SMOKING AND TUBERCULOSIS

Smoking and tuberculosis: an association overlooked
V. Maurya, V. K. Vijayan, A. Shah
S U M M A RY
Department of Respiratory Medicine, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India
OBJECTIVES: This article discusses the role of smoking
as a risk factor for tuberculosis. A review of the evidence
that has been documented is presented.
DATA SOURCES: Relevant articles in the medical literature
derived from searching the Medline database (1966
to present) with key terms ‘smoking’ and ‘tuberculosis’.
The bibliographies of all papers thus located were
searched for further relevant articles.
RESULTS: On searching the database, a total of 12
studies were found. A search of the bibliographies yielded
four more articles. Sixteen studies published between
1956 to the present were included in this review. The
evidence suggests that smoking could be considered as
an important risk factor for the development of tuberculosis.
Not only does active smoking appear to heighten
the chances of contracting pulmonary tuberculosis,
smokers also seem to be at an increased risk for extrapulmonary
tuberculosis. Exposure to environmental
tobacco smoke in children seems to enhance the hazards
of acquiring tuberculosis. Increased tuberculin reactivity,
in a dose-dependent manner, was recorded in smokers as
compared to non-smokers.
CONCLUSIONS: Although an association between smoking
and tuberculosis appears evident, prospective studies
would help to confirm the evidence and to highlight this
noxious association. Nevertheless, smoking should be
considered as an important risk factor for tuberculosis.
KEY WORDS: smoking; tuberculosis
TOBACCO USE, particularly smoking, is widely recognised
by the medical community as well as the general
public as a major public health problem. It is the
single most important preventable risk to human
health in industrialised countries, and an important
cause of premature deaths worldwide.1 The annual
tobacco-attributable mortality was about 1.7 million
in 1985, 3.0 million in 1990 and has been projected
to rise to 8.4 million by 2020.2 Smoking not only contributes
to mortality from pulmonary diseases, which
includes 87% of deaths from lung cancer and 82%
from chronic obstructive pulmonary disease; it also
contributes to cardiovascular diseases. It is responsible
for 21% of deaths from coronary heart disease
and 18% from cases of stroke.3 Risk from tobacco
smoke is not limited to the smoker alone but also
affects those around the smoker. The hazards of environmental
tobacco exposure are increasingly being
recognised. Exposure to environmental tobacco
smoke (ETS) increases the risk of lung cancer by 30%
and also contributes to work absenteeism in nonsmoking
adults due to respiratory illnesses.1
Tuberculosis has re-emerged to become the world’s
leading cause of death from a single infectious agent,
accounting for a quarter of the avoidable adult deaths
in the developing world.4 In 1992, when it was estimated
that approximately a third of the world’s
population (1.7 billion people) was latently infected
with Mycobacterium tuberculosis, the World Health
Organization (WHO) declared tuberculosis a ‘global
emergency’.4
Current opinion holds that the world is deluged by
three epidemics from tuberculosis. A resurgence of
tuberculosis first noticed in the early nineteen-eighties
was termed the ‘first epidemic’. Infection with the
human immunodeficiency virus (HIV) is the strongest
risk factor known for progression from latent infection
with M. tuberculosis to active disease.5 In addition,
newly infected persons have an increased risk of
developing primary disease, often with rapid progression.
6 This HIV-related tuberculosis, termed the ‘second
epidemic’, is also known as the ‘new tuberculosis’,
and bears only a resemblance to its older sibling.7
The surge of multidrug-resistant tuberculosis, designated
the ‘third epidemic’, is another challenge and
poses problems from both clinical and public health
perspectives. It is difficult to treat, requires longer
duration of therapy and puts an enormous economic
burden on the patient, the family, the health care
facilities and society at large. The emergence of HIVrelated
tuberculosis and multidrug-resistant tuberculosis
have brought into focus the importance of
Correspondence to: Professor Ashok Shah, Department of Respiratory Medicine, Vallabhbhai Patel Chest Institute, University
of Delhi, Delhi, India. Tel: ( 91) 11-543 3783. Fax: ( 91) 11-766 7420. e-mail: ashokshah99@yahoo.com, ashokshah99@
hotmail.com
Article submitted 15 January 2002. Final version accepted 23 July 2002.
REVIEW ARTICLE
Smoking and tuberculosis: an association overlooked 943
socio-economic conditions, including poverty, crowding,
homelessness, malnutrition, immigration and alcohol
abuse. Although it is a major health hazard, smoking
has unfortunately received social acceptance
worldwide. This harmful socio-economic factor is
less thought of as a contributor to the morbidity and
mortality of tuberculosis, and this prompted us to
review its influence or association with tuberculosis, a
disease that is pandemic.
SMOKING AND THE LUNGS
Smoking adversely affects many organ systems, but
the lungs suffer by far the most damage. It is well recognised
as a major risk factor for the development of
lung cancer and chronic obstructive pulmonary disease.
