Early Onset Emphysema in Smokers with Additional Exposure to Toxic Fumes; Occurrence and Diagnosis
Mehdi Mir Mohammad,
The aim of this study was to determine the occurrence
of emphysema and accuracy of Pulmonary Function Test (PFT), comparing
with chest High Resolution Computed Tomography (HRCT), in smokers with
history of exposure to toxic fumes (Sulfur Mustard; SM). This was a cross
sectional study (2003-2004) on 20 symptomatic smokers with mild SM exposure
(Group 1) and 20 smokers without SM exposure (Group 2). PFT and chest
HRCT were performed for all patients to detect emphysema. Sensitivity,
specificity and positive and negative predictive values were calculated
for PFT. Spirometry did not diagnose emphysema in group 1 while chest
HRCT diagnosed five patients (sensitivity = 0). Group 2 developed emphysema
(11 of 20, 55%) more frequently than group 1 (5 of 20, 20%, p<0.05).
No alpha-1 antitrypsin deficiency was found in all 70 individuals. We
conclude that smokers with an additional risk factor, such as exposure
to toxic fumes, develop emphysema at younger ages while they have normal
PFT. Chest HRCT should be regarded as a useful tool in the early diagnosis
of emphysema in such cases.
Emphysema is morphologically defined as the permanent enlargement of
airspace distal to the terminal bronchiole and the destruction of its
wall with no obvious fibrosis. Aging and cigarette smoking are its main
causes (Snider et al., 1985). Alpha-1 antitrypsin deficiency is
a genetic condition that can lead to early onset emphysema (Wewers, 1989).
The principal methods used to detect emphysema are Pulmonary Function
Tests (PFT) and chest radiological examination (Burrows, 1974; Sanders,
1991; Thurlbeck and Muller, 1994). However, these methods are not sensitive
enough to detect earlier morphological and functional abnormalities of
the small airways (Kubo et al., 1999). High Resolution Computed
Tomography (HRCT) has thus been actively applied for morphological assessment
of the extent and severity of emphysematous alterations (Soejima et
Some studies showed that air trapping may not be in relation with PFT
result abnormalities (Mastora et al., 2001). PFT may not detect
subtle longitudinal changes in acinar structures caused by special factors
like aging and smoking (Soejima et al., 2000). When an additional
respiratory risk as exposure to toxic fumes exists the condition of symptom
occurrence and diagnosing approach may differ. Concerning the high prevalence
of such exposure (in cities and industries) would lead us to approach
emphysema in patients with more than one risk factor.
As a known respiratory toxin, sulfur mustard (SM) is well known to cause
pulmonary damages (Ghanei et al., 2004a). Bronchiectasis and increased
thickening of bronchial wall can be detected in chest HRCT images (Ghanei
et al., 2004b; Bagheri et al., 2003). Some studies suggest
that SM can cause emphysema along with other known complications (Bagheri
et al., 2003). But recently, after removal of confounding factors
like smoking we showed that emphysema could not correlate with exposure
to SM (Ghanei et al., 2004a). Significant air trapping and mosaic
pattern were reported as the most frequent radiological findings in both
symptomatic as well as asymptomatic patients (Ghanei et al., 2004a;
Dompeling et al., 2004; Emad et al., 1995). We aimed to
study the occurrence of emphysema and accuracy of Pulmonary Function Test
(PFT) in smokers with history of
exposure to toxic fumes (SM). PFT results were compared with chest HRCT
findings in symptomatic smokers with/without history of exposure to SM.
MATERIALS AND METHODS
This was a cross sectional study on two different groups of current smokers
with a respiratory symptom: Group 1 (20 patients) had a history of SM
exposure while Group 2 (20 patients) did not. These groups were studied
along with 10 non smoker males with history of SM exposure (Control 1)
and 20 without any exposure to SM (Control 2). All subjects were recruited
from volunteers consulted the Baqiyatallah University Hospital between
2003 and 2004, with a respiratory complain.
Patients with exposure to SM (group 1 and control 1) were considered
as; Exposed group while others without any SM exposure considered as Non-exposed
group. Those in exposed group with pre-exposure respiratory disease/s
were excluded from the study.
Exposed patients were those who had been in SM contaminated area during
Iran-Iraq war. We defined SM contaminated area as regions which were attacked
by chemical missiles or bombardment based on the army documentations.
Patients with high dose exposure can not usually keep on smoking due to
their respiratory problems. Thus our subjects were selected among all
those who had registered for annual checkup, due to subclinical (mild)
exposure. Subclinical exposure was defined as absence of any acute symptom
at the time of exposure (Sartin, 2000). Individuals who were present in
contaminated areas without any acute signs and symptoms at the time of
exposure entered our study. We excluded those who had even minor symptoms
like lacrimation, cough, red eyes, or any other at the time of exposure
(Epler, 2001). Accidental exposure to residual SM in the environment after
chemical attacks was another documented form of exposure. We excluded
patients with following concurrent and potentially confounding conditions:
Having dusty jobs, problems with lung involvement such as collagen vascular
diseases, immunological disorders, heart diseases, organ transplantation,
radiation therapy, chronic thyroidits, recurrent pulmonary infectious
diseases, or even use of drugs like phenytoin, bleomycin, methotrexate,
or carbamazepin, which are known to have etiologies of drug-induced lung
diseases (Epler, 2001). In all 70 subjects chest HRCT and PFT were performed.
Alpha-1 antitrypsin serum level was checked for all patients.
Chest high-resolution computed tomography: All patients were imaged
on an axial GE Hi-speed Advantage CT scanner (FXI-plus; GE Medical Systems,
Milwaukee, WI) at 120 kVp and 200 to 250 mA with 1 mm collimation and
10 mm intervals from proximal trachea to the diaphragm. The scans were
obtained in the supine position in deep inspiration and also in deep expiration
at the supra aortic arch, aortic arch, carina and 5 to 10 cm below the
carina according to the method used by Aquino and colleagues Remy-Jardin
et al. (1993a). The films were reviewed using eFilm workstation
(eFilm Medical, Toronto, ON, Canada) and the anteroposterior diameter
of the trachea and bronchi in each cut was measured by this program with
a precision of 1 mm. Air trapping was evaluated in three of the four obtained
anatomical levels in each case: Upper lung zone, defined as the level
of superior aspect of aortic arch; middle lung zone, defined as the level
of carina; and lower lung zone, defined as the level 5 to 10 cm below
the carina, according to the method used by Zhang et al. (2004).
Air trapping was defined as the presence of a radiolucent region of the
lungs on expiratory images (Lee et al., 2000; Austin et al.,
1996). The degree of air trapping was assessed by comparing end inspiratory
and expiratory images from the same anatomic level and grading each of
the three levels on a 5-point scale: 0, no air trapping; 1, 1-25% cross-sectional
area affected; 2, 26-50% cross-sectional area affected; 3, 51-75% cross-sectional
area affected and 4, 76-100% cross-sectional area affected. A total air-trapping
score was obtained by summing the individual grades for the three levels
(maximum possible score, 12 for each lung and 24 for both) (Zhang et
al., 2004). Emphysematous destruction was identified as areas of low
attenuation and hypovascular regions in the lungs (Foster et al.,
1986; Gurney et al., 1992).
Previous studies have shown good intra-and interobserver correlations
for the subjective estimation of emphysema (Foster et al., 1986;
Morrison et al., 1989). Hence all radiographs were interpreted
by a chest radiologist who had no knowledge of the clinical, functional
or SM exposure history.
Pulmonary function tests: Spirometry was performed according to
American Thoracic Society criteria and results were expressed as a percentage
of the expected (predicted) normal values (Quanjer et al., 1993).
The FVC and FEV1 were measured, under the direction of physicians,
using a standard spirometer (Jaeger, Hochberg, Germany). Subjects were
seated with a nose clip in place and were asked to perform at least three
forced expiratory maneuvers. Both the patients and the technician received
visual feedback from a monitor during the test, which was repeated until
three technically satisfactory curves with reproducible contour were obtained.
All the indices used for the analysis were derived from the same maneuver,
which was the one with the largest FVC. COPD diagnosis was based on what
GOLD experts had defined; FEV1/FVC ratio <70% (National
Institutes of Health, 2003).
Statistical analysis: The data in the text and tables are presented
as means±SD. Median was obtained for air trapping grade and t-test
was applied to compare means. We used Man Whitney test where data did
not show normal distribution. Percentage of PFT and chest HRCT findings
and patients symptoms were calculated. Chi square was applied to compare
percentages. PFT diagnostic values including: sensitivity, specificity
and positive and negative predictive values (PPV, NPV) were calculated.
All statistic methods were performed by SPSS (11) while a p-value of less
than 0.05 was considered significant.
RESULTS AND DISCUSSION
PFT (FEV1/FVC) was not able to diagnose emphysema in group
1 while chest HRCT had confirmed the diagnosis in five patients (PPV =
0, Table 1). FEV1/FVC was 100% sensitive to
COPD in group 2 (Table 1).
In average, group 2 were older than group I (Table 2).
As it is shown in Table 2, FEV1/FVC results
showed more abnormal values among group 2 (16 of 20, 80%) than in group
1 (3 of 20, 15%, p<0.05). According to chest HRCT results group 2 developed
emphysema (11 of 20, 55%) more frequently than group 1 (5 of 20, 20%,
p<0.05). All five emphysematous patients had grade 1 of the disease.
Two of 11 emphysematous patients in group 2 showed grade 2 of emphysema
while remaining (9 of 11) showed grade 1. However the difference of emphysema
grade between groups was not significant (0.056).
Group 1 had higher grade of air trapping (median, 2.5) than group 2 (1)
while this was not statistically significant (p = 0.3). In general, chemical
patients had higher grade of air trapping than non exposed subjects (2.0,
||Diagnostic values of FEV1/FVC
|FEV1: Forced Expiratory Volume in one second;
FVC: Forced Vital Capacity PPV: Positive Predictive Value, NPV: Negative
Predictive Value, Values are presented as present (95% CI)
||Age, spirometry results and air trapping in different
groups of the study
|Values are expressed as mean±SD. FEV1:
Forced Expiratory Volume in one second; FVC: Forced Vital Capacity.
*p<0.05 compared with group 1
||Prevalence (%) of different respiratory symptoms among
There were no significant difference in age between exposed group (mean±SD,
42.33±6) and non exposed group (42.23±12.8, p = 0.96). The
median of cigarette smoking was 1.5 (pack/years) in group 1 and 17.5 (pack/years)
in group 2 (p<0.05). No emphysema was found in non smokers either in
control 1 or in control 2.
Cough and sputum were more frequent in cigarette smokers with history
of SM exposure while other symptoms did not differ between groups (Table
According to chest HRCT findings, different subtypes of emphysema had
similar prevalence in group 1 (p = 0.19). Where as, central (7 of 40,
35%) and para-septal emphysema (7 of 40, 35%) were the most common subtypes
in group 2 (p<0.05). No alpha1-antitrypsin deficiency was found in
all 70 individuals.
PFT (FEV1/FVC) could not discriminate emphysematous patients
in smokers with history of SM exposure. However it has a good diagnostic
value in non exposed smokers (PPV = 60%, sensitivity = 100%). Smokers
with history of SM exposure experienced respiratory symptoms earlier than
other smokers. In average they were about 12 years younger than others.
Thus other factors, except alpha-1 antitrypsin deficiency, may cause symptomatic
emphysema in younger ages than expected. Comparing with non exposed smokers,
smokers with SM exposure are suffering from similar symptoms, with lower
grades of emphysema in younger ages. As smokers in Exposed group had more
risk factors for respiratory problems, they showed more cough and sputum
than others even in younger ages along with higher grades of air trapping.
We assume that when symptomatic emphysema occurs in younger ages than
expected, a previous exposure to a respiratory toxin (i.e., SM) should
be suspected. Concerning that our patients had sub clinical exposures
to SM, we suggest that even mild exposure to toxic fumes may accelerate
emphysema and related respiratory symptoms. Thus even patients do not
remember any acute symptoms of exposure to respiratory toxins; previous
exposure to toxic fumes should be taken into account in early onset emphysema.
On the other hand in such conditions routine spirometry is not accurate
enough and chest HRCT will be the modality of choice to diagnose emphysema.
Previous studies on patients with symptoms of emphysema found a good
correlation between chest HRCT and lung function tests (Remy-Jardin
et al., 1993a, b). But recent studies reported that chest HRCT revealed
emphysematous change in smokers, despite normal PFT (Remy-Jardin et
al., 1993b). Sanders et al. (1988) found CT evidences of emphysema
in 69% (24/35) of patients who did not have functional findings of emphysema.
Similar findings have been recently reported by Lee et al. (2000)
who observed that PFT results were within normal ranges in all participants,
regardless of the presence of air trapping. FEV1 and FEV1/FVC%
could be also close to normal and almost identical among smokers with
and without emphysematous lesions (Tylen et al., 2000).
This apparent discrepancy may be due to the possibility of identifying
focal abnormalities on CT scans, whereas the spirometric measurements
provide a more global measure of lung function (Tylen et al., 2000).
Accordingly, cigarette smokers with previous exposure to respiratory toxins
are susceptible to develop emphysema at younger ages while spirometry
is not fully capable of diagnosing emphysema in them. Thus routine screening
tests in patients with known history of exposure to toxic fumes should
include chest HRCT beside PFT especially in symptomatic individuals.
Chest HRCT is the modality of choice for diagnosing early emphysema in
symptomatic smokers with an additional risk factor of respiratory disease
(as SM exposure). Although measurements of residual volume, total lung
capacity and inspiratory capacity might be predictive of pulmonary hyperinflation,
FEV1/FVC which is usually performed in routine spirometry would
not help. It was previously shown that chest HRCT may be more useful in
the early diagnosis of smoking-related lung disease (Tylen et al.,
2000). It allows detection of emphysema in symptomatic smokers even when
pulmonary function appears to be normal and mild emphysema is assumed
(Sanders et al., 1988; Srinakarin et al., 2003). Chest HRCT
scans provide sensitivity of 100% and a specificity of 91% in comparison
with pathology (Quanjer et al., 1993). Thus chest HRCT should be
performed for symptomatic current smokers with even mild exposure to respiratory
toxins in order to detect emphysema early on.
SM exposure does not cause emphysema. Similar to normal population, chest
HRCT of exposed patients showed less areas of emphysema or air trapping
in non smokers than smokers (Lee et al., 2000; Remy-Jardin et
al., 1993a, b; Ghanei et al., 2006). Primarily, emphysema was
reported in association with SM exposure, but concerning confounding effect
of smoking, evidences did not support the correlation between emphysema
and exposure to SM (Ghanei et al., 2004a, b). No emphysema was
found in nonsmokers. That`s why cigarette smoking is the main cause of
emphysema in SM exposure as well as general population (Snider et al.,
1985; Soejima et al., 2000).
Emphysema increases significantly with age. As age increases, lung undergoes
a predictable set of morphologic changes, which include increased alveolar
duct air; decreased complexity of the alveolar surface or surface to volume
ratio; loss of alveolar wall tissue, elastic tissue and bronchiolar muscle
and increased frequency of emphysema (Lee et al., 2000). Considering
that group 2 were older than group 1, we can say that chest HRCT was more
helpful in group 1 because of earlier stage of disease. Group 2 developed
emphysema (11 of 20, 55%) more frequently than group 1 (5 of 20, 20%).
Alternatively, results showed a higher grade of emphysema in non exposed
smokers than the other group but it was not statistically significant.
Emphysema and chronic bronchitis are a significant cost burdens to society,
which together accounted for $14.5 billion in direct costs in 1996 in
United States. Per patient costs demonstrate the higher disease severity
of emphysema patients (Wilson et al., 2000). This study may lead
us to diagnose emphysema in younger ages and also early stages, in symptomatic
smokers with exposure to hazardous materials so that we can reduce hospitalization
and medication burden which account for most of the costs (Wilson et
al., 2000). Previous studies showed that knowledge of risk factor
(i.e., alpha-1 antitrypsin deficiency) status may lead to positive health
changes such as attempts to quit smoking (Wewers, 1989). Thus we should
inform smokers with history of exposure to toxic fumes about the risk
of emphysema and this may make them quit smoking.
The present study had some limitations. