nonsmokers, with a trend of increased risk with increased number of
cigarettes smoked.

In Israel, the lifetime prevalence of PUD is 89/1000 men (37), similar
to that in the United States. Smokers or ex-smokers had a prevalence
of PUD (primarily duodenal) of 10.2 percent compared to 6.2 percent of
nonsmokers (25). These differences were highly significant. Medalie, et
al. made the interesting observation that as the smoking habits of
first-generation Israelis of European descent increased, so did the
prevalence of duodenal ulcer in this group (97').

Thus, when the question, "Do cigarette smokers have more peptic
ulcers than nonsmokers?' is asked, results are strikingly consistent.
Table 1 lists the six studies which investigated this problem (22, 23, 25,
28,31, /I) with a summary of their characteristics and results. In each
of the studies there was an increased prevalence of PUD in cigarette
smokers compared to nonsmokers. Despite the fact that these studies
were done at different times and in four different countries, the ratios
for men are very similar, the median being 1.7 and the mean 1.9. The
ratios for women are similar with the exception of the Polish study, in
which very few women smoked. The ratios for ex-smokers (not shown)
are also consistently greater than 1.0. In addition, the majority of the
studies provided evidence of increased frequency of peptic ulcer with
increases in the amount smoked.

Course of Peptic Ulcer Disease

Since cigarette smoking appears to be related to the prevalence of
PUD, several other issues must be addressed. First, if a smoker does
develop PUD, will cigarette smoking influence its healing and should
the patient therefore be advised to stop smoking? Second, what, if any,
role will smoking play in the chances of the patient dying from PUD?

Effect on Healing and Remrrence

In a classic study, Doll, et al. (18) examined the effect of continued
smoking on the healing rate of gastric ulcers. Of the 86 smokers in the
study, half Were advised-to stop smoking, the other half were allowed
to continue smoking. Treatment for the ulcer disease was otherwise
equivalent (although not the same for all patients). The investigators
then compared the two groups in regard to percent showing marked
healing of the ulcer at 4 weeks (marked healing is defined as 2/3 or
greater reduction in ulcer size). Of those who were advised t.o
discontinue smoking, 75 percent showed marked healing, compared to
only 58 percent of those who continued to smoke. In fact, 45 percent of
the patients advised to stop smoking did not do so completely:Of those
who did, 86 percent (19122) healed as opposed to 61 percent of those
who only decreased their smoking. The healing rate of the 24
nonsmokers was 53 percent, similar to that of smokers. Study design

9-8


and technical aspects were offered as explanation for this latter
observation.
Herrmann and Piper (27) retrospectively looked at 101 patients with
benign gastric ulcer, all radiologically diagnosed. At 3 weeks, 6'7
percent of nonsmokers had healed compared to 43 percent of smokers
who continued smoking. Differences were less marked at 6 weeks (85
percent vs. `75 percent). Although the numbers were smaller, those
smokers who stopped did not do as well as either of the other two
groups. The mean ulcer size in smokers was larger than in nonsmokers
(120 mm* vs. 40 mm*). Those who smoked cigarettes and ingested
salicylates had the largest ulcers, but mean ulcer size was significantly
larger in smokers than in nonsmokers, even when those ingesting
salicylates were excluded.
piper, et al. (a), while investigating gastric ulcer, noted increased
rates of recurrence. for those discharged unhealed, for those with
larger ulcers, and for smokers. In a 4year follow-up study of these
patients, Piper, et al. (4~) recently confirmed their previous report.
They found that, of the 33 patients who were discharged with unhealed
ulcers, 4'7 percent (8/1'7) of nonsmokers had recurrence, whereas 75
percent (12116) of smokers had recurrence.
Only one study has been made on the effect of smoking on the
healing of duodenal ulcers. Peterson, et al. (4.~) recently showed for the
first time the efficacy of antacids over placebo in the healing of
duodenal ulcer (Table 2). In this study, 78 percent of the antacid-
treated group healed at 4 weeks as compared to 45 percent of the
placebo group. When these groups were broken down into smokers and
nonsmokers, 69 percent of the ulcers of nonsmokers who took placebo
healed versus 32 percent of ulcers of smokers who took placebo (p <
.05). In the antacid group, 87 percent of nonsmokers healed versus 75
percent of smokers (p > .05). Nonsmokers showed good healing even
on placebo; antacids appeared to make the most difference in treating
the duodenal ulcers of smokers.
Although there have been many recent clinical trials concerning the
treatment of both gastric and duodenal ulcers using the new histamine
& receptor antagonist, cimetidine, none of these has carefully
addressed the question of the influence of smoking on healing rates
(67'). Certainly, with all the international trials being undertaken to
evaluate the plethora of new ulcer treatments, such as cimetidine,
Prostaglandins, bismuth, etc., the smoking habits of the patients should
be examined. Such studies would provide information on the effect of
smoking on the healing of untreated ulcers and on whether any of the
treatments can overcome the presumed adverse effect of smoking on
healing.
In summary, cigarette smoking in males probably retards the
healing rates of both gastric and duodenal ulcers.


TABLE 2.-Percentage of patients whose duodenal ulcers were
     healed by endoscopic examination at 4 weeks,
     classified according to treatment with placebo or
     antacid and according to whether patients were
     smokers or nonsmokers of cigarettes. Numbers in
     parentheses are the number healed over the total
      number observed in each category.

                   Ptrctnthalaf~t4waks

PI&l&O
Antacid
Total

Smokers         Nonsmoker

32% (W25)       69% (9113)
75% (21/28)       88% (5%)
55% (29/53)       76% (16/21)

Total

45% (17B3)
78% ww

SOURCE: Peterson, w. L. (43).

TABLE b-Ulcer mortality of male cigarette smokers and
       nonsmokers

Reference

No. of
deaths

Rates: age-    ulcer    Mortality      Dose
sdjusted     type      ratio      respom

Hammond, E.C. (1953)
cw
Dam, H.F. (1959) (20)
Weir, J.N. (1970) (64)

Doll, R (1976) (19)

DU
GU
PU
DU
GU
PU

2.8
>I.@b
28
.B
>l.pd
2.5

*Smokera include regular cigarette smokers. many of whom alao smoked cigar8 and pipes.
%tio it. 46/o.