In addition, it is associated with other respiratory
diseases (Table 1).8 Smoking results in pathophysiological
changes in virtually all parts of the
lower respiratory tract, and includes peribronchial
inflammation and fibrosis, alterations in the epithelial
structure and function, vascular intimal thickening
and destruction of the alveoli.9
Functional aberrations caused by smoking comprise
decreased clearance of inhaled substances,
changes in pathogen adherence and abnormal vascular
and epithelial permeability.8 Bronchoalveolar
lavage (BAL) studies have shown that smokers had
manifold increase in the total number of cells recovered,
with a proportionally greater increase in the
number of macrophages and polymorphonuclear leukocytes
(PMNs) in the respiratory tract.10,11 The number
of lymphocytes in the BAL fluid was unchanged,
but the percentage of CD4 cells was increased, as
was the CD4/CD8 ratio.10 Smoking also affected the
appearance and function of pulmonary inflammatory
cells. Alveolar macrophages obtained by BAL were
larger in smokers than in non-smokers.12 They also
had abnormal surface morphology, characteristic
intra-cytoplasmic inclusions, and an impaired antigenpresenting
function.12 Immunoglobulin levels, too,
were increased in both BAL fluid and serum in smokers.
10 The mitogen response of pulmonary lymphocytes
was decreased in smokers, but not that of
peripheral blood lymphocytes.13 Smoking has been
associated with an increase in the number of neutrophils
in the blood,14 and with the alteration of neutrophil
chemotaxis from the vascular spaces into the lung.15
Dose-related increases in the concentrations of the
pro-inflammatory cytokines interleukin (IL)-1 and IL-8
in the BAL fluid of smokers and an altered macrophage
cytokine response to stimuli have also been reported.11
A reversible depression of natural killer-cell function
has been recorded among active smokers.16
The lungs of smokers are also subjected to increased
oxidative stress from the oxidants contained in cigarette
smoke and those formed in the lung.8 It has been
observed that there is a reduction in the serum antioxidant
levels of smokers and a decrease in the anti-oxidant
defences of the alveolar macrophages of older
smokers. This imbalance of oxidant and anti-oxidant
levels may result in tissue damage in the lungs of
smokers.
Physiologically, the lung functions are also affected.
The effect of cigarette smoking and smoking cessation
on lung function was documented by the prospective
trial by Fletcher and Peto.17 Tobacco smoking
is a potent etiological factor in the accelerated
decline of lung function, but cessation reduces the
rate of decline. Studies have also indicated that women
may be more susceptible than men to lung impairment
caused by tobacco. Among adolescent smokers,
lung function among girls begins to decline earlier
than in boys, while in adult smokers women’s lung
function decreases faster than men. Exposure to ETS
also results in impaired lung function.18,19 Children of
smoking mothers have poorer lung function as compared
to children of non-smoking mothers.20,21
HYPOTHESIS
Certain data support the biological mechanisms for
the association between smoking and pulmonary
tuberculosis. The occurrence of tuberculosis is thought
to be linked to altered immune response, multiple
defects in macrophage/monocyte immune responses
and CD4 lymphopenia22 and/or other mechanisms
such as hormonal effects and mechanical disruption
of cilia function or membrane competence.23 Tobacco
smoke could alter native and acquired resistance to
M. tuberculosis. Exposure to tobacco smoke also
results in morphological and functional changes in
the alveolar macrophages.12 All of these factors, in combination,
may contribute to increased susceptibility
of an individual to tuberculosis infection and occurrence
of the disease.
DATA SOURCES
The Medline database was used to search for articles
that had been published in the medical literature
(1966 to present) with the key words ‘smoking’ and
Table 1 Smoking associated respiratory diseases;8 incidence
or severity definitely or possibly increased by smoking
Common cold
Influenza
Bacterial pneumonia
Tuberculosis infection
Varicella pneumonitis
Pulmonary haemmorrhage
Pulmonary metastatic disease
Spontaneous pneumothorax
Eosinophilic granuloma
Respiratory bronchiolitis-associated interstitial lung disease
Idiopathic pulmonary fibrosis
Asbestosis
Rheumatoid arthritis-associated interstitial lung disease
944 The International Journal of Tuberculosis and Lung Disease
‘tuberculosis’. The bibliographies of all papers thus
located were searched for further relevant articles.
Any study, whether case-control, retrospective, crosssectional
or longitudinal, was included.
RESULTS
A total of 12 studies were found on searching the database.
A further search of the bibliographies of these
studies disclosed four more articles. The studies thus
included were published between 1956 to the present.
Five studies each were conducted in the UK and the
USA, two in Spain and one each in Australia, China,
Romania and Russia. Of the 16 studies, seven investigated
the link between active smoking and pulmonary
tuberculosis,23–29 one reviewed the data available,30 two
explored the link between alcohol, smoking and pulmonary
tuberculosis,31,32 one studied smoking, alcohol
and extra-pulmonary tuberculosis,33 one probed environmental
tobacco smoke and pulmonary tuberculosis,
22 and four examined smoking and tuberculin reactivity.
