h
TABLE A25.-E.rperiments concerning the effect of smoking and nicotine upon blood lipids (cont.)
                             (Human Studies)
Author,
war.
country.
reference
Murchison
and
Fyfe.
1966.
Scotland
(139).
Numm;rz';"d
  population
-~
R male and 4
female mod-
erate smokers
with various
diseases 37-
67 years of
age.
Smoking       Plasma free
procedure       fatty acids
2 cigarettes
in 15 minutes.
I. I.it-riga-
   rettes.
II. Unlit-ciga-
   rettes.
I. Definite     No change.   No change.                 Both regular and sham smokers
   increase.                                     showed significant increases
II. No change.   No change.   No change.                   in concentration of serum
                                             P!Pif xid 2nd significznt
                                             decreases in concentration of
                                            serum palmitic acid.
Serum      Serum
cholesterol  triglycerides       0tIxi             comments
Kershbaum 6 normal
Various types
et al..
1967,
U.S.A.
(105).
heavy
cigarette
smokers
28-45 years
of age.
of cigarettes
of known
nicotine
content.
Regular cigarettes,
filter cigarettes.
charcoal-filte,
cigarettes. pipe
tobacco plus
cigarettes all
showed similar
increase in FFA.
Lettuce leaf
cigarettes had
negligible effect.
Ruth catecholaminc and
nicotine excretion rates showed
wsponses to the various ciga-
rettes similar to that of the
FFA response.

TABLE A25a.-Experiments concerning the effect of smoking and nicotine u/Ion blood lipids
                            (Animal Studies 1
ANIMAL AND Ih' VITRO STUDIES
Author.
ye==,
countrv.
Plasma free
fatty acids
SelUll     Serum
cholesterol triglycerides
Other           Comme"ts
reference  poG&tion
Wenael and 49 male     I. Untreated co"tro&                                     Group II and IV   The authors consider a" el-
Beckloff,   N.3V        12 subjecta.                                            showed an im-   evated cholesterol/ p&s-
1958.     Zealand   II. Regular diet plus                                          mediate in-      pholipid ratio to be a
U.S.A.    white       0.1 percent cboleaterol-                                     crease in plasma   notable indication of
ml6).     rabbits.       12 subjects.                                        cholestero) and    atherogenic susceptibility.
             III. Regular diet plus 2.28                                     phospholipids    The concomitant increase
                 mg./kg./day nicotine                                      with a level-     in phospholipids with the
                 in water-12 subjects.                                      with B leveling    cholesterol may negate
              IV. Diet plus-                                             of respon*e      the ilnportance of nico-
                 (a) 0.1 percent cholesterol                                   at 4 weeks.      tine-induced hypercho-
                (b) 2.28 mg./kg./day                                  Group IV showed    lrsterolemis as an
                      nicotine in water-                                    n further in-     atherogenic stimuius.
                  12 subjects.                                            crease at R-12
                                                                wrek period.
Kershbaum 6 monarel   Intravenous infusion of 20       Definite increase in
et al.,     dogs.     mg./kg. nicotine             lS,/l5 observations.
l!)Rl,             in 20 minutes.
1' S.A.
t ,34).
Kc,, ilbaum 20 adult     I. 9 received IM nicotine        I. Sirrnilirant inrrease         No change
c d..     mongrel      daily for 6 weeks:            in U/9 doas.              in "ny
otj      dogs.        up to 1 ma./ka.          II. No rhange.                BrOUP.
`-.S.A.           II. 5 placebo injection.        III. NI\ change.
(1071.           III. 6 control.

5
TABLE A25a.-Experiments concerning the eflect of smoking and nicotine upon blood lipids (cont.)
                              (Animal Studies)
         ANIMAL AND IN VITRO STUDIES
-
Author.   NWIlber
yeer,      and
country.    tYPe of
reference  population
Smoking
Procedure
Serum       Plasma frer   SeIWll
triglycerides     fatty acids  cholesterol      Other
Cnmments
Kershbaum 2X adult    Intravenous infusion of nicotine.                   No change.
et al.,     mongrel
1DGG.     doa%
U.S.A.
(Inn).
                                                      -.
Kersbbsw,, Spraaw-   Nicotine perfusion.
et al.,     Dawlev
1867.     rat
1J.S.A.     fat-pad
(110).    tissue.
The authors report on the
results of the use of ne-
thnlide (a Beta-ndrener-
gic blockrr), phenoxy-
benzamine, and chlor-
promazine to block the
FFA response to nicotine.
Only nethnlide rna~ suc-
rc.`cuC1,1 1,11{ !i:i:: c<,r.y!i-
tutes an indication that
nicotinr stimulatfzs Beta-
adrcnergie receptors to
release rntecholamines
which. in turn, stimulnte
the release of FFA.
4lthough nicotine perfusion
WBS not associated with
FI:A wlense from fat tis-
sue. epinephrine did
producr a significant in-
rwaw in FFA release.
The authors conclude
that the sympathetic
TLFI`YOUS system mediates
the FFA response to
nicotine in the intact
animal.

K jf2ldsrn
and
DRmanard
l!ltiX,
Denmark
(11.5).
K jeldsen,
1060,
Denmnrk
, 1 ,:,1
K it~ldsm,
l!lG!l.
I)r,nmnrk
(J1.1).
Number and
type of
population
4 male students zs-27
y<`<al's of age.
-
I. 12 control and 12 exposed
  togradunlly increasing CO
  c,mcentrations (0.015-0.40
  peri.x,t) over n 4-week
  period.
II. 12 control nnd 12 exposed to
   0.020 pwccnt co for 35 days.
III. 12 control and 12 cxposcd to
   to 0.020 perrent co for
   7 wwkq. then 0.036
   tte'rernt CO for 3 weeks.
serum I,h&ster,,l nnd triplyccride conwntrations rose to significantly higher
lr~r]~ during :l of tht. s wwks. No rhnngcs noted in serum phospholipida.

