisition of legionnaires disease. Arch
Intern Med. 1996;156:1685-1692.
63. Fischer M, Hedberg K, Cardosi P, et al. Tobacco
smoke as a risk factor for meningococcal disease.
Pediatr Infect Dis J. 1997;16:979-983.
64. Imrey PB, Jackson LA, Ludwinski PH, et al. Outbreak of serogroup C meningococcal disease associated with campus bar patronage. Am J
Epidemiol. 1996;143:624-630.
65. Stuart JM, Cartwright KA, Robinson PM, Noah
ND. Effect of smoking on meningococcal carriage.
Lancet. 1989;2:723-725.
66. Caugant DA, Hoiby EA, Magnus P, et al. Asymptomatic carriage of Neisseria meningitidis in a
randomly sampled population. J Clin Microbiol.
1994;32:323-330.
67. Blackwell CC, Tzanakaki G, Kremastinou J, et al.
Factors affecting carriage of Neisseria meningitidis among Greek military recruits. Epidemiol Infect. 1992;108:441-448.
68. Haneberg B, Tonjum T, Rodahl K, Gedde-Dahl
TW. Factors preceding the onset of meningococcal disease, with special emphasis on passive smoking, symptoms of ill health. NIPH Ann.
1983;6:169-173.
69. Tappero JW, Reporter R, Wenger JD, et al. Meningococcal disease in Los Angeles County, California, and among men in the county jails. N Engl
J Med. 1996;335:833-840.
70. Kitchens GG. Relationship of environmental tobacco smoke to otitis media in young children.
Laryngoscope. 1995;105:1-13.
71. Ilicali OC, Keles N, Deger K, Savas I. Relationship of passive cigarette smoking to otitis media.
Arch Otolaryngol Head Neck Surg. 1999;125:
758-762.
72. Stathis SL, O’Callaghan DM, Williams GM, Najman JM, Andersen MJ, Bor W. Maternal cigarette smoking during pregnancy is an independent predictor for symptoms of middle ear
disease at five years’ postdelivery [serial online].
Pediatrics. 1999;104:e16.
73. Barbour SE, Nakashima K, Zhang JB, et al. Tobacco and smoking: environmental factors that
modify the host response (immune system) and
have an impact on periodontal health. Crit Rev
Oral Biol Med. 1997;8:437-460.
74. Arbes SJ Jr, Agustsdottir H, Slade GD. Environmental tobacco smoke and periodontal disease
in the United States. Am J Public Health. 2001;
91:253-257.
75. Tomar SL, Asma S. Smoking-attributable periodontitis in the United States: findings from
NHANES III: National Health and Nutrition Examination Survey. J Periodontol. 2000;71:
743-751.
76. Muller HP. Smoking and periodontal health [in
German]. Gesundheitswesen. 2000;62:400408.
77. Genco RJ. Current view of risk factors for periodontal diseases. J Periodontol. 1996;67:
1041-1049.
78. van der Weijden GA, de Slegte C, Timmerman
MF, van der Velden U. Periodontitis in smokers
andnon-smokers:intra-oraldistributionofpockets.
J Clin Periodontol. 2001;28:955-960.
79. Haffajee AD, Socransky SS. Relationship of ciga-
WWW.ARCHINTERNMED.COM
©2004 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 03/10/2022
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
rette smoking to the subgingival microbiota.
J Clin Periodontol. 2001;28:377-388.
Shiloah J, Patters MR, Waring MB. The prevalence of pathogenic periodontal microflora in
healthy young adult smokers. J Periodontol.
2000;71:562-567.
Anda RF, Williamson DF, Escobedo LG, Remington PL. Smoking and the risk of peptic ulcer
disease among women in the United States. Arch
Intern Med. 1990;150:1437-1441.
Kato I, Nomura AM, Stemmermann GN, Chyou
PH. A prospective study of gastric and duodenal ulcer and its relation to smoking, alcohol, and
diet. Am J Epidemiol. 1992;135:521-530.
Sontag S, Graham DY, Belsito A, et al. Cimetidine, cigarette smoking, and recurrence of duodenal ulcer. N Engl J Med. 1984;311:689-693.
Korman MG, Hansky J, Eaves ER, Schmidt GT. Influence of cigarette smoking on healing and relapse
in duodenal ulcer disease. Gastroenterology. 1983;
85:871-874.
Endoh K, Leung FW. Effects of smoking and nicotine on the gastric mucosa: a review of clinical
and experimental evidence. Gastroenterology.
1994;107:864-878.
Moshkowitz M, Brill S, Konikoff FM, Averbuch
M, Arber N, Halpern Z. Additive deleterious effect
of smoking on gastroduodenal pathology and
clinical course in Helicobacter pylori–positive dyspeptic patients. Isr Med Assoc J. 2000;2:
892-895.