34–37 A review of these studies is presented.
Active smoking and pulmonary tuberculosis
There is a paucity of data regarding the association of
smoking with tuberculosis. Over the years, only a few
studies have assessed this association (Table 2).
The first ever study was conducted in the UK by
Lowe in 1956.24 In a case-control study, the smoking
habits of 1200 patients with tuberculosis were compared
with 979 controls. Results were compared
between patients of both sexes and a control group,
and also between 10-yearly age groups. He observed
that patients of over 30 years of age with pulmonary
tuberculosis of both sexes had a ‘highly significant
deficiency of non-smokers and light smokers and an
excess of moderate and heavy smokers’. This was in
comparison with controls (11.7% of males with
tuberculosis were non-smokers or had smoked fewer
than 10 cigarettes/day compared with 21.0% of the
controls, and 50.1% had smoked 20 or more cigarettes/
day compared with 43.4% of the controls.
Among females, 57.8% of patients with tuberculosis
were non-smokers or had smoked fewer than 10
cigarettes/day compared with 77.1% of the controls,
Table 2 Active smoking and pulmonary tuberculosis
Authors Year Country Study population
Type of
study Results
Lowe24 1956 England 1200 cases and
979 controls
Case-control No. of cigarettes/day 0–9 10–19 20
Males Cases 11.7% 38.1% 50.1%
Controls 21.0% 35.6% 43.4%
Females Cases 57.8% 30.8% 11.4%
Controls 77.1% 20.5% 2.4%
Edwards30 1957 England Analysed the
published data
Review Relative liability to tuberculosis ∝ (no. of cigarettes/day)3
[doubled at 8 and trebled at 27]
Adelstein &
Rimington25
1967 England 76 589
volunteers
Longitudinal Rate of tuberculosis ∝ no. of cigarettes smoked.
Rates per 1000
( 35 yrs of age)
Males Females
Non-smokers 0.53 0.40
1–9 cigarettes/day 1.13 0.90
10–19 cigarettes/day 2.47 1.46
20 cigarettes/day 3.17 4.25
Yu et al.26 1988 China 30 289
volunteers
Cross-sectional 202 pulmonary tuberculosis cases identified. (Prevalence
rate 6.67/1000). Relative risk of heavy smokers as compared
to non-smokers was 2.17 (95%CI–1.29-3.63).
Buskin et al.23 1994 America 151 cases and
545 controls
Case-control Risk of tuberculosis was 30%–50% higher among current and
former cigarette smokers than never smokers. Persons
smoking for 20 years had 2–3 times higher risk than never
smokers
Shprykov &
Zhadnov27
1994 Russia 297 cases and
141 controls
Case-control Smokers had more severe & disseminated pattern of
tuberculosis associated with slow involution of disease
and 10% had persistent bacillary discharge
Milhatan
et al.28
1995 Romania 485 hospitalised
patients with
pulmonary
tuberculosis
Cross-sectional 87.7% of males and 68.2% of females were smokers. This
figure far exceeded the frequency of smoking in the general
population
Alcaide
et al.29
1996 Spain 46 cases and
46 controls
Case-control Cigarette smoking favoured the development of pulmonary
tuberculosis in young infected adults who were in close
contact with recently diagnosed pulmonary tuberculosis
patients. OR 3.65 (95%CI 1.4–9.5; P 0.01) in active
smokers and when smoker was both active and passive,
OR 5.7 (95%CI 2.0–17.5; P 0.001)
Smoking and tuberculosis: an association overlooked 945
and 11.4% had smoked 20 or more cigarettes/day
compared with 2.4% of the controls). He also observed,
‘for both sexes there was in each ten yearly age group
a consistent excess of heavy smokers and deficiency of
light smokers and non-smokers when compared with
the corresponding control group’. The author concluded
that an association exists between smoking
and respiratory tuberculosis. He also postulated that
smoking may be an important cause of the breakdown
of healed or quiescent respiratory tuberculosis
in middle and late life and perhaps the principle reason
for the rapidly increasing sex difference in mortality
at these ages.
In 1957, Edwards analysed the published data to
evaluate the impact of cigarette smoking on respiratory
diseases, and in particular three of the major respiratory
causes of death in the UK, namely carcinoma
of the lung, tuberculosis and chronic bronchitis.30 He
estimated the relative liability of smokers towards a
given disease and found that the relative risk of tuberculosis
was approximately proportional to the cube
root of the number of cigarettes smoked daily (about
doubled at 8 and trebled at 27 cigarettes a day). Concurring
with Lowe, Edwards too felt that smoking in
young adults had ‘little influence on the acquiring of
infection, but may encourage the breakdown of old
infection’.