                          TABLE A27.Smoking and thrombosis
     - ___~~   -___~                                                                     -
4:      Author.
       year,   Number and   Experi-  tit2           Partial Recalcified
                                      PI-O-   thrombo-   plasma   Platelet   Platelet   Platelet   Platelet
      country.    type of     mental    clotting   tbrombin  plasti"   clotting  adhesive-   count   survival  turnover    Other      COHlllle"tS
      reference  poPulati0"   conditions '    time     time     time     time "ess
     ~___~         .~___
     Black-    16 adult     12 individuals                                                         Pl4Z.Wla
burn     schizo-      smoked 2
et al..    phrenic     high-
196!l.    patients, 8    nicotine
U.S.A.   university    stananra
(25)    studrnts, all   brand
       smokers.     cigarettes.
  -~ ~~-_- ___
MUhtmi   7 white males Comparctl
ana     with either   after
Murphy.  CVD 0,     periods of
t!ml.    COPI). "11    abstincncr
U.S.A.   hravy      or continua-
iljl).    smc,kr~m 3%   tion of
        72 YPB1'6 of   smoking.
        8BC.
--~~ __-~   ___~
Ambrrls   20 healthy    Drrp inhala-
and     malt? nc,n-    tic," <lf one
Mink.    sm<,kinp     nonfiltcred
l!l64.    mrdiral     rigarettt-.
U.S.A.   stdrnl~ <::30
(4).     yeal's of PPE.
hshby    27 male     13 wntrots
et al..    medical     measured at
1 9 6 5 (    students and   2 separate
Iwland   hxwl,ital     times 14
(8).     staff       subjects
        memtrers.    measured
                 before and
                 afte,
                sm(,ki"a 2
                 cigarettes
                 in 20
                 minutes.
(-)
(-)
(-)
(-)
(-)
     --
       (-)
  __.
(6)      (+-)
     increase
         .-
       (i-l
     incremr
                    stupvan
                     time
                     (6)
              Platelet ___--
                  clumping
                     time
(-)    (f)    (+)       (t)
     Avv-0RFP incrmre
                  --- ~~-. ____ __-
                3'hromhoplastin 2 students
                   r,c 2,~ r-rrtion    became ill.
(-)                   tip,,,      Results
                     `- 1      reflect
                            data on 1x.
                           Increase of
                            subjects
                            greater
                            than that
                            of controls
                            at p<O.Ol.

Author.                     Whole          Pnrtial  ltecalcified
Year,   Number arrd   Experi-     blood    Pro-   thrombo-   plasma   Platelet   Platelet   Platelet   rkitdet
country,    type of     mental    clotting  tbrombin   plastin   clotting  ndhesive-   count   survival  turnover    Other     commc"ts
referrnce  populntion   conditions 1    time     time     time     time     "es?3
Sogani   I1 obsrrvations Smoked 2 cis-                                                       Fihrinolvsi.?  fjiri-- ~
and     on "Isle     arettes or                                                          (f)      tobacco
Joshi.    >mokers all   :! biris or                                                          CllXLY%3~    wrapped in
1965,     regular      rhrwrrl 1     (-)     (6)           I --I      (f)                                 l~,bZiCW
India    tobacco      hetcl nut                              Inrreasc                                leaf.
(174). IlhPI`S.      rluid in 20
                minutes,
Engel-                                        .- ~-___
      40 male and   2 cigarettes
berg,    20 female    in 20
1 !I 6 5,    huspital pa-   minutes
U.S.A.   ticnts. all
(5.Y).    smokers IT-
      6X years of
      ;ige.
sc,n      4 fernalp     in 15
""d     patients     minutes.
Fyfr,    with       lit UT unlit                               (t)
lOfiR, various      cigawttrs.
Scotland  diseases, all
(MD,.    heavy
      smokers 37-
      67 years
      <>f age.
ChlWldlCT
(in ritm)
thrombosis
time
  +
decrease
Throw&
time
(*)
decrease
(f)
increase
t Smoking both
lit and unlit
cigarettes
caused a rise
in platelet
adhesiveness
which the
authors
correlated
with rise in
plasma non-
esterified
fatty acids.

TABLE A27.-Smoking and thrombosis (cont.)
z       Author,                     Whole          Partial Recalcified
       Year.   Number and   Experi-     blood    Pro-   thrombo-  plasma   Platelet   Platelet   Platelet   Platelet
      country,    type of     mental    clotting  thrombin  plastin   clotting  adhesive-   count   survival  turnover    Other      Comments
      reference  population   conditions 1    time    time     time     time ness
     C.lynn    21) male and   :i cigarettes                                                          Platelet   Smokers found
       et al.,    li fcmalc    in 30                                                             scrotinin    to have a
       19GG.    smokers and   minutes.                               (-)                          (6)      greater
       C*"*d*   9 male and                                                                   Plutclet     t~ndcncy for
       (71).    21 frmale                                                                   adcxosinc    platelet
             nvnsmukcrs                                                                 nucleotidc    aggregation
             Ii-i6 jears                                                                   (6)      than non-
             of age.                                                                           smokers.
Engelbrr~ 9.1 male and   1 cinarette
and     53 female    in 5 minutes
Futter-   patients and
man.    mcdicnl
l!lGi,    h<,uw ~ltatf.
U.S.A.
(5s).
Thmmbuu   No relation
jormu tion    found with
time      increase in
(+)      free Patty
decrease     acids.
                            Platclct
                           ndhwxncc to
(i)     (2)     C-t)            sYlsclLlnr
increase  increase  decrease          Lndothclircm
                            (+)
                            increase
                          Fibrinolusis
                             (5)
                            decrease
                           Thrombus
                           jormntiom
                             timt
                             (+)
                            decreasr

TABLE A30.-Experiments concerning the effect oj nicotine ant1 smoking xpon
           the peripheral vascular system
Author, year
country. reference
Moyer and Maddock,   20 subjects (including heavy smokers) were studied for the effects of
1940. U.S.A. (I%,).    the following procedures on skin temperature: the inhalation of a
             lit cigarette, inhalation through an empty paper tube. or the ad-
             ministration of 1 mg. nicotine intravenously. All subjects rrsponded
               with decreased cutaneous temperature following the smoking and
              nicotine procedures. No changes were noted following sham smoking.
Mulinos and Shulman,   A number of experimental groups, each consisting of 6-17 persons,
1940, U.S.A. (198).    were studied for the effects of deep breathing and cigarette smoking
              on skin temperature and digit or limb plethysmography. The au-
              thors concluded that deep breathing alone could account for the
             changes in temperature snd blood flow noted upon smoking and
               noted that denicotinized cigarettes evoked the same or greater
              vasoconstriction as that noted following the smoking of a standard
                cigarette.
Shepherd, 1951,
Ireland (179).
50 young male smokers were studied with plethysmography before
and after the normal and rapid inhalation of a standard cigarette.
The author noted that rapid inhalation was associated with a pro-
longed decrease in extremity blood flow while a more natural rate
of inhalation was followed by a momentary deerease in flow. The
author considered the former reaction to represent the pharmacolo-
gic effect of the smoke and the latter tu represent the physiologic
response to deep breathing, as the natural inhalation of r.n unlit
cigarette produced the fame transient decrease in flow as did the
natural inhalation of the lit cigarette.
Friedell. 1953.
U.S.A. (70).
52 male and 48 female young smokers and nonsmokers were studied
for the effects of smoking on hand blood volume as measured by
the use of radioactive iodinated albumin. The inhalation of un-
filtered cigarettes was associated with an average decrease in hand
blood volume of 19 percent in men and 33 percent in women; while
filtered cigarettes showed respective decreases of I1 percent and
21 percent.
StrBmhlad. 1959,
Sweden (18f ).
11 male and female subjects (smokers and nonsmokers) were studied
for the effect of the intra-arterial administration of nicotine (bra-
chial artery) on blood flow to the hand as measured by venous
occlusion plethysmogrsphy. Increasing doses of nicotine were asso-
ciated with increasing numbers of individuals manifesting vase-
constriction. The vasoconstrictive effects of nicotine were abolished
by the prior administration of either hexamethonium or pentolinium.
Bamett and Boake     9 male patients with intermittent claudication (7 were heavy smokers)
1960 Australia (~8)    were studied for the effect of smoking on blood flow to the leg BS
               measured hy venous occlusion plethysmography. Smoking an un-
               filtered cigarette was found not to produce any consistent changes
                in blood flow to the calf or foot of the affected leg,
Freud and Ward,
1960. U.S.A. (68)
15 mde prison inmates  (1 ess than 35 years of age) and 14 male
patients with peripheral vascular disease (approximately 65 years
of age) were studied for the effect of smoking on digital circulation
as measured by skin temperature, plethysmography, and radiosodium
clrarance from the skin. Smoking was found to adversely affect
the first and third measurej in a significant manner (while plethys-
mographic values were variable)  only in the healthy prisoners
and not at all in the parient group.
R&h and Schick,      100 normal individuals underwent 425 experimental procedures con-
1960,U.S.A. (161).     cerning the effect of smoking on the peripheral circulation. Smok-
               ing was found to be associated with a decrease in extremity skin
                temperature.
133

TABLE A30.-Esperiments conwrning the effect of nicotine and smoking upOn
         the peripkeral vascular system (cont.)
Author, year,
country. reference
Rottenstein et al..     8 males (18~1 yeam of age) were studied for the effect of intm.
1960, U.S.A. (162).   venous .nicotine on extremity temperature and bled flow. Intra.
             venous nicotine was found to evoke a decrease in skin temperature
            while increasing muscle blood flow. The former effect began swner
                and lasted kmger than the latter.
Allison and Roth,
1969. U.S.A. (4).
30 healthy indzviduals (19-59 years of age) were studied for the effect
of smoking two cigarettes on eXtreIdY Puke vohm?s and ski,,
temDerature. Smoking was found to be associated with a 2-6 per.
cent deereast, in skin temperature and ZI 45-50 percent decrease in
blood pulse volumes to segments of the finger. calf. and toe.
134

CHAPTER 3
Chronic Obstructive Bronchopulmonary Disease

Contents
Introduction .........................................
Epidemiological Studies ..............................
  COPD Mortality. ................................
  COPD Morbidity. ...............................
  Ventilatory Function. ............................
  Genetic Factors. ................................
    Alpha,-antitrypsin ...........................
  Air Pollution ....................................
  Occupational Hazards. ...........................
     Cadmium ...................................
Pathological Studies  .................................
Experimental Studies  ................................
  Animal Studies  .................................
   Studies in Humans  ..............................
  Studies Concerning Pulmonary Clearance  ..........
     Overall Clearance  ...........................
     Ciliary Function  ............................
     Phagocytosis ................................
  Studies Concerning the Surfactant System  .........
Other Respiratory Disorders  ..........................
  Infectious Respiratory Diseases ....................
  Postoperative Complications  ......................
Summary and Conclusions  ...........................
References  .........................................
FIGURES
1. Percent of lung sections with Grade IV or V fibrosis . . .   161
2. Percent of lung sections with Grade II or III emphysema   162
LIST OF TABLES
(A indicates tables located in appendix at end of chapter)
1. Chronic obstructive bronchopulmonary disease mor-
  tality ratios. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Page
139
141
141
145
146
148
150
152
153
154
154
158
158
163
164
164
164
165
172
172
172
174
175
1'76
142
137