%nokera include ex-smekers; nonsmokers include pipe and/or cigar.
dJkti0 for smokers of 1 pa&f&y to tboae smoking leas.
DIJ - deadenal ulcer; GU - gastric ulcer; PU - peptic ulcer.

Effect on Mortality

Mortality, as well as morbidity, in PUD is related to cigarette smoking.
The four studies discussed below are summarized in Table 3. In one of
the earliest and largest studies on smoking and death rates, Hammond
and Horn (26) pointed out smoking's harmful influence on PUD.
Deaths from duodenal ulcer for smokers of more than a half pack per
day of cigarettes were 2.5 times the rate for nonsmokers; for those
smoking one-half pack per day or less, the rate was 1.5 times the rate
for nonsmokers. There were no gastric ulcer deaths among nonsmok-
ers, but there were 46 among smokers; the death rate also increased
with smoking more than a half pack per day of cigarettes. Thus,
smoking was clearly associated with a higher occurrence of death in
both types of ulcer disease.

Dom (20), in another large study, had similar results. The ratio of
observed deaths from both duodenal ulcer and gastric ulcer in smokers


to expected deaths from these diseases was 2.8. Those who smoked
more than two packs per day had more deaths than those who smoked
one to two packs per day, who in turn fared worse than those who
smoked less than one pack per day.
In a prospective study of smoking and mortality in 68,153 middle
aged men, Weir and Dunn (64), just as Hammond and Horn (26), found
no deaths from gastric ulcer in nonsmokers but a significant number of
smokers dying from gastric ulcer disease. Their results, however, for
duodenal ulcer were completely opposite, in that the relative risk of
death from duodenal ulcer in smokers was half that in nonsmokers.
Why this discrepancy should exist is not clear.
Doll and Peto (19), in a study of more than. 10,000 British physicians,
found a significant increase in death from peptic ulcer disease (specific
location of ulcer not stated) in smokers as compared to nonsmokers,
with a higher rate in moderate or heavy smokers than in light smokers.
Finally, Din and Small (15) proposed that the long-term survival of
patients after gastrectomy was decreased by smoking. They felt the
increased mortality rate was due to cigarette smoking (and perhaps
alcohol, too) and not to the operation. The evidence for this is unclear.
A summary of the important data from the four studies (19, 20, 26,
64) which bear on the epidemiological question, "Does smoking
influence a person's chance of dying from his ulcer disease?" can be
found in Table 3. These data show that mortality from gastric ulcer is
greater in male cigarette smokers than in nonsmokers and, except in
one study (64). also is greater in male cigarette smokers with duodenal
ulcer disease. In the study that was the exception, the results are
clouded by inclusion of ex-smokers in the smoking group. So, in
general, it can be concluded that male cigarette smokers have more
than a twofold greater chance of dying from ulcer disease than
nonsmokers. It is not clear how much of this excess risk is due to the
increased prevalence of ulcer disease in smokers and how much is due
to the reduced ability of the smoker to survive an ulcer due to a greater
prevalence of chronic heart and lung disease.

The Ouestion of the Etiologlcal Role of Smoking in Peptic
Ulcer Disease

The studies reviewed have consistently shown an increased frequency
of PUD in smokers as opposed to nonsmokers. In addition, the
frequency of PUD rises with increases in the amount smoked, and
smoking appears to retard peptic ulcer healing. All this, of course, does
not provide a definitive answer to the question: "Is cigarette smoking
a cause of peptic ulcer disease, or is it just associated with a cause such
as genetic predisposition, personality type, and so on?" Epidemiologi-
CA, Casecontrol, and genetic studies cannot exclude the possibility that
cigarette smoking is only associated with the cause(s) of PUD. An

9-11


essential link in establishing whether cigarette smoking is a causative
factor in PUD is a convincing demonstration that smoking has an
effect on physiological mechanisms that might allow an ulcer to
develop. This question is difficult to deal with since it is still not known
why certain patients develop PUD under any condition. We do know
that (with rare exceptions) acid must be present (30). Although there is
marked overlap with normals, on the average, patients with duodenal
ulcer hypersecrete acid (68), so the effect of smoking on gastric acid
secretion is of interest. Pancreatic buffering of acid may serve to
protect the duodenum; does smoking interfere with this defense
mechanism? Finally, since the pathogenesis of gastric ulcer may be
different from duodenal ulcer (&), what other factors may smoking
influence that might alter the stomach's defenses?

Gastric Secretion

Studies of the effects of smoking or nicotine on gastric acid secretion
have been performed in rats, cats, dogs, and man-many with
contradictory results even in the same species. One of the earliest
studies (53) in dogs showed that neither cigarette smoking nor
subcutaneous injections of 0.2,0.4, or 1 mg of nicotine increased gastric
acid secretion in the fasting state. Konturek, et al. (36) studied the
effect of intravenous nicotine (100 E/kg) in dogs and found no change
in either basal acid output or half-maximal gastric acid secretion
stimulated by histamine or pentagastrin. In addition, they found no
effect on mucosal blood flow, and no interruption of the mucosal
barrier to back diffusion of hydrogen ions by either intravenous or
topical nicotine.

Nicotine, 100 pg/kg, injected into rats, depressed histamine-stimu-
lated secretion of acid and pepsin. It also depressed basal secretion and
submaximal pentagastrin-stimulated secretion. Tobacco smoke in 10
percent et!.anol had no effect on acid secretion but reduced pepsin
output (56). The effects of chronic nicotine administration in rats was
also studied by the same investigators (58). Rats receiving 100 pg/kg
nicotine 3 times daily for 15 days (the equivalent of smoking 10 to 15
cigarettes per day) doubled their gastric acid output and increased
their pepsin output (p < 0.01). This effect could be blocked by either
vagotomy or anterior hypothalamic lesions (57). Acute administration
of nicotine to the chronically treated rats inhibited gastric acid and
pepsin output. Robert and his colleagues have shown that nicotine can
increase the number and severity of duodenal ulcers formed in rats by
hydrochloric acid perfusion (51) or by subcutanmus infusion of
pentagastrin and carbachol (50). Nicotine alone did not produce any
ulcers in the animals.