Adelstein and Rimington, in a longitudinal study
in 1967, recorded the smoking habits of 76 589 volunteers
undergoing mass miniature radiography and
analysed the relationship between smoking and pulmonary
tuberculosis.25 This was prompted by the observation
of Doll and Hill in 1966, quoted by the authors:
‘the relationship between smoking and mortality
from pulmonary tuberculosis is distinct, but with a
disease so influenced by social factors more precise
data are needed to justify a direct cause and effect
hypothesis’.25 The study found that the rate of tuberculosis
rises according to the number of cigarettes
smoked. In men aged over 35 years the rates per 1000
were 0.53 for non-smokers, 1.13 for smokers of 1–9
cigarettes, 2.47 for 10–19 cigarettes and 3.17 for 20
or more cigarettes a day. Similarly, in women aged
over 35 the rates per 1000 were 0.40 for non-smokers,
0.90 for smokers of 1–9 cigarettes, 1.46 for 10–19
cigarettes and 4.25 for 20 or more cigarettes a day.
The authors observed that among smokers of more
than 20 cigarettes per day, women had a higher tuberculosis
rate than men. They also found that smokers
with tuberculosis had a higher rate of sputum positivity
in each age and sex category. They argued that
smoking could possibly function as an expectorant
and facilitate the finding of tubercle bacilli in the sputum.
The author concluded that smoking could be a
factor in the difference in rates of tuberculosis between
men and women above 35 years of age.
Yu et al. conducted a cross-sectional study to analyse
the risk factors and prevalence of pulmonary tuberculosis
among health workers in Shanghai, China.26
Of the 30 289 subjects studied, 202 cases of pulmonary
tuberculosis were identified (prevalence rate
6.67/1000 population). Age over 50 years, males, history
of contact, heavy smokers and administrative
staff had a higher prevalence of tuberculosis. There
was an upward trend of risk with increased age and
the amount smoked: the older the age or the greater
the amount smoked, the higher the relative risk of
tuberculosis. The potential confounding factors, which
included age, sex, smoking history, history of contact,
area of housing and type of work, were then adjusted
for one another in a binomial regression model. The
results indicated that no statistically significant effects
in age, sex, and type of work were found after adjustment.
However, the relative risk of heavy smoking
and history of contact remained highly significant.
The relative risk of heavy smokers compared with
non-smokers was 3.64 (95% confidence interval [CI]
1.29–3.63), which was reduced to 2.17 when adjusted
with other factors. The relative risk of tuberculosis
for persons with a history of contact compared with
those without was 2.10 (95%CI 1.34–3.29). The
study showed that although males and old age were
associated with a higher risk of tuberculosis than
females and young age, these differences were due to
the smoking factor. The authors concluded that
smoking, and in particular heavy smoking, had a very
strong association with the prevalence of pulmonary
tuberculosis after simultaneous adjustment for other
factors.
Buskin and colleagues conducted a questionnairebased
case-control study in King County, Washington,
USA, from 1988 to 1990 to examine the risk factors
for tuberculosis in adults.23 Of the 14 321
patients attending the clinic during this period, 151
tuberculosis patients entered the study as case patients,
and another 545 non-tuberculous patients served as
controls. Socio-economic status (SES) was considered
based on family income, housing condition and years
of education. Low SES was defined as being in the
lower category with at least two of these factors. They
observed that relative to persons with higher income,
more stable living situations, and any post-secondary
education, persons with the lowest SES were approximately
four times more likely to develop tuberculosis.
The authors did not statistically adjust the relative
risk associated with smoking for the development of
tuberculosis with these socio-economic factors. They
found that current and former cigarette smokers had
a risk of tuberculosis of about 30%–50% higher than
that of never smokers. The risk associated with current
smoking was greatest for persons who had
smoked for 20 years or more. The risk in such
patients was two to three times higher than that of
never smokers. They also detected a slight trend
toward increasing tuberculosis risk with an increasing
number of cigarettes per day.
946 The International Journal of Tuberculosis and Lung Disease
From Russia, Shprykov and Zhadnov in 1994 reported
a retrospective case-control study on the
effects of tobacco smoking on the course of infiltrative
pulmonary tuberculosis among 297 smoking and
141 non-smoking patients.27 They observed that
smokers had a more severe disseminated pattern,
with pulmonary tissue destruction and bacterial discharge
associated with slow involution of the disease,
and prolonged hospital stay. Sputum conversion
occurred in all of the non-smokers, but 10% of the
smokers had persistent bacillary discharge. Similarly,
cavity closure was achieved in 76% of non-smokers
as compared to 58% of smokers. They advocated a
strong anti-smoking educational programme for
patients with pulmonary tuberculosis who continued
to smoke.
Milhatan and colleagues, in a cross-sectional study in
Romania, reported the association of smoking and pulmonary
tuberculosis among 485 hospitalised patients.28
They recorded a very high frequency of smoking in
these patients: 87.7% of males and 68.2% of females.
The authors observed that this figure far exceeded the
frequency of smoking in the general population.
A recent case-control study from Barcelona, Spain,
assessed the influence of cigarette smoking on the
development of active pulmonary tuberculosis in
young people who were in close contact with a case of
newly diagnosed sputum-positive pulmonary tuberculosis.
29 They included 46 subjects who were in close
contact with a sputum-positive patient and who themselves
had active pulmonary tuberculosis. The 46 subjects
in the control group had a positive tuberculin
reaction but no bacteriological or clinico-radiological
evidence of pulmonary tuberculosis. The smoking
habits of both groups were investigated with the help
of a questionnaire. The patients were categorised as
active and passive smokers as per WHO criteria.38
Occupation and socio-economic status were codified
according to their National Occupational Classification,
in which groups I–III correspond to the most
highly qualified occupations (professionals, directors,
businessmen, technicians, salesmen, etc.), groups IV–V
to those in the hotel trade, housekeeping, agriculture,
etc., and group VI to those who were not classified
under any occupation, such as students, unemployed,
retired, pensioners, etc. Seventy-two per cent of cases
and 41% of controls were considered active smokers,
whereas 76% of cases and 54% of controls were considered
passive smokers. It was found that cigarette
smoking favoured the development of pulmonary
tuberculosis in young infected adults who were in
close contact with recently diagnosed cases of pulmonary
tuberculosis. The crude odds ratio (OR) was
3.65 (95%CI 1.4–9.5; P 0.01) in active (daily plus
occasional) smokers, and had the highest value when
the smoker was both active (daily) and passive (OR
5.7; 95%CI 2.0–17.5; P 0.001). The adjusted OR
for age, sex and socio-economic status had statistically
significant differences in active smokers (daily
and occasional) (P 0.01), and in daily smokers (P
0.05). The crude OR of passive smokers (OR 2.7;
95%CI 1.01–7.2) had statistically significant differences
(P 0.05), but become non-significant when
adjusted (OR 2.5; 95%CI 1–6.2). These data showed
an association between smoking and pulmonary tuberculosis
and the risk of becoming diseased when
infected by M. tuberculosis increased when the person
was both an active and passive smoker. The multiple
logistic regression model showed that only smoking
was independently associated with pulmonary tuberculosis;
the adjusted OR was 3.8 (95%CI 1.5–9.8) for
active smoking. There was also a dose-response relationship
between the number of cigarettes the person
smoked daily and the risk of active pulmonary tuberculosis.
The authors concluded that cigarette smoking
was a risk factor for pulmonary tuberculosis in young
people, and that there was a dose-response relationship
with the number of cigarettes consumed daily.
Alcohol, smoking and pulmonary tuberculosis
Two studies assessed the influence of tobacco smoking
and alcohol consumption on tuberculosis (Table 3).31,32
In 1961, Brown and Campbell conducted a casecontrol
study with the help of a questionnaire to
Table 3 Alcohol, smoking and pulmonary tuberculosis
Authors Year Country
Study
population Type of study Results
Brown &
Campbell31
1961 Australia Victoria
Cases 102
Controls 104
Queensland
Cases 306
Controls 221
Case-control Definite deficiency of non-drinkers and light drinkers of alcohol
amongst the tuberculous group was seen, which had an
excess of heavy consumers of alcohol (P 0.001). Smokers
were in excess amongst tuberculous patients merely because
heavy drinkers were likely to be heavy smokers. The
relationship between tuberculosis and alcohol was more
direct and was independent of smoking habits.
Lewis &
Chamberlain32
1963 England Cases 100
Controls 200
(two groups
of 100
controls
each)
Case-control An excess of regular drinkers in the pulmonary tuberculosis
group compared with both control groups was seen. The
difference in each case was found to be significant (P
0.01). Proportion of smokers in all three groups was similar.
This study offered ‘no support for the contention that
smoking predisposes to pulmonary tuberculosis’
Smoking and tuberculosis: an association overlooked 947
determine the influence of tobacco smoking and alcohol
consumption on tuberculosis.31 The smoking
habits and alcohol consumption of 102 consecutive
tuberculosis patients were compared with 104 controls
in Victoria, Australia. Another group of 306
tuberculosis patients in Queensland was also enrolled,
and their smoking habits were compared with 221
controls. The authors observed ‘a definite deficiency
of non-drinkers and light drinkers of alcohol amongst
the tuberculous group, which had an excess of heavy
consumers of alcohol’. The difference was highly significant
(P 0.001). They also found a significant
excess of tobacco consumption amongst the tuberculous
group in Victoria (0.05 P 0.02) and in Queensland
(P 0.001). They then determined whether heavy
alcohol and tobacco consumption were more common
in the same individual or whether either or both
were linked with an increased incidence of tuberculosis.