   LIST OF TABLES (Continued)
(A indicates tablets located in appendix at end of chapter)
A2. Smoking and chronic obstructive pulmonary disease
    symptoms-percent prevalence. . . . . . . . . . . . . . . . .
A3. Smoking and ventilatory function . . . . . . . . . . . . , . . .
A4. Glossary of terms used in tables and text on smoking
    and ventilatory function. . . . . . . . . . . . . . . . . .
5. Cessation of smoking and human pulmonary function
A6. Epidemiological studies concerning the relationship
    of air pollution, social class, and smoking to chronic
    obstructive bronchopulmonary disease (COPD) . .
A7. Epidemiological studies concerning the relationship
    of occupational exposure and smoking to chronic
    obstructive bronchopulmonary disease. . . . . . . . . . .
8. Studies concerning the relation of human pulmonary
    histology and smoking . . . . . . . . . . . . . . . . . . . . .
9. Experiments concerning the effect of the inhalation of
   cigarette smoke upon the tracheobronchial tree and
   pulmonary parenchyma of animals . . . . . . . . . . . . . .
AlO. Experiments concerning the effect of the chronic in-
    halation of NO:> upon the tracheobronchial tree and
   pulmonary parenchy-ma of animals . . . . . . . . . . . . .
11. Experiments concerning the acute effect of cigarette
    smoke inhalation on human pulmonary function. .
12. Experiments concerning the effect of cigarette smoke
    on human and animal pulmonary clearance. . . . . . .
A13. Experiments concerning the effect of cigarette smoke
    or its constituents upon ciliary function . . . . . . . .
A14. Experiments concerning the effect of cigarette smoke
    on pulmonary surfactant and surface tension . . . .
A15. Studies concerning the relationship of smoking to in-
    fectious respiratory disease in humans . . . . . . . . .
A16. Complications developing in the postoperative period
    in patients undergoing abdominal operations . .
A17. Arterial oxygen saturation before and after operation
Pafie
195
206
215
l-19
216
218
155
I.59
220
166
170
221
`LP;,
226
230
"30
130

              INTRODUCTION
Chronic obstructive bronchopulmonary disease (COPD) is char-
acterized by chronic obstruction to airflow within the lungs. The
term COPD refers to three common respiratory ailments; namely,
chronic bronchitis, pulmonary emphysema, and reversible obstruc-
tive lung disease (bronchial asthma) ,*
Chronic bronchitis has been defined as the chronic or recurrent
excessive mucus secretion of the bronchial tree. It is characterized
by cough with the production of sputum on most days for at least
three months in the year during at least two consecutive years
(217).
Pulmonary emphysema is that anatomically defined condition of
the iung characterized by an abnormal, permanent increase in the
size of the distal air spaces (beyond the terminal bronchiole) ac-
companied by destructive changes (217).
Patients can suffer from both of these conditions simultaneously.
The symptoms as well as the abnormalities in pulmonary function
observed in the presence of the two ailments may be quite similar.
Patients with chronic bronchitis suffer from productive cough with
or without dyspnea (breathlessness both at rest or on exertion)
while pulmonary emphysema is characterized mainly by dyspnea.
COPD comprises a spectrum of clinical manifestations; thus, it is
frequently difficult to determine whether a particular patient is
suffering from one of the two specified diseases alone or which one
predominates when both are thought to be present.
COPD is responsible for significant mortality in the United
States. In 1967, a total of 21,507 men and 3,88.5 women were re-
corded as dying from chronic bronchitis and emphysema (221).
This figure does not include a sizable number of individuals for
whom COPD was a contributory cause of death.
During the past two decades, a major increase has taken place
in the mortality from COPD in the United States. In 1949. the
death rate from COPD was 2.1 per lO!J,OOO resident population,
while in 1960 it was 6.0 (zz~), and in 1967, 12.9 (221). Although
* Because mortality from bronchial asthma does not appear to be related to Cigarette smoking.
the term COPD will be used henceforth to refer only to chronic bronchitis and Dulmonam
emphysema. Exacerbation of preexisting bronchial asthma has been observed among Cigarette
smokers, Further elaboration ,,f this question may be found in a pretiow l'ublic Health Service
Review CZ.M).
                                                        139

much of this rise is probab y due to changes in certification and
recording methods as well as to an increased interest on the part
of the medical community, an appreciable proportion is also gene
erally accepted as reflecting a real increase in disease. Similar in-
creases over the past `LO to N years have also been observed in
Canada (7) and in Israel (54). The lack of a similar increase in
Great Britain, a country with an extremely high rate of COPD,
may be the result of a number of factors including improved
therapy and decreased air pollution. Moreover, it is also likely that
the diagnosis of COPD has been made more commonly and ac-
curately in Great Britain for a longer time than in the United
States, or elsewhere. Furthermore, the British definitions of hron-
chitis and emphysema have differed in the past from those used in
the United States.
The mortality from and prevalence of COPD is probably under-
estimated. In a study of death certificates, Moriyama, et al. (170)
reported that COPD is often omitted as a contributing cause of
death. In a study of more than 350 autopsies, Mitchell, et al. (169)
noted that the disease often goes unreported and that emphysema
was occasionally found unassociated with severe clinical airway
obstruction. Hepper, et al. (I 10) observed that ventilatory test re-
sults were abnormal in 10 percent of 714 patients in whom no
symptoms, signs, or past history of pulmonary disease were noted.
They concluded that severe degrees of ventilatory impairment may
be undetected by history and physical examination alone. Boushy,
et al. (10) evaluated clinical symptoms, physiologic measurements
of airway obstruction, and morphologic bronchial and parenchymal
changes in 90 males with bronchogenic carcinoma. The authors
found that when either clinical, physiologic, or pathologic evidence
of COPD was used alone, one-third to one-fourth of the patients
were considered normal, but when all three criteria were used to-
gether, only one patient wa:; free of COPD. The importance of
COPD as a contributing cause of mortality is now beginning to be
more fully recognized.
Clinicians have long observed that the majority of their patients
suffering from COPD lvere cigarette smokers (2, 150). Epidemio-
logical studies have validated this impression by indicating that
cigarette smokers are at a much greater risk of developing or dying
from this disease and that the risk increases with increased dosage
of cigarette smoke, reaching in the smoker of two packs or more a
day a level as high as 18 times that of the nonsmokers (132). The
salutary effect of giving up smoking has also been borne out by
clinical obsel-vation and epidemiological studies.
In a number of studies, smokers were found to suffer more fre-
quently than nonsmokers from pulmonary symptoms including
140

cough, cough with production of phlegm, and dyspnea. By a variety
of pulmonary function tests, smokers were shown to have dimin-
ished function as compared to nonsmokers and also to have a
steeper slope of the expected decline of function with age. Tests of
ventilation/perfusion relationships in the lung have revealed ab-
normal function in smokers. Autopsy studies have indicated that
smokers dying of causes other than COPD have significantly more
changes characteristic of emphysema than nqnsmokers.
Several recent studies have validated the clinical impression that
among patients who undergo surgery, cigarette smokers run a
greater risk of developing complications in the post-operative
period than nonsmokers.
Abundant experimental evidence of the role of smoking in
bronchopulmonary disease has been obtained from experiments
employing animals and tissue and cell cultures. Recent work has
demonstrated, in dogs trained to inhale cigarette smoke through a
tracheostoma, that emphysema, pulmonary fibrosis, and other path-
ologic changes in the pulmonary parenchyma and bronchi develop
and that these changes are proportional to the total dosage of cig-
arette smoke inhaled. In vivo and in v&-o studies have shown that
whole cigarette smoke, or certain fractions thereof, inhibit ciliary
activity of the bronchial epithelium, adversely affect the mucous
sheath, and inhibit the phagocytic activity of the pulmonary
alveolar macrophage. These abnormalities lead to retarded clear-
ance of inhaled foreign matter including infectious agents from
the lungs, thus predisposing the individual to respiratory infec-
tions. Evidence also exists that pulmonary surfactant may be ad-
versely affected by cigarette smoke.
The convergence of these lines of evidence, which will be de-
scribed in more detail in the body of this chapter, leads to the
judgment that cigarette smoking is the most important cause of
COPD in man.
EPIDEMIOLOGICAL STUDIES
    COPD MORTALITY
Numerous epidemiological studies, based on a variety of POP-
ulations and carried on in a number of countries, have investi-
gated the association between cigarette smoking and COPD. They
have shown a greatly increased mortality and morbidity from
COPD among smokers as compared to nonsmokers. Results from
the major prospective studies relating smoking and COPD mortal-
ity are presented in table 1. The majority of the studies separate
141

TABLD L-Chronic obstructive bronchopulmonary disease mortality ratios
           (Actual number of deaths shown in parentheses)'
               SM = Smokers.     NS = Nonsmokers
PROSPECTIVE STUDIES
Author,
year,  Nummyd      Data     Follow-up    Number      Cigarettes/day        Chronic
country,              collection     Y=WS     of deaths      pipes. cigars        bronchitis        Emphysema       Other
reference    population
Hammond
and
Horn,
1958.
U.S.A.
(1oK).
-
Doll and
Hill
1964
Great
Britain
(70).
187,783 white Questionnaire
males in 9    and follow-up
states 50-69   of death
year8 of age.   certificate.
3%
Approximately Questionnaire
41,000 male   and follow-up
British      of death
physicians.    certificate.
10
      338     Cigarettes
SM ,308  NS . . . .I.00 (30)
NS . 30  <lO . .1.67 (10)
         IO-20 .3.00 (67)
         >20 . .3.64 (40)
         All . .2.85(231)
             Pipes
         NS  .l.OO (30)
         SM  . .1.77 (23)
              Cigars
         NS  .I.00 (30)
          SM  . . . . 1.29 (18)
      292                    Cigarette8
  Chronic                  NS  . .l.OO
bsonchitia                 1-14  .6.80
      111                 16-24 .12.80
  Other                  >25 .21.20
      181                 All  . . .11x0
                        Pipes and
                          Cigars
                        SM  _. .3.00
Cigarettes
NS _. .l.OO
1-14 .0.66
15-24 .1.08
>26 .0.63
AU  .0.81
Pipes and
  Cigars
SM . . ...0.78

TABLE l.-Chronic obstvuctive broncl~opulvvlov~f~~~ disease mortality ratios (cont.)
Author,
Year,
country,
reference
NutTmyoyd
population
Data
collection
    (Actual number of deaths shown in parentheses)'
        SM = Smokers.    NS = Nonsmokers
Follow-UP    Number      Cigarettes/day        Chronic
Years     of deaths      pipes, cignrs        bronchitis
           PROSPECTIVE STUDIES
Emphysema       Other
Best,     Approximately Questionnaire     6           124                  Cigarettes        Cigarcttcs
1966.     78,000 male   and follow-up                                 NS  . ..l.OO      NS  .l.OO
Canada    Canadian     of death                                    <lO  . . . ..7.02(17)   <lo  .4.81 (9)
(JO).     veterans.     certificate.                                   lo-20 .13.65(49)   lo-20  .6.12(21)
                                                         >20 t. .14.63(12)   >20  ..t. 6.93 (7)
                                                          All  .11.42(78)   All .._.. 5.X5(37)
                                                             Pipe8            Pipe8
                                                          SM  ,,..,, 2.11 (5)   SM .._._. 0.75 (2)
                                                             Cigars            Cignra
                                                          SM  .3.57 (1)   SM . ..3.33 (1)
Hammond,  440,658 males  Interviews by     4
1966,     662,671      ACS volun-
U.S.A.    females      teers.
(103).    35-84 years
        of age in
        25 states.
Kahn.    U.S. male     Questionnaire     8 `h
1966,     veterans     and
1J.S.A.    2.265,674     follow-up
(132).    person years.   of death
                  certificate.
      389
SM . . . ...369
NS . . . ...20
     nfnks
NS  .l.OO (20)
SM (age
45-64) .6.55(194)
SM (age
65-79) .11.41(175)
Bronchitis   NS  .l.OO (31)
SM .,...., 64 AllSM . ..6.49(348)
NS .13  Current cigs-
Emphgsema    retk  .10.08(229)
SM . . . ...284       Pipes
NS ..,,.. 18 SM .2.36 (9)
              Cigars
         SM _. .0.79 (5)
  Cursrllt ciga-       Current ciga-
   rcttcn o,dy        rrttl27 onlg
NS  .1.00(13)   NS  .l.OO (18)
l-9  . ..3.63 (5)   l-9  .5.33 (10)
lo-20 .4.61(22)   10-20 .14.04 (93)
21-39  .4.67(12)   21-39 _. .17.04 (62)
>39 . . ...8.31 (4)   >39  .25.34 (17)
All  . ..4.49(43)   All  .14.17(186)

f
TABLE l.-Chwnic obstructive bronchopdmonary disease mortality ratios (cont.)
             (Actual number of deaths shown in parentheses)'
                 SM = Smokers.     NS = Nonsmokers
Author.
Year,
country.
reference
Num;ebb"f"d
population
Data     FOllOWUP
collection     Years
Number
of deaths
Cigarettes/ day
pipes, cigars
Chronic
bronchitis
Emphysema
Other
PROSPECTIVE STUDY
Weir and  68,163 males   Questionnaire    S-8            58                                 Cigarettes
Dunn. in various     and                                                     NS  ._ `1.00
1970,     occuPstions   follow-up                                                 &lO  . .8.18
U.S.A.    in California.  of death                                                  220 . . ...11.80
.._.
I.zZ.2,.              certlticate.                                               ,>30  .20.86
                                                                        Ail  .12.33
RETROSPECTIVE STUDY --
Wicken,   1,189 males.   Personal inter-         1,188 obtained                 Cigarettes
1966,               view with            retrospec-                    odu
NOtih-              relatives of           tively.                    NS  . ..1.00(124)
em                individuals          SM . . .1,064                I-10  .2.95(246)
Ireland             listed on            NS  ,124                11-22  . . .3.43(300)
017).              death                                     >23  . .4.44(168)
                 register.                                        Mixed
                                                          SM  . . ,156 (62)
                                                     Pipes 07 cigars
                                                          SM  . . . . ..1.84(289)
1 Unless otherwise specified, disparities between the total number of deaths
and the sum of the individual smoking categories are due to the exclusion
of either occasional, miscellaneous, mixed, or ex-smokers.
? NS includes pipe and cigar smokers; SM includes e-x-smokers.

the findings for chronic bronchitis and emphysema. Such specific
grouping of the mortality data should be viewed with some reser-
vations in the light of the difficulties mentioned above in dis-
tinguishing the two diseases clinically.
The dose relationship of increased mortality ratios with increased
consumption of cigarettes is indicated by the results of all the
studies which present rates for different levels of smoking. Kahn
(132)) for instance, noted that those smoking only 1 to 9 cigarettes
per day incurred an emphysema mortality ratio of .5.33 while those
smoking over 39 per day incurred one of 2.5.34. Pipe and cigar
smokers were found in some studies to have slightly elevated mor-
tality ratios in comparison with nonsmokers although other studies
did not show this. The risk of dying from COPD among cigar and
pipe smokers appears to be much less than that incurred by
cigarette smokers but may be somewhat greater than that among
nonsmokers (table 1) .
The effect of stopping smoking on COPD mortality is reflected in
t.he results of Doll and Hill (70, 71) in their study of British physi-
cians. They found that during the years immediately following
cessation of smoking, mortality ratios remained elevated and did
not begin to decline below the level of continuing smokers until
nearly a decade later. This delay in response is probably due to two
factors: the presence in the ex-smokers' group of many who quit
for reasons of ill health and the long-term effects of cigarette
smoke on the respiratory tree, some of which are irreversible.
Kahn (1.32) aIso noted that the age-specific mortality ratios for
ex-smokers were lower than those for continuing smokers of cor-
responding amounts of cigarettes.
A better estimate of the potential effect of stopping smoking on
COPD mortality can be gained by studying the death rates in a
population in which a high proportion of smokers have stopped
smoking to protect their hea1t.h rather than as a response to ill
health. Among doctors age 35-64 in England and Wales, many of
whom have stopped smoking cigarettes, there was a 2~1 percent
reduction in bronchitis mortality between 1953-.57 and 1961-65,
as compared with a reduction of only 4 percent in all men of t.he
same age in England and Wales, among whom there was no reduc-
tion of cigarette smoking. (85).
COPD MORBIDITY
Many investigators have studied the prevalence of bronchopul-
monary symptoms (including those of chronic nonspecific respira-
tory disease) amon, rr smokers and nonsmokers. These studies are
outlined in table AZ. Their results indicate that the cigarette
145

smoker is much more 1ikel.v to suffer from respiratory symptoms
such as cough, sputum prc'duction, and dyspnea than is the non-
smoker. Such symptoms, particularly cough and sputum produc-
tion, increase with increasing dosage of cigarette smoke. Table A2
also shows that pipe and cig.lr smokers experience COPD symptoms
more frequently than nonsmokers although not to the degree found
in cigarette smokers. These morbidity findings are similar to the
mortality findings presented above.
Similarly, cessation of cigarette smoking has been shown to be
associated with a decrease in symptom prevalence. Mitchell, et al,
(168) studied 60 patients who succeeded in stopping smoking and
84 continuing smokers. Among the ex-smokers, more than 70 per-
cent reported improvement in their cough while less than 5 percent
of the continuing smokers did so. Wynder, et al. (237) followed
224 ex-smokers of cigarettes and noted that `7'7 percent reported
cessation of persistent cough and an additional 17 percent reported
definite improvement. Hammond (102) reported similar results
concerning cough and shortness of breath in a study of a large
group of ex-smokers.
VENTILATORY FUNCTION
Another type of quantification of the effects of smoking on the
bronchopulmonary system has been obtained by those groups of
investigators who have studied pulmonary function in various
groups. Results are presented in table A3, and a glossary of the
terms used in the various tests is presented in table A4. The pa-
rameters investigated have included maximal breathing capacity
(maximal voluntary ventila.tion) , expiratory flow rates, forced
expiratory volume, and vital capacity. Although certain of these
parameters appear to be more sensitive measures of pulmonary
dysfunction than others, the overwhelming majority of these stud-
ies have shown diminished function among smokers. An increase in
the expected age-diminution rate in smokers has been observed in
those studies which employed either repeated examinations or
examinations at many different age levels. Higgins, et al. (117)
conducted a nine-year follow-up examination of 385 male residents
of a British industrial town who were age 55-64 at the beginning
of the study. Among the survivors who were tested initially and
nine years later, the average decline in FEV,,,;, was smallest in non-
smokers, slightly greater in ex-smokers, and greatest in smokers.
As with COPD mortality and symptom prevalence, the impairment
of pulmonary function shows a dose-relationship with increasing
amounts of cigarettes smoked.
146

The data contained in table A3 provide two different kinds of
information. The majority of the studies were conducted on un-
selected populations, which probably include a number of individ-
uals with clinically manifest COPD. Therefore, these studies re-
flect the prevalence of COPD-related dysfunction (as determined
by pulmonary function tests) in relation to smoking. However,
some studies of younger individuals have revealed that pulmonary
function tests are abnormal in clinically asymptomatic smokers.
Krumholz, et al. (140) and Rankin, et al. (189) have shown that
pulmonary diffusing capacity is impaired in young asymptomatic
smokers when compared with age-matched nonsmokers. Similar
impairment in other pulmonary function tests was noted by Peters
and Ferris (182, 183) in an asymptomatic college-age group and
by Zwi, et al. (241) and Krumholz, et al. (140, 142) in groups of
young asymptomatic physicians and medical students.
Several investigators have employed tests which measure the
relationship of ventilation and perfusion (V/Q relationships) in
the various pulmonary segments. These tests are predicated on
observations that some segments of the lung may be relatively
under or overperfused and that, likewise, segments may be under
or overventilated. Anthonisen, et al. (IO) investigated pulmonary
function in 10 male smokers with clinically mild chronic bronchitis,
all of whom had smoked cigarettes for at least 20 years. Regional
pulmonary function was studied using radioactive xenon. Despite
the fact that overall pulmonary function was nearly normal in sev-
eral patients, all had depressed V/Q ratios in some lung regions
with the basal areas being those most commonly affected. The au-
thors suggested that significant disease in the peripheral airways
may exist in patients whose chronic bronchitis is clinically mild
and who show no present impairment of ventilatory capacity. The
radioactive xenon test may reveal severe compromise of local gas
exchange when usual studies of ventilatory capacity do not reveal
any impairment. Similar results concerning peripheral airway ob-
struction in bronchitic patients with normal, or only minimally in-
creased pulmonary resistance, have been observed by Woolcock,
et al. (234). These authors also noted that their patients demon-
strated frequency-dependent compliance which was unaffected by
the administration of bronchodilator aerosols.
Strieder, et al. (214) have recently investigated the mechanism
of postural hypoxemia in 24 asymptomatic smokers and non-
smokers. They found that standard ventilatory tests and lung vol.-
umes were normal in both the smoking and nonsmoking groups.
However, the arterial ~0' measured in the supine position was
significantly lower among the smokers and alveolar-arterial oxygen
gradients, while breathing room air, were larger in smokers than in
147