Bateson MC. Cigarette smoking and Helicobacter pylori infection. Postgrad Med J. 1993;
69:41-44.
Martin DF, Montgomery E, Dobek AS, Patrissi
GA, Peura DA. Campylobacter pylori, NSAIDS,
and smoking: risk factors for peptic ulcer disease.
Am J Gastroenterol. 1989;84:1268-1272.
Nakamura M, Haruma K, Kamada T, et al. Cigarette smoking promotes atrophic gastritis in Helicobacter pylori–positive subjects. Dig Dis Sci.
2002;47:675-681.
Cover TL, Vaughn SG, Cao P, Blaser MJ. Potentiation of Helicobacter pylori vacuolating toxin
activity by nicotine and other weak bases. J Infect Dis. 1992;166:1073-1078.
O’Connor HJ, Kanduru C, Bhutta AS, Meehan JM,
Feeley KM, Cunnane K. Effect of Helicobacter pylori eradication on peptic ulcer healing. Postgrad Med J. 1995;71:90-93.
Borody TJ, George LL, Brandl S, Andrews P, Jankiewicz E, Ostapowicz N. Smoking does not contribute to duodenal ulcer relapse after Helicobacter pylori eradication. Am J Gastroenterol.
1992;87:1390-1393.
Blake GH, Abell TD, Stanley WG. Cigarette smoking and upper respiratory infection among recruits in basic combat training. Ann Intern Med.
1988;109:198-202.
Cohen S, Tyrrell DA, Russell MA, Jarvis MJ, Smith
AP. Smoking, alcohol consumption, and susceptibility to the common cold. Am J Public
Health. 1993;83:1277-1283.
Vitalis TZ, Keicho N, Itabashi S, Hayashi S, Hogg
JC. A model of latent adenovirus 5 infection in
the guinea pig (Cavia porcellus). Am J Respir Cell
Mol Biol. 1996;14:225-231.
Hogg JC. Latent adenoviral infection in the pathogenesis of emphysema: the Parker B. Francis
Lectureship. Chest. 2000;117(5, suppl 1): 282S285S.
Finklea JF, Sandifer SH, Smith DD. Cigarette
smoking and epidemic influenza. Am J Epidemiol.
1969;90:390-399.
98. Kark JD, Lebiush M. Smoking and epidemic influenza-like illness in female military recruits: a
brief survey. Am J Public Health. 1981;71:
530-532.
99. Kark JD, Lebiush M, Rannon L. Cigarette smoking as a risk factor for epidemic A(H1N1) influenza in young men. N Engl J Med. 1982;307:
1042-1046.
100. Hament JM, Kimpen JL, Fleer A, Wolfs TF. Respiratory viral infection predisposing for bacterial disease: a concise review. FEMS Immunol
Med Microbiol. 1999;26:189-195.
101. Miyaura S, Eguchi H, Johnston JM. Effect of a
cigarette smoke extract on the metabolism of the
proinflammatory autacoid, platelet-activating
factor. Circ Res. 1992;70:341-347.
102. Ichimaru T, Tai HH. Alteration of platelet activating factor (PAF) metabolism in rat pulmonary alveolar macrophages and plasma by cigarette smoking. Prostaglandins Leukot Essent Fatty
Acids. 1992;47:123-128.
103. Cruijff M, Thijs C, Govaert T, Aretz K, Dinant GJ,
Knottnerus A. The effect of smoking on influenza, influenza vaccination efficacy and on the
antibody response to influenza vaccination.
Vaccine. 1999;17:426-432.
104. Ellis ME, Neal KR, Webb AK. Is smoking a risk
factor for pneumonia in adults with chickenpox?
BMJ (Clin Res Ed). 1987;294:1002.
105. Grayson ML, Newton-John H. Smoking and varicella pneumonia [letter]. J Infect. 1988;16:
312.
106. Sedlacek TV. Advances in the diagnosis and treatment of human papillomavirus infections. Clin
Obstet Gynecol. 1999;42:206-220.
107. Schneider A, Kirchhoff T, Meinhardt G, Gissmann L. Repeated evaluation of human papillomavirus 16 status in cervical swabs of young
women with a history of normal Papanicolaou
smears. Obstet Gynecol. 1992;79:683-688.
108. Moscicki AB, Shiboski S, Broering J, et al. The
natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women. J Pediatr. 1998;
132:277-284.
109. Kataja V, Syrjanen S, Yliskoski M, et al. Risk factors associated with cervical human papillomavirus infections: a case-control study. Am J
Epidemiol. 1993;138:735-745.
110. Hellberg D, Nilsson S, Haley NJ, Hoffman D, Wynder E. Smoking and cervical intraepithelial neoplasia: nicotine and cotinine in serum and cervical mucus in smokers and nonsmokers. Am J
Obstet Gynecol. 1988;158:910-913.
111. Arany I, Tyring SK. Status of local cellular immunity in interferon-responsive and -nonresponsive human papillomavirus-associated lesions.
Sex Transm Dis. 1996;23:475-480.
112. Winkelstein W Jr. Smoking and cervical cancer—
current status: a review. Am J Epidemiol. 1990;
131:945-960.
113. Newell GR, Mansell PW, Wilson MB, Lynch HK,
Spitz MR, Hersh EM. Risk factor analysis among
men referred for possible acquired immune deficiency syndrome. Prev Med. 1985;14:8191.
114. Royce RA, Winkelstein W Jr. HIV infection, cigarette smoking and CD4+ T-lymphocyte counts:
preliminary results from the San Francisco Men’s
Health Study. AIDS. 1990;4:327-333.
115. Boulos R, Halsey NA, Holt E, et al; Cite Soleil/
JHU AIDS Project Team. HIV-1 in Haitian women
1982-1988. J Acquir Immune Defic Syndr. 1990;
3:721-728.
(REPRINTED) ARCH INTERN MED/ VOL 164, NOV 8, 2004
2216
116. Burns DN, Kramer A, Yellin F, et al. Cigarette
smoking: a modifier of human immunodeficiency virus type 1 infection? J Acquir Immune
Defic Syndr. 1991;4:76-83.
117. Craib KJ, Schechter MT, Montaner JS, et al. The
effect of cigarette smoking on lymphocyte subsets and progression to AIDS in a cohort of homosexual men. Clin Invest Med. 1992;15:
301-308.
118. Sasson IM, Haley NJ, Hoffmann D, Wynder EL,
Hellberg D, Nilsson S. Cigarette smoking and neoplasia of the uterine cervix: smoke constituents
in cervical mucus. N Engl J Med. 1985;312:
315-316.
119. Winkelstein W Jr. Smoking and cervical cancer: current status. Am J Epidemiol. 1990;
131:945-957.
120. Hirschtick RE, Glassroth J, Jordan MC, et al; Pulmonary Complications of HIV Infection Study
Group. Bacterial pneumonia in persons infected with the human immunodeficiency virus.
N Engl J Med. 1995;333:845-851.
121. Park LP, Margolick JB, Giorgi JV, et al. Influence of HIV-1 infection and cigarette smoking
on leukocyte profiles in homosexual men: the
Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr. 1992;5:1124-1130.
122. Conley LJ, Bush TJ, Buchbinder SP, Penley KA,
Judson FN, Holmberg SD. The association between cigarette smoking and selected HIVrelated medical conditions. AIDS. 1996;10:
1121-1126.
123. Yu GP, Hsieh CC, Peng J. Risk factors associated with the prevalence of pulmonary tuberculosis among sanitary workers in Shanghai.
Tubercle. 1988;69:105-112.
124. Buskin SE, Gale JL, Weiss NS, Nolan CM. Tuberculosis risk factors in adults in King County,
Washington, 1988 through 1990. Am J Public
Health. 1994;84:1750-1756.
125. Alcaide J, Altet MN, Plans P, et al. Cigarette smoking as a risk factor for tuberculosis in young
adults: a case-control study. Tuber Lung Dis.
1996;77:112-116.
126. McCurdy SA, Arretz DS, Bates RO. Tuberculin
reactivity among California Hispanic migrant farm
workers. Am J Ind Med. 1997;32:600-605.
127. Anderson RH, Sy FS, Thompson S, Addy C. Cigarette smoking and tuberculin skin test conversion among incarcerated adults. Am J Prev Med.
1997;13:175-181.
128. Gajalakshmi V, Peto R, Kanaka TS, Jha P. Smoking and mortality from tuberculosis and other diseases in India: retrospective study of 43 000 adult
male deaths and 35 000 controls. Lancet. 2003;
362:507-515.
129. Altet MN, Alcaide J, Plans P, et al. Passive
smoking and risk of pulmonary tuberculosis in
children immediately following infection: a
case-control study. Tuber Lung Dis. 1996;
77:537-544.
130. Rich EA, Ellner JJ. Pathogenesis of tuberculosis.
In: Friedman LN, ed. Tuberculosis: Current Concepts and Treatment. Boca Raton, Fla: CRC Press;
1994:27-31.
131. Onwubbalili JK, Edwards AJ, Palmer L. T4 lymphopenia in human tuberculosis. Tubercle. 1987;
68:195-200.
132. Kluger R. Ashes to Ashes: America’s HundredYear Cigarette War, the Public Health, and the
Unabashed Triumph of Philip Morris. New York,
NY: Alfred A Knopf; 1996:19.
WWW.ARCHINTERNMED.COM
©2004 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 03/10/2022