The authors felt that ‘smoking and drinking habits
tend to be linked together quite independently of
tuberculosis. Consequently only one of the habits
need be related to tuberculosis for both to be found
excessive in the tuberculous group’. When the authors
matched the tuberculous groups and controls according
to alcohol consumption they found that the study
group had a similar distribution of smokers as the
controls, with no statistical difference. In contrast,
when the tuberculous groups and the controls were
matched according to the amount of tobacco smoked,
there was still an excess of heavy consumers of alcohol
in the study group (P 0.001). It appeared to
the authors that ‘smokers are in excess amongst
tuberculous patients merely because heavy drinkers
are likely to be heavy smokers. The relationship
between tuberculosis and alcohol is more direct and is
independent of smoking habits’. The authors were of
the opinion that their study supported the observations
made by Lowe that tuberculous patients smoked more
heavily than controls. However, they were unable to
show a direct relationship between smoking and
tuberculosis. They thus concluded, ‘of the two habits,
alcohol and not smoking was more directly associated
with tuberculosis’.
In 1963, Lewis and Chamberlain, in London, UK,
conducted a case-control study to determine the effect of
alcohol consumption and smoking habits on the development
of tuberculosis in male patients.32 One hundred
patients with tuberculosis were taken as cases; two
groups comprising 100 non-tuberculous patients each,
matched for social class and for age by decade from two
different hospitals, served as controls. The authors
observed ‘an excess of regular drinkers in the pulmonary
tuberculosis group compared with both control
groups’ and the difference in each case was found to be
significant ( 2 12 and 6.82 for both control groups,
respectively, P 0.01). They also found that the proportion
of smokers in all three groups was similar, and
that their study offered ‘no support for the contention
that smoking predisposes to pulmonary tuberculosis’,
although the authors expected most smokers to be in the
tuberculous group because of the known association
between smoking and drinking. An excess of drinkers
in the tuberculosis group was present irrespective of
smoking habit. The authors concluded that a significant
excess of regular drinkers was found in the tuberculous
patients and that they did not smoke more than
those in the control groups. The authors also felt that
their study gave no evidence that indirect factors such
as occupation, marital status, smoking habit or race
were in any way linked with the data obtained by them.
Smoking, alcohol and extra-pulmonary tuberculosis
Smoking has also been implicated as a risk factor for
extra-pulmonary tuberculosis.33 A retrospective crosssectional
study was conducted in Spain in 107 patients
with extra-pulmonary tuberculosis. The most common
forms of the disease were tuberculous pleural
effusion (29%) and genito-urinary (22%) and lymph
node disease (20.5%). The authors observed that
smoking and alcohol (53.6% and 36.5%, respectively)
were the greatest risk factors.
Environmental tobacco smoke and tuberculosis
The Barcelona group also assessed the effect of passive
smoking on the development of active tuberculosis
in children immediately after detection of a new
case of sputum-positive pulmonary tuberculosis in
the family.22 In this case-control study, the authors
included 93 cases (contacts who developed active
pulmonary tuberculosis) and 95 controls (tuberculinpositive
children without evidence of active disease)
in their study. All these children were household contacts
of the newly diagnosed cases of bacillary pulmonary
tuberculosis. To obtain information on passive
exposure to cigarette smoke, a specially designed
questionnaire was administered. Occupation and
socio-economic status were also assessed and codified
according to the National Occupational Classification
described previously. Other indicators of
socio-economic status were also investigated, such as
type of housing and overcrowding. The authors then
compared the degree of exposure to passive smoking
among the study and control groups. They found
that passive smoking was a risk factor for the development
of pulmonary tuberculosis immediately following
infection with M. tuberculosis (OR 5.29;
95%CI 2.33–12.82; P 0.00005). They also
observed that when passive smoker contacts were
exposed both at home and outside the home the risk
increased (OR 6.35; 95%CI 3.20–12.72; P
0.00001), but there was no statistically significant
difference between both ORs. Among the indicators
of SES analysed, only the father’s social class IV–V
was a risk factor for tuberculosis (OR 2.17; 95%CI
1.16–4.07); other indicators did not achieve statistically
significant values as risk factors of tuberculosis.
948 The International Journal of Tuberculosis and Lung Disease
The association between passive smoking at home
and pulmonary tuberculosis immediately following
infection persisted after adjusting for children’s age
and socio-economic status (OR 5.39; 95%CI 2.44–
11.91; P 0.00001). There was a dose-response
relationship between the number of cigarettes members
of the family smoked daily and the risk of contracting
tuberculosis. The risk increased when contacts
were passive smokers both at home and outside
the home within the family (OR 6.35; 95%CI 3.20–
12.72; P 0.00001). Contacts aged 0–4 and 5–9
years showed a significantly higher risk than those
aged 10 years. Urinary cotinine concentration, a
major metabolite of nicotine, was used as the objective
biomarker of exposure. The mean ( standard
deviation) urinary cotinine concentration was
119.46 (68.61) ng/ml in contacts who became cases
and 91.87 (73.10) ng/ml in contacts who did not
become cases. This difference of urinary cotinine
concentration was highly significant (P 0.001).
The author concluded that passive exposure to
tobacco smoke in children was associated with an
increased risk of developing pulmonary tuberculosis
immediately following infection.
Smoking and tuberculin reactivity
The effect of smoking on tuberculin reactivity has
also been documented (Table 4). Kuemmerer and
Comstock in 1967 studied various social factors,
including smoking, that affected the tuberculin sensitivity
among junior and high school students in the
state of Maryland in America.34 In this cross-sectional
study, they examined the relationship of the students’
tuberculin sensitivity to a history of smoking by the
head of the household and by the spouse if present. It
was found that tuberculin sensitivity was not associated
with a history of smoking by either parent alone.
On the other hand, for students whose parents both
smoked, ‘the frequency of large reactions (11 or more
mm induration) was more than twice as high as for
those with at least one non-smoking parent’. The frequency
of small reactions (2–10 mm induration) was
only slightly increased if either parent smoked.
This study also assessed other sociological concomitants
of tuberculin sensitivity. The authors analysed
the association of the education of the parent
classified as head of the household with frequency of
reaction to tuberculosis. They observed that large tuberculin
reactions were more commonly found among students
whose parents had completed less than 12
grades of schooling; for small reactions, the trend was
reversed, with a slight excess among children of bettereducated
parents. The frequency of reactions was also
examined in relation to present residence and immigration.
Large reactions were more common among
urban than rural residents, while the rate of small
reactions was higher among immigrants. When these
two factors were examined in combination, there was
a slightly higher prevalence of large reactions (18.6/
1000) among students who were urban residents and
who had lived in Washington county all of their lives.
The prevalence of small reactions among urban immigrants
was 57.2/1000. Students living in crowded
homes were found to have larger reactions than those
living in less crowded conditions. The authors, however,
did not statistically adjust the socio-economic
factors in relation to smoking and were thus unable
to comment upon the effect of these factors on tuberculin
positivity with regard to smoking.
In 1993, Nisar and colleagues, from the UK, conducted
a cross-sectional study by tuberculin testing to
evaluate the frequency of tuberculous infection in residents
of homes for the elderly.35 Heaf testing was
conducted in 2665 residents (75% women) and a detailed
questionnaire, which included smoking habits,
was also completed. The authors sought to study the
relationship of tuberculin reactivity to the length of
stay, but were unable to detect any correlation. How-
Table 4 Smoking and tuberculin reactivity
Authors Year Country
Study
population Type of study Results
Kuemmerer &
Comstock34
1967 America 7787 volunteers Cross-sectional Frequency of large reactions in tuberculin test was more
than twice as high for students whose parents both
smoked as for those with at least one non-smoking
parent.
Nisar et al.35 1963 England 2665 volunteers Cross-sectional Smoking was associated with increased Heaf grade reaction.
For ex-smokers, OR was 1.20 and it was 1.59 for
current smokers as compared with never smokers.
Anderson et al.36 1997 America Prison inmates
in South
Carolina
Case-control Inmates who smoked 1–20 cigarettes/day (OR 1.32,
95%CI 0.76–2.31) and those who smoked 20
cigarettes/day (OR 1.75, 95%CI 0.83–3.71) prior to
incarceration, were more likely to become converters
during incarceration than non-smokers, suggesting a
dose-response effect.
McCurdy et al.37 1997 America Migrant farm
workers in
California
Cross-sectional Significant relationship between the prevalence of
tuberculin skin test reactivity and smoking status was
detected. OR was 3.11 for former smokers and
OR 1.87 for current smokers.
Smoking and tuberculosis: an association overlooked 949
ever, the study revealed an unexpected finding that
smoking appeared to be associated with an increased
Heaf grade reaction, with ex-smokers having an OR
of 1.20 and current smokers an OR of 1.59 as compared
with never smokers. Increased smoking, assessed
in pack years, was also found to be associated with a
stronger Heaf grade in both current and ex-smokers.
In summary, smokers had significantly stronger Heaf
tests than ex-smokers, who in turn had stronger tests
than non-smokers. The authors stated that they were
the first to detail the tuberculin status in smokers and
concluded that smoking and male sex was associated
with increased Heaf test positivity.