Radecki, et al. (47) studied the response of cats to nicotine in both the
basal and pentagastrin-stimulated states. Doses of nicotine up to Xl0
pg/kg did not alter acid secretion in either state. A dose of 400 I.cg/kg

9-12


depressed stimulated acid secretion by 36 percent; it also produced
restlessness, vomiting, and diarrhea. Nicotine (200 &kg) did,
however, potentiate the development of pentagastrin-induced experi-
mental duodenal ulcers in these cats (35).

Studies of the effects of smoking on acid secretion in human subjects
have given contradictory results. Schnedorf and Ivy (53) studied the
effect of acute smoking on acid secretion in 46 normals (smokers and
nonsmokers) and in 26 patients with duodenal ulcer. Mean acid output
fell during smoking in both the normals and the ulcer patients, but no
statistical analysis was done, so the significance of the decrease cannot
be evaluated. Steigmann, et al. (55) reported that 26 of 4-4 controls and
46 of 45 ulcer patients increased acid production while smoking an
unfiltered cigarette; a control study without smoking was not done.
Cooper and Knight (12) recorded no difference in basal acid secretion
between 60 patients with duodenal ulcer who smoked during the test
and 66 patients who did not. Fung and Tye (24) investigated the effects
of smoking 3 cigarettes per hour on 16 smokers and 16 nonsmokers, 23
of whom had duodenal ulcer and 7, gastric ulcer. There was no
significant difference between basal acid output and acid output
during smoking in either group. Another study showed that smoking
four cigarettes an hour did not alter acid, pepsin, or mucus production
in either normal subjects or ulcer patients who were smokers (65). This
is particularly interesting in that the same laboratory reported
different findings 15 years earlier when they found that smoking
increased gastric secretion in man (4.5). Murthy, et al. (40) studied
secretory response to smoking one cigarette per 15 minutes for 1 hour
in smokers with duodenal ulcer and in normal smokers and nonsmok-
ers. In the first 15 minutes, there was a significant increase in acid
secretion in the ulcer patients. No significant effect was seen in either
group of normals. Debas, et al. (14) studied I2 subjects, 6 smokers and 6
nonsmokers, of both sexes. The subjects smoked three cigarettes per
hour while gastric secretion was maintained at half maximal rate with
pentagastrin. Smoking caused no significant change in mean rate of
acid secretion or pepsin secretion in either group. In a separate study
(IO), the same investigators found that while cigarettes alone had no
effect on acid output, nausea induced by smoking in nonsmokers did
inhibit acid production. Debas and Cohen (13) noted that smoking
produced substantial inhibition of acid secretion in the majority of
subjects during the first test but this could not be reproduced on
repeated testing. They suspected that the inhibition was due to nausea,
not smoking, per se. They also reported (13) that intravenous infusion
of 2 mg of nicotine produced essentially no change in pentagastrin-
stimulated acid and pepsin secretion in eight subjects.
Wilkinson and Johnston (66) also studied the effects of smoking on
Pentagastrin-stimulated acid secretion and found depression of acid
output in response to smoking one or two cigarettes in three groups (33

9-13


percent in normals, 21 percent in duodenal ulcer patients, and 18
percent in gastric ulcer patients). All subjects experienced tachycardia
and elevation of blood pressure while smoking.

In summary, most of the studies in human subjects have shown that
smoking one or a few cigarettes exerts an inconsistent effect on acid
secretion. A few studies found inhibition of acid secretion by smoking,
but these involved first attempts at smoking with a gastric tube in
place. Such procedures often produce nausea which by itself can inhibit
acid secretion. There has been no systematic study of the effect of
chronic smoking on acid secretion.

Pancreatic Secretion

It is generally accepted that an acid milieu is required for the
development of duodenal ulcers; thus, smoking might influence
duodenal ulcer formation by an effect on duodenal acidity. Smoking
has not been clearly shown to increase gastric secretion, so perhaps it
affects pancreatic buffering mechanisms. Mm-thy, et al. (39) showed
that smoking may alter the duodenal environment. They found that
smoking lowered duodenal pH from a range of 6.2-7.4 to 1.7-2.5 in five
hypersecretors (BAO 5 to 16.5 mElq hr), but produced only a small
effect in normal secretors.

Schnedorf and Ivy (53) found no significant change in either
pancreatic or biliary secretion in dogs during smoking. Konturek and
his colleagues (36) gave graded doses of nicotine (12.5 to 100 M kg1 h-1
intravenously) to dogs on a background of maximal secretin stimula-
tion and noted graded inhibition of bicarbonate secretion (23 to 62
percent). All values returned to control levels after cessation of the
nicotine. Similarly, nicotine (100 pg kgih-1) reduced hepatic bile volume
and bicarbonate by 50 percent. In a subsequent study (34), they
reconfirmed that intravenous nicotine reduced the pancreatic response
to intravenous secretin. Topical nicotine, however, did not alter the
response to secretin. In addition, as the dose of secretin was increased
from .37 to 3 U kg1 h-1, the inhibition of bicarbonate secretion by
intravenous nicotine decreased from 75 to 15 percent. To examine the
effect of nicotine on pancreatic secretion induced by endogenous
secretin, pancreatic secretion was stimulated by intraduodenal admin-
istration of HCl with a response equivalent to .75 U kg1 h-1 of
intravenous secretin. Both intravenous nicotine and topical nicotine
reduced the response to the acid by about 25 percent. However,
nicotine had no significant effect on cholecystokinin-induced stimula-
tion of pancreatic secretion.

Boden and his associates (7) found in their dog experiments that
basal and HCI (9.6 mEq/30 min) stimulated bicarbonate outputs were
insignificantly decreased by intravenous infusion of nicotine (100 c(g
kg1 h-l), and nicotine did not decrease bicarbonate output in response to
intravenous secretin (1.0 U kg1 h-1). In addition, nicotine had no

9-14


significant effect on the serum secretin level (measured by radioimmu-
noassay) except to delay the appearance of the peak value. It should be
noted that Boden used 2.4 times as much acid to stimulate pancreatic
secretion as did Konturek, et al. (34).