nonsmokers (more so in the sllpine than in the erect position). The
increase in alveolar-arterial O2 gradients was greater for heavy
than for light smokers. The authors concluded that maldistribution
of ventilation and perfusion accounted for the observed hypoxemia.
They also felt that this mild diffuse airway disease among asympto..
matic smokers is physiologically significant mainly because of in-
volvement of small bronchi, as expressed by maldistribution unac-
companied by gross airway obstruction. A similar ventilatory
distribution abnormality among smokers has also been observed
by Ross, et al. (198) with the more severe alterations found in the
long-term smokers.
Although of concern in the consideration of COPD, such dis-
turbances of the V/Q relationship may also have adverse effects
upon cardiac function depending upon the level of hypoxemia (219).
The discussion in the section on Coronary Heart Disease noted that
carbon monoxide has adverse effects on both oxygen transport and
alveolar-arterial exchange as well as on oxygen debt developed with
exercise (50). Further research is needed on the joint effect of these
pulmonary and carbon monoxide induced hypoxemic influences,
A number of other studies have provided further evidence con-
cerning the adverse effect of smoking on ventilatory function,
Table 5 presents those experjments which deal with the effect of
cessation of smoking on pulmonary function. Among the param-
eters which have been noted to improve after stopping smoking
are : diffusing capacity, compliance, resistance, maximal breathing
capacity, and forced expiratory volumes. These parameters showed
improvement within 3 to 4 weeks after cessation of smoking.
GENE'TIC FACTORS
Recent interest has been shown in the possible contribution of
genetic factors to the pathogenesis of COPD. Earlier studies (127,
147') had noted the existence of kindreds with high incidences of
chronic bronchitis, emphysema, or both diseases. In addition to the
presence of genetic susceptibility, Larson, et al. (1.47') also observed
that all but one of the 11 symptomatic individuals in their two
kindreds were smokers. They postulated that the susceptibility of
some smokers to develop emphysema may be, at least partially,
genetically detemined.
More recently, Larson, et al. (148) studied 156 relatives of COPD
patients and 86 control individuals. The subjects underwent pul-
monary function testing, including forced expiratory volume and
residual volume total lung capacity measurements. The authors
observed that pulmonary function abnormalities were most prev-
alent among the relatives who smoked and least prevalent among
148

TABLE 5.-Cessation of smoh-ing and hman pulmonary function'
Author,
Ye=-.
country,
reference
Krumholz
et al.,
1965,
U.S.A.
(141).
10 physicians
25-33 years
of age.
Wilhelmsen,  16 smokers.
1967,       (43.7 mean
U.S.A.      e-t`).
(130).
  Following 3 weeks abstinence     RoUowing 0 wrcks abstincncc (6 subjects only)t t All subjects were >5 pack
Lung volumes--no significant change.   Lung volumes:                        per year smokers.
Peak expiratow flow rate-increase    Inspiratow reserve volume-increase (g<O.O6).
(P<O.Ol)                  Functional residual capacity-increase (p<O.O5).
                      Maximal breathing capacity-increase (p<O.O2).
Mean diffusing capacity:           Mean diffusing capacity-no change.
Resting-increase (p<O.SZ)
Exercise-no change.
Compliance-increased in 6/8 tested.   Compliance-continued to show increase.
Vrrluc prior to ccasatim           Vnlue after cessation      Significanec      Mean duration of the non-
Vital capacity .4.50               4.57          Not significant.      smoking period was 40
FEvl.cl  ..,, .3.38               3.52          p<o.o5.           days.
FEV&FVC  .75.0               76.8           Not significant.
PEFN  .F.97               7.45          Not significant.
MEFR 50%  ., ,, . ..3.81               3.93          Not significant.
MEFR 25%  .1.31               1.50          p<o.o5.
Inspiratory resistance .2.07               1.43          p<o.o25.
Expiratory resistance .2.80               2.04          p<n.o2.
Compliance  No change          ~. .~                            .-
Alter 1 month ccsaatim         After 18 months cessatim
?KDC increase (p<O.OOl).          Increase (P<O.Ol).
FEV l.D increase (piO.01).          Increase.
Petrrson
et al.,
1968,
U.S.A.
(184).
12 smokers
studied at
m&us
intervals and
compared with
12 continuing
smokers.
1 Abbreviations are explained in the glossary of bronrhnpulmonnry table A4.

the nonsmoking controls. No relationship of this increased preva-
lence could be demonstrated to alpha,-antitrypsin deficiency (see
below). In addition, nonsmoking relatives and smoking controls
were observed to show approximately the same prevalence of ab-
normalities. However, due to t.he large proportion of females in the
nonsmoking relative group and to the clustering of two-thirds of
the affected relatives in 10 families, firm conclusions cannot at
present be drawn from this study concerning the relative contribu-
tions of smoking and of heredity to the pathogenesis of COPD.
In order to determine the relative significance of smoking and
heredity in the pathogenesis of COPD, Cederlof, et al. (45,16) have
used the twin-study methods on registries in both Sweden and the
USA. The specific details of this method are described in the set-
tion on Coronary Heart Disease. As may be noted from a summary
of their work at the end of table A2, the authors compared the
symptom prevalence among monozygotic and dizygotic twins who
were both discordant and concordant for smoking habits. They
observed that the hypermorbidity for COPD symptoms related to
smoking persisted even after controlling for zygosity and concluded
that a causal relationship of smoking and COPD symptoms was sup-
ported. However, genetic factors were still found to have an appre-
ciable influence. Lundmann (15.9) has applied this method to the
study of pulmonary function. He studied 37 monozygotic and 6:!
dizygotic twin pairs, measuring forced expiratory volumes and
nitrogen washout gradients, and matched the various pairs for
smoking discordancy. He observed that both of these parameters
were adversely affected in twin,; who smoked and that these changes
were correlated with cigarette consumption. The results are out-
lined at the end of table A3.
AZpha,-cmtit~~~psin (A,AT) --Of more recent note and discus-
sion has been the discovery of an association between a hereditary
predisposition to COPD and t;he relative or absolute absence of
alpha,-antitrypsin, a serum glycoprotein enzyme. Eriksson (78)
was the first investigator to observe a relationship between the
presence of markedly decreased serum trypsin inhibitory capacity
and panlobular emphysema. Since Eriksson's paper, much added
research has been published concerning many facets of this intrigu-
ing area.
It appears that A,AT deficency is inherited as an autosomal
recessive trait (78, 216) although Kueppers (12.:) considers the
transmission to be by an autosomal codominant allele. It has been
estimated that up to .5 percent of the general population may be
heterozygous for this gene (l,TJ) although full cross-sectional
studies of the population remain to be done.
Homozygous or severe deficiency of this enzyme has been asso-
150