The findings of Nisar et al.35 appeared to be supported
by two studies from the USA.36,37 Anderson
and colleagues conducted a case-control study among
prison inmates in South Carolina to determine whether
smoking played a role in tuberculin test conversion.36
Inmates who smoked 1 to 20 cigarettes per day prior
to incarceration (OR 1.32, 95%CI 0.76–2.31), and
those who smoked 20 cigarettes per day prior to
incarceration (OR 1.75, 95%CI 0.83–3.71) were
more likely to have become converters during incarceration
than non-smokers, suggesting a dose-response
effect. The authors observed that the main findings of
their study indicated that smokers were more likely to
become tuberculin skin test converters during incarceration
than non-smokers. The authors concluded
that the cumulative effects of smoking could be more
important than the number of cigarettes smoked with
regard to tuberculin skin test conversion. Another crosssectional
study of Californian migrant farm workers
also detected a significant relationship between the prevalence
of tuberculin skin test reactivity and smoking status.
37 The relationship was stronger for former smokers
(OR 3.11) than for current smokers (OR 1.87).
Socio-economic factors, smoking and tuberculosis
Socio-economic factors are closely related to tuberculosis.
This disease, which affects all sections of society,
disproportionately affects socially and economically
disadvantaged communities.22 Socio-economic
level is a potential confounding factor, because in
addition to being a risk factor for tuberculosis, occupational
status is associated with cigarette smoking.
In the above studies, socio-economic factors failed to
significantly affect the development of tuberculosis
when adjusted with smoking (active or passive). In
the five studies, the effect of socio-economic factors on
tuberculosis was discussed.22,23,26,29,34 Three studies
were from those discussing the relationship between
active smoking and pulmonary tuberculosis,23,26,29
and one each from those analysing the relationship
between passive smoking and tuberculosis22 and
between smoking and tuberculin reactivity.34 In the
two studies, one by Yu et al.26 and another by Alcaide
et al.,29 socio-economic factors such as history of contact,
area of housing, type of work and education
were found to be associated with tuberculosis, but the
relationship became non-significant when these factors
were adjusted with smoking. Altet et al. found
that only the father’s social class IV–V was a risk factor
for tuberculosis (OR 2.17; 95%CI 1.16–4.07);
other indicators such as type of housing and crowding
did not achieve statistically significant values as risk
factors of tuberculosis.22 Kuemmerer and Comstock34
also discussed the effect of socio-economic factors
such as education, overcrowding and immigration on
tuberculin reactivity, and reported an increased sensitivity.
However, these factors were not statistically
adjusted with smoking.
CONCLUSION
A review of the literature suggests that smoking could
be considered an important risk factor for the development
of tuberculosis. All seven studies on active
smoking and tuberculosis demonstrated a direct relationship,
23–29 and four studies even showed that the
rate of developing tuberculosis was directly proportional
to the number of cigarettes smoked.23–25,29 In
one study, it was hypothesised that smoking may be
an important cause of the breakdown of healed or
quiescent respiratory tuberculosis in middle and late
life, and perhaps the principle reason for the rapidly
increasing sex differences in mortality at these ages.24
Another study showed that cigarette smoking favoured
the development of pulmonary tuberculosis in young
infected adults who were in close contact with recently
diagnosed cases of pulmonary tuberculosis.29 The
two studies on alcohol, smoking and pulmonary
tuberculosis demonstrated a strong link with alcohol,
but were unable to show a direct link with smoking.
One study showed an indirect relation with smoking,31
while the other was unable to link smoking to pulmonary
tuberculosis.32 Not only does active smoking
appear to heighten the chances of contracting pulmonary
tuberculosis, smokers also seem to be at an
increased risk for extra-pulmonary tuberculosis.33
Exposure to ETS in children was also found to be
associated with an increased risk of developing pulmonary
tuberculosis immediately following infection.
22 Four studies analysed the relationship between
tuberculin reactivity and smoking.34–37 Greater tuberculin
reactivity in a dose-dependent manner was
observed among current smokers than in ex-smokers,
who in turn had stronger tests than non-smokers.
A mounting body of evidence has emerged to
incriminate smoking as an important risk factor for
the development of tuberculosis. The effect of ETS on
the development of tuberculosis in children also needs
to be viewed with great concern.22 However, this
adverse association is yet to receive the attention it
deserves from physicians treating tuberculosis. This is
highlighted by the fact that there is hardly any emphasis
on recording the history of smoking in a patient
950 The International Journal of Tuberculosis and Lung Disease
with tuberculosis. Cough in smokers is usually attributed
to smoking, and this often results in a diagnostic
delay in a patient with tuberculosis who smokes.
Another factor that could possibly explain the lack of
awareness of this ominous association is that it has
been overshadowed by the direct link that has been
established between smoking and graver diseases such
as carcinoma of the lung, chronic obstructive pulmonary
disease (COPD) and ischaemic heart diseases.
Although an association between smoking and
tuberculosis appears evident, prospective studies would
help to confirm the available data and to highlight this
noxious association. Nevertheless, smoking should be
considered as an important risk factor for tuberculosis.
All efforts must be made to check the initiation of
smoking in teenagers so as to avoid nicotine addiction
and prevent the morbidity and mortality caused by
this self-inflicted scourge of humanity.