Solomon, et al. (54) studied the effect of nicotine on the rabbit
pancreas. Nicotine infused at rates of 100 to 400 pg kg1 h-1 decreased
pancreatic secretion in a dose-dependent fashion. Since nicotine is a
stimulant of autonomic ganglia (62), the effect of norepinephrine and
epinephrine was studied. Norepinephrine at 2 or 4 M kg1 min-1 and
epinephrine at 2 c(g kg-1 inhibited secretory flow and bicarbonate
output. Phenoxybenzamine, an a-adrenergic blocker, increased water
and bicarbonate secretion and blocked the inhibitory action of nicotine
and norepinephrine on pancreatic secretion. On the basis of these
results, they concluded that nicotine indirectly inhibits pancreatic
secretion by stimulating catecholamine release, an effect that is
negated by alpha adrenergic blockade.
The evidence for smoking's effect in man parallels that in animals.
Bynum and his colleagues (9) studied the acute effecta in light and
heavy chronic smokers of smoking four cigarettes an hour on
bicarbonate output in response to secretin. The light smokers
responded normally to secretin during the control period but had
decreased pancreatic bicarbonate output while smoking. Heavy
smokers had a decreased response to secretin during the control period
and this was not further affected by smoking. In a study of subjects
who smoked regularly (5), smoking three cigarettes significantly
decreased baaal bicarbonate output.

Brown (8) investigated the effect of smoking on pancreatic secretion
in 14 healthy smokers, 7 heavy and 7 light smokers. Heavy smokers had
lower responses to secretin (2 U/kg) than light smokers. In addition,
smoking cigarettes reduced even further the volume and bicarbonate
content of the duodenal juice in both groups.

Murthy, et al. (40) studied the effects of smoking in smokers with
and without duodenal ulcer and in nonsmokers. They found that
smoking depressed basal bicarbonate and volume in both normals and
patients with duodenal ulcer and in both smokers and nonsmokers.
Changes in plasma nicotine were inversely correlated with pancreatic
secretion. In addition, smoking had no effect on gastrin or secretin
levels as measured by radioimmunoassay.

Bloom and Ward (4) reported depressed secretin release in response
to intraduodenal acid instillation in patients with duodenal ulcer in
contrast to controls. Actually, the increase in secretin over basal values
was approximately the same in the ulcer patients as in the normal
controls. Those patients who smoked more had smaller peak secretin
values than lighter smokers. There was no difference in secretin
release between smoking and nonsmoking controls. A subsequent
study by Isenberg, et al. (29), using the same radioimmunoassay for

9-15


secretin, did not demonstrate a difference in secretin release between
duodenal ulcer patients and normals. In light of this, the purported
effect of smoking on secretin release must be questioned.

Four studies in man (5, 8, 9, $0) all show decreases in bicarbonate
output in response to smoking. There is no evidence that this is due to
inhibition of secretin release.

Pyloric Reflux and Gastric Ulcer

What is smoking's relationship to the pathogenesis of gastric ulcer?
The possible causes of gastric ulcer have been reviewed (49), and
several hypotheses have been proposed. Various pharmacologic agents
have been shown to disrupt the mucosal barrier to back diffusion of
hydrogen ions, which might contribute to the development of gastric
ulcer. However, no such effect has been demonstrated with smoking
(36). Another hypothesis is that excessive reflux of duodenal contents,
i.e. bile and pancreatic juice, through an incompetent pyloric sphincter,
may be implicated in the pathogenesis of gastric ulcer (52). Recently,
manometric studies of the human pylorus showed that smoking one
cigarette decreased basal pressure significantly from 10.2 to 7.9 mm
Hg (61). This supported previous work by Read and Grech (48) who
found that smoking increased radiologic evidence of duodenogastric
reflux. Whitecross, et al. (65), while studying the effect of smoking on
gastric secretion, also noticed more marked bile staining of their
gastric aspirates during the hour of smoking as compared to the
control hour. Dippy and his colleagues found that smoking increased
the degree of bile reflux in gastric ulcer patients (16).

Other possible etiological relationships have been examined. Ed-
wards and Coghill (21) found that chronic atrophic gastritis was twice
as common in persons who smoked more than 20 cigarettes a day as in
nonsmokers. Since the majority of patients with gastric ulcer have
chronic atrophic gastritis (I), smoking may predispose to gastric ulcer
by producing chronic atrophic gastritis, which in turn may be a
precursor of gastric ulcer.

Summary

If smoking does indeed influence the development and course of peptic
ulcer disease, how does it do so? Experiments investigating the effect
of smoking and nicotine on gastrointestinal function in animals and
man have not established conclusively any mechanisms by which
smoking might contribute to peptic ulcer formation. Most studies show
little or no effect of smoking on acid secretion. Smoking and nicotine
inhibit pancreatic secretion of bicarbonate; the consequent lowered
capacity to neutralize gastric acid is a plausible but unproven
mechanism by which smoking could favor occurrence of duodenal
ulcer. Smoking also appears to increase reflux of duodenal contents
into the stomach, which could be relevant in the light of the hypothesis

9-16


that injury to the gastric mucosa by bile acids and other constituents of
duodenal contents is a factor in the pathogenesis of gastric ulcer.

Medical-Economic Implications

Peptic ulcer disease is one of the major health problems in the United
States today. During their lifetime, about 10 percent of the persons in
the United States can expect to suffer with this problem. Each year
400,000 patients are hospitalized and 150,006 undergo surgery for
PUD. In addition, physicians see 2.5 million patients with peptic ulcers
every year. Considering these facts, it comes as no surprise that, in
1975, the four million persons with ulcers cost the country an estimated
$2.6 billion and are calculated to have cost it $3.7 billion in 1977 (63).
These amounts include both medical care costs as well as indirect costs
of earnings lost because of illness and disability and lifetime earnings
lost because of early death.

Conclusions

The previous sections of this chapter have reviewed the various pieces
of epidemiological and experimental evidence linking cigarette smok-
ing with peptic ulcer disease. Three epidemiological questions have
been addressed: (1) Does smoking increase the risk of getting an ulcer?
(2) Does smoking retard healing of an ulcer? (3) Does smoking increase
the risk of dying from ulcer?

Five studies show a higher proportion of smokers among PUD
patients than among controls. Six studies show a greater prevalence of
PUD among male cigarette smokers than among nonsmokers, the
median ratio being 1.7. Ftesults in women and the positive relationship
between prevalence and amount smoked provide additional support.
There is suggestive evidence for males that smoking retards ulcer
healing. Four studies indicate that mortality due to ulcer is more than
twice as high among male smokers as among nonsmokers.

What physiological effects produced by smoking might be relevant
to the pathogenesis of ulcer? In regard to duodenal ulcer, evidence
suggests that smoking inhibits pancreatic secretion of bicarbonate. As
for gastric ulcer, smoking allows increased reflux of duodenal contents
into the stomach. These effects, however, have not been shown to be
directly related to the development of an ulcer.

9-17


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(88) MURTHY, S. N. S., DINOSO, V. P., CLEARFIELD, H. R Serial pH changes in
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   October 1977.

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  college students. XIII. Early precursors of peptic ulcer. American Journal of
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10. ALLERGY AND IMMUNITY.

National Institute of Allergy and Infectious Diseases


CONTENTS

Introduction .............................................................. 5

Basic Mechanisms.. ..................................................... 8

Tobacco as  an Antigen ............................................... 9

Identification of the Tobacco Antigen(s) . . . . . . . . . . . . . . . . , . . . . . . 11

Epidemiology.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Effects of Cigarette Smoking on the Immune System . . . .14

Target Organs of the Allergic Response . . . . . . . . . . . . . . . . . . . . . . . 20

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Conclusion and Comment ........................................... .24

References .............................................................. .25

103


Introduction

Tobacco and its products, including smoke, can affect the immune
system in two ways. As antigens, they can interact with the immune
system to induce specific responses evidenced by production of specific
antibody or sensitized cells. Or, as irritant, pharmacologic, and toxic
agents, they can interact with cellular elements of the host defense
system, thereby influencing the functional ability of these elements.

Physicians have long noted the association between the development
or aggravation of allergic or allergic-like symptoms and direct
exposure to tobacco and tobacco products, including smoke, thus giving
grounds for suspicion that tobacco can be causally related to the
symptoms. There is evidence that tobacco smoke condensate can induce
an immune response in animal models and in humans. The existence of
a tobacco smoke allergy in humans is unproven, however, and is
complicated by the difficulty of demonstrating a cause and effect
relationship between the immunologic event and its manifestations.

The problem can best be understood by appreciating the current
concept of that which characterizes an allergic individual-the ability
to produce a unique serum antibody upon exposure to a given antigen.
A property of that antibody is its selective fixation to cells located in
certain tissues, such as skin and respiratory membranes.

Upon subsequent exposure, the antigen becomes bound at the cell
surface by the preformed antibody. This phenomenon has been the
basis of the skin test-an important aid in the diagnosis of allergy. In
this procedure, introduction of the antigen into the skin, rendered
sensitive by these previous events, induces pathophysiologic changes
similar to those that occur in nasal and bronchial membranes upon
natural exposure. The end result is an immediate wheal and flare
inflammatory response.

Much of the past research in this area has relied heavily upon the use
of skin tests. However, in the &year interval since the first Surgeon
General's Report on smoking, r esearch developments have made it
possible to add new insights to the topic of tobacco allergy. In 1967, the
Ishizakas (51) identified the skin sensitizing factor or reaginic antibody
as immunoglobulin E (IgE), thus providing a major breakthrough in
the understanding of allergy. Subsequently came descriptions of the
specific localization of IgE, on membranes of tissue mast cells (111) and
the release of chemical mediators from the protoplasm of these cells
when IgE reacts with corresponding surface antigens (5.2). In such
instances, the antigen can be classified as an allergen.
Along with these advances came an appreciation of some of the
limitations of skin testing. Among these is the fact that mast cell
chemical mediators can also be released by nonspecific irritation (81,
$9). Also, the presence of specific IgE fixed in the skin, as noted by the
wheal and flare test response, is not the sole determinant for clinical
expression of an allergy. Skin testing, done with appropriate materials

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and controls, can give useful results to support a clinical impression,
but it is not the sole diagnostic criterion.

Much of the previous work in assessing the possibility of tobacco
allergy has been questioned because the extracts of the whole leaf or
smoke used for skin testing represent a complex mixture of compo-
nents; while one or more of the components may be allergenic, others
are primarily irritant. However, a potential breakthrough has come
about through the application of biochemical expertise in isolating and
identifying a single component of tobacco which has been shown to
cause positive, immediate reactions in skin tests in humans. (9, 10).
Whether this glycoprotein will ultimately be shown to be a causative
agent of symptoms in humans awaits further study.

Even though skin testing remains the most sensitive indicator of
reaginic antibody, in some cases there is reason to question its
specificity. Verification of its validity is now possible because of the
development of in vitro tests, such as' the radioallergoabsorbent test
(RAST) (1%). While this assay is showing promise in diagnosis of
pollen and insect venom allergy, further technology is required to
make it suitable for general use. It may be possible to employ RAST in
the study of tobacco smoke or leaf allergy, once the chemical properties
of any true allergens that are discovered are characterized and adapted
for the required solid phase studies.

The development of critical in titro assays is important in the
diagnosis of possible tobacco allergy because the nonspecific irritant
qualities of tobacco extracts often leave the interpretation of skin tests
and provocation tests in doubt. Awaiting such technology, several
other approaches to exclude irritating effects have been employed:
demonstration of the nonreactivity of the test extract in normal
controls, end point titration, passive serum transfer (Prausnitz-Kuestc
ner [P-K] test), and exhaustion of the response at the site of a passive
serum transfer reaction by previous absorption of the test serum with
a specific antigen.

Perhaps the term tobacco allergy has been used too loosely. In the
past, reports of diagnosis have been based on a history of symptoms
upon exposure to tobacco or its products, elimination of symptoms on
withdrawal, demonstration of the occurrence of symptoms on reexpo-
sure, and emphasis on skin test results. These criteria must be
reevaluated, since approaches for verification with precise methods
and chemically-characterized specific tobacco antigen(s) are now on the
horizon. In retrospect, it would appear that only those studies fulfilling
a minimum set of criteria should have been considered acceptable as
diagnostic of tobacco allergy. These criteria include the following:

1. Demonstration that tobacco smoke or a derivative product is
capable of inducing those specific immune responses that are
responsible for producing symptoms of allergy.

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2. Demonstration upon exposure to tobacco smoke or a tobacco
smoke product of reproducible symptoms characteristic of an allergic
response, e.g., asthma, rhinitis or related upper respiratory symptoms,
conjunctivitis,  urticaria/angioedema, dermatitis, or anaphylactic
shock. These symptoms must be reversible upon removal of tobacco or
its derivatives; other possible effects of tobacco, such as irritant or
pharmacological effects, must be excluded.
3. Demonstration of the affected person's ability to mount a reaginic
response, as evidenced by an immediate wheal and flare response to
the application of appropriate tobacco smoke extract by conventional
prick, scratch, or intracutaneous routes, again provided nonspecific
irritant properties have been excluded.
4. Demonstration of an association between the immunologically
demonstrated reaction and the clinical symptoms. Further credence is
given to this relationship if there is failure to manifest identical
symptoms on exposure to potentially irritating gaseous or particulate
matter that is not derived from tobacco.

While the discussion thus far and the thrust of this report will deal
with the type of allergy known as immediate hypersensitivity, an
additional fact to be considered is that tobacco can affect the immune
system in a manner quite apart from the classic allergic state. It should
be recognized that expressions of other immune mechanisms are often
considered allergic. Thus, it is plausible that tobacco as an antigen
could play a causative role in disease entities mediated by immunoglob-
ulins in other classes (humoral IgG and IgM and secretory IgA at the
mucous membrane surface). Direct cellular injury can arise from the
action of cytotoxic antibodies, causing tissue inflammation by deposi-
tion of immune complexes through the sequence of antigen-antibody
reactions, activation of the complement cascade, and migration of
inflammatory cells into affected sites. In the case of delayed
hypersensitivity, contact dermatitis of skin and mucous membranes
emerges as a manifestation of cell-mediated immune mechanisms.
Additionally, some physicians consider cardiovascular symptoms to be
allergic because of the association of skin tests positive to tobacco
extract with reproducible cardiac pathophysiologic expressions. How-
ever, exact differentiation between those responses that are truly
immunologically mediated and those of pharmacologic idiosyncratic
origin remains to be defined.
Though some of the reported studies may have adhered to one or
more of the criteria listed above for diagnosis of an immediate allergic
reaction, other demands of clinical investigation were not always met.
Evaluation of many studies pertaining to tobacco allergy is difficult
because of the lack of necessary data or because of poor experimental
design. Controlled double-blind protocols have seldom been used. The
Presence of a positive skin test has been equated with the presence of
clinical tobacco allergy,   even  in the absence of clinical

10-7


symptomatology. There have been failures in appreciating the role of
tobacco smoke as a pollutant serving as a secondary or an aggravating
factor rather than as an initiating agent, and provocative testing was
not always carried out in patients in a basal asymptomatic state; thus,
the influence of coincidentally present allergens and irritants could not
be excluded. Other experimental deficiencies include failure to
standardize the potency or antigenicity of extracts, inadequate
definition of the term allergic when a subpopulation of "allergic
patients" was studied, and failure to define the degree of exposure to
tobacco among individual subjects.

When trying to compare studies, additional problems arise because
of the many variables in the experimental protocols used. Criteria for
scoring a skin test positive were not always defined, leaving no basis
for comparison among different studies. Evident differences among
the populations studied included age, sex, occupation, presence or
absence of other allergies, environmental exposures, and smoking
history. Additional variables included differences in source of tobacco
used for testing, state of the tobacco (raw vs. cured), use of
fractionated extracts as opposed to whole leaf extracts, differences in
extraction methods, the presence or absence of additives or nicotine,
and, most importantly, the use of smoke extracts as opposed to tobacco
leaf extracts.

On the basis of clinical experience, many physicians are convinced
that tobacco products can and do act through a primary allergic
mechanism. However, this impression is not uniformly held and has not
been unequivocally proven. That tobacco and/or its products can
exacerbate underlying allergic conditions in both smokers and
nonsmokers is generally accepted by clinicians on the basis of
documented irritant and pharmacologic effects. Again, however,
difficulties in the evaluation of studies examining these factors arise
from problems in separating the effects of tobacco and smoke from
other environmental allergens and pollutants and in knowing whether
a given effect is primary or secondary.

The purpose of this chapter is to review critically the experimental
evidence which may shed light on the unresolved relationship of
tobacco smoking to allergy and other immune phenomena.

Bask Mechanisms
The term allergy, coined by Von Pirquet in 1906 (115), embraced any
type of altered reaction to a substance brought about during the course
of prior exposure. Hence, mechanisms both of enhanced resistance or
immunity and of enhanced reactivity or hypersensitivity were referred
to as the allergic state. During subsequent years, the term began to
take on only the latter meaning; so that, currently, allergy is
considered synonymous with hypersensitivity. Thus, whereas early in

10-8


the century allergy was given a broad scientific definition, the term is
now more narrowly interpreted and, especially to a lay person, is
associated with the symptoms of itching, sneezing, and wheezing
characteristic of eczema, hives, hay fever, and asthma. Actually,
however, there are several types of allergic states and their mecha-
nisms are best understood in terms of the Gel1 and Coombs
classification of hypersensitivity reactions (%`).

1. Type I, or immediate hypersensitivity reaction, embraces the
commonly-known classic allergic disorders mentioned above. A major
portion of this report concerns itself with manifestations of this type of
allergy; the details of its mediation involving the antibody known as
IgE are presented in an earlier section.
2. Type II hypersensitivity is mediated by an antibody directed
against a cell membrane or cell membrane-associated substance such as
the injury to red blood cells that occurs during an incompatible blood
transfusion. Serum complement is involved in this cytotoxic type
reaction.

3. Type III is mediated by antigen-antibody combinations (immune
complexes) resulting from their interaction and deposition in tissues.
Serum sickness and the local Arthus-type reaction are the classic
examples of this mechanism.
4. Type IV reaction is mediated by sensitized thymusdependent
lymphocytes (T cells), not by circulating antibodies. Contact dermatitis
is an example of this delayed hypersensitivity reaction.

Tobacco as an Antigen

In order to demonstrate that any substance may be a cause of allergy,
it is necessary (but not sufficient) to prove that the substance is
antigenic. An antigen is capable of binding to the antibody whose
formation it has induced, in humoral immunity, or is responsible for
the development of sensitized cells, in delayed hypersensitivity. The
term allergen has a slightly different connotation in that it is usually
an environmental or food antigen to which only allergically predis-
posed individuals become specifically sensitized upon spontaneous
contact by inhalation or ingestion. The mechanisms for allergenicity
can proceed by any of the four types of hypersensitivity discussed
above. There is evidence that tobacco leaf and its products are
antigenic in animals and man, capable of both evoking a wide range of
antibodies, including reaginic antibodies, and sensitizing small lympho-
cytes responsible for delayed type hypersensitivity (4,41,53,60,80,10.4).
Evidence that tobacco smoke is antigenic in man, however, is meager
and controversial at present.
There are several studies on experimental animals demonstrating
stimulation of antibody production by tobacco products. Harkavy (41)
injected rats with tobacco leaf extract. Upon subsequent challenge

10-9


with this material, he was able to demonstrate positive Schultz-Dale
reactions with the sensitized intestinal strips. Armen and Cohen (4)
were able to raise precipitating antibodies in rabbits injected with an
extract of cured tobacco leaves but found this material to be weakly
antigenic, requiring simultaneous injection of an adjuvant to induce
the responses. Panayotopoulos, et al. (80) described the isolation of five
components from tobacco leaf extracts capable of inducing precipitat-
ing antibodies. Recently, a mouse model for production of IgE and
reaginic IgG against tobacco components has been developed by Justus
and Adams (53), with identification of the antibodies by passive
cutaneous anaphylaxis assay. Of potential importance are recent
studies by Lehrer, et al. employing tobacco smoke and smoke in
combination with host protein carriers. In these studies, sera from
rabbits immunized with tobacco smoke components reacted by
immunoprecipitation with tobacco smoke or leaf antigens (62). These
investigators have also demonstrated reaginic antibodies in the sera of
mice immunized with smoke extracts.

Human studies have also been revealing. Kreis, et al. (60) demon-
strated that two of the five tobacco components inducing antibody
formation in rabbits also reacted in vitro with human sera. Since these
antigenic components were identified only in tobacco leaf extracts and
not in the smoke, it was suspected that some contact with the leaf or
cross reacting antigens must take place in humans. In the studies by
Panayotopoulos, et al. (80), serum-precipitating antibodies to the five
components of tobacco leaf were also identified in humans. Seventy-
five percent of the subjects demonstrating this finding reacted with
positive Arthus skin test reactions characteristic of this type of
antibody when challenged intradermally with the extract, and smokers
reacted more frequently than nonsmokers.

Of special interest and relevance are studies concerned with the
demonstration of reaginic antibody against tobacco leaf in humans.
This has been a controversial subject and is discussed in further detail
in a later portion of this report. As early as 1923, Brown (12),
attempting to demonstrate positive immediate skin tests to tobacco
leaf extracts in humans, reported positive findings in 1 percent of
asthmatic patients studied.  This work was later extended
(9,10,38,.@,&',64,83) by workers who demonstrated not only the
presence of positive skin test reactions to tobacco leaf extracts but also
the ability to transfer this reaction passively to normal control
subjects. Others (2O,lO4,105,113,12~), however,were unable to confirm
the studies done with tobacco leaf extracts. Similar studies, perhaps
more relevant to this report, have been done with extracts prepared
from tobacco smoke, showing that these, too, are capable of reacting
with reaginic antibody in humans (9,10,85). These studies were
dependent primarily on skin reactivity, however, and, therefore,
require further investigation. Delayed reactions following intradermal

10-10


test injections of tobacco extracts have also been reported in humans
(104. This and other related studies discussed in a later section suggest
that tobacco leaf may play a role as antigen in cell-mediated delayed
hypersensitivity.

ldentlfication ot the Tobacco Ant&ten(s)

The tobacco plant is a member of the botanical family Sotieae, as
are potatoes and tomatoes. Since the raw leaf contains many high
molecular weight proteins, theoretically it is potentially antigenic. In
addition, the raw leaf may contain residues of insecticides or may be
contaminated with bacteria, fungi, and even other known airborne
allergens deposited on its surface, such as ragweed pollen. During
curing and aging of the green leaves, chemical reactions take place
within the tobacco leaf substance, and an array of additives further
influences its composition. Aside from the exposure of tobacco and
cigarette factory workers to raw and cured leaf, the possible antigens
in tobacco smoke may be more relevant. Here again, this tobacco
combustion product is a heterogeneous mixture of an estimated 2,000
particulate, gaseous, and semivolatile components (75). Furthermore,
recent investigations show differences between the puff of smoke
actively inhaled through the cigarette by the smoker and the so-called
side-stream smoke discharged into the air by the burning cigarette tip,
a source of potential inhalation by exposed nonsmokers (48). The issue
is further complicated by the fact that tobacco and its products have
both irritant and pharmacologic effects which can be mistakenly
interpreted as allergenic. Isolation and purification of one or more
substances responsible for the antigenicity of tobacco and its products
will be necessary to clarify these findings.
Harkavy (39, 40) has shown that nicotine is not the responsible
antigenic component of tobacco leaf, although its role as a hapten (68)
is a possibility. Chu, et al. (21) have isolated five protein carbohydrate
complexes with molecular weights varying between 20,000 and 60,000
from aqueous extracts of cigar and pipe tobacco. Kreis and coworkers
(60) reported that two components of a soluble extract of tobacco leaf
capable of stimulating antibody formation in rabbits and precipitating
with human sera had molecular weights of 10,000 to 20,000. In another
study (80), five antigenic plant proteins, immunoelectrophoretically
localized in positions corresponding to the LYP, a~-, and /3-globulins and
isolated from the leaves of Nicotiuna tdmum, had the property of
precipitating with human sera. Differences in antigenic reactivity
were described among different varieties of tobacco leaf tested.
Because the serum precipitins were more prevalent in smokers, these
investigators proposed that antigenic substances were carried in smoke
passing through the cigarette, thus exposing the smoker. However,
they did not attempt to demonstrate these substances in the tobacco

10-11


smoke. Becker, et al. (9, 10) reported that a tobacco glycoprotein gave
positive and immediate skin test reactions in approximately one-&ii
of the people tested, but the atopic status of these people and the
irritant threshold of the extract were not determined.

Eplckmiology

Few studies have attempted to relate the incidence of clinical allergy
to active or passive effects of smoking. Asthma has occurred either in
association with or following respiratory infections (.%.Y). Hence, any
factor predisposing to infections of the lower respiratory tract,
especially during childhood years, is relevant to this discussion on
tobacco as a health hazard. One study (75u), surveying the incidence of
respiratory symptoms and infections among 1,119 children, revealed
that the percentage with symptoms increased with the definable level
of smoking in the household. Another study, by Colley and coworkers
(2%) surveying 2,205 infants, showed that the incidence of pneumonia
and bronchitis in the first year of life was associated with parental
smoking habits; the risk to the infant of parents both of whom smoked
was almost twice that of nonsmoking parents. Cameron, et al. (15), in a
survey of children from 727 families, found the prevalence of
respiratory disorders to be 5.9 percent in homes where parents smoked
compared with 3.1 percent in homes of nonsmoking parents.

Looking at the same problem from a different viewpoint, a study of
hospital records of 10,762 infants by Harlap and Davies (4%) disclosed
a significantly higher admission rate for bronchitis and pneumonia for
those whose mothers smoked. It is, however, difficult to evaluate the
impact of these infectious processes on the subsequent development of
allergic diseases in the children studied because of several factors:
differentiation among possible causative organisms (microbial or viral)
was not always determined; the presence or absence of wheezing was
not noted; and, apparently, follow-up studies were not undertaken.

Studies such as these also suffer from the criticism of failing to
consider sufficiently other possible explanations for the increased
prevalence of respiratory symptoms and disorders, such as socio-
economic factors, genetic differences, and frequency of respiratory
infection in parents. Thus, adverse consequences of passive smoking
among healthy adults has been surveyed. Speer (102) examined the
frequency of symptoms reported by 250 nonallergic, nonsmoking
individuals, passively exposed in environments characterized by
smoking. Nasal symptoms such as sneezing and itchiness were found in
29.2 percent, cough in 25.2 percent, headache in 33.0 percent, and eye
irritation in 70.0 percent, emphasizing that irritant effects of smoke
can simulate allergic symptoms.

As might be anticipated, persons with identified allergic disorders
such as rhinitis or asthma have been more thoroughly investigated in

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efforts to define causal connections between tobacco or smoke and
their specific illnesses. Studies also have been made to ascertain
whether smoking may aggravate preexisting allergic conditions.
Zussman (130, 131) made an effort to learn whether tobacco leaf
allergy played a causal role among allergic patients suffering from
nasal, ocular, or bronchial involvement. Among a randomly selected
group of 200 people, 16 percent were found to be clinically irritated by
tobacco smoke. Thirteen of sixteen individuals manifesting positive
skin tests to tobacco leaf extracts were reported to benefit from
"desensitization" injections, in which tobacco extract was included
among other allergens in the treatment mixtures. However, "benefit"
was evaluated by the patient reporting without the advantage of
objective assessment. It should also be noted that the tobacco leaf
extract employed was contaminated with house dust antigen. In any
case, the use of such a heterogenous mixture as tobacco extract in
injection treatments is considered controversial.

In another study, Fontana and coworkers (33) found that 64 percent
of 25 allergic children gave positive skin test reactions to tobacco leaf
extract, compared with only 6 percent of nonallergic control subjects.
Rosen (91) reported positive skin reactions to tobacco leaf extract in 12
percent of asthma patients, and Speer (102), in 15 percent of 191
allergically predisposed individuals. By retrospective suwey, Pipes (85)
made an effort to distinguish allergy to smoke from allergy to tobacco,
noting that 13 percent of 3'70 allergic patients had positive skin test
reactions to tobacco leaf extract. Ten percent of the study population
also experienced aggravation of symptoms upon exposure to smoke,
but none gave positive skin reactions to the tobacco smoke prepara-
tions utilized.

It is relevant to note that available tobacco leaf extracts utilized in
skin testing are multicomponent mixtures that may contain both
irritant and allergenic fractions and that it is a characteristic feature
of the allergic state for an affected person to have positive skin
reactions to allergenic extracts other than tobacco. Thus, the problem
of precise interpretation of skin tests in clinical settings where allergic
conditions have multifactorial features makes it impossible to deter-
mine what role, if any, allergy to tobacco smoke played in the clinical
disorders of patients reported in these series. Fontana and coworkers
(33) reported that 15 percent of 641 volunteers reacted with positive
skin tests to one or more of the tobacco leaf extracts used, without a
significant difference occurring between smokers and nonsmokers.
The above findings indicate that tobacco proteins are able to produce
positive skin tests on an irritant basis. They further suggest that the
Predominant effect of smoke is an irritant superimposed upon an
already pathophysiologically altered allergic membrane. In a study of
191 allergic nonsmokers and 259 nonallergic smokers, intolerance of
tobacco smoke was a common occurrence in both groups (102).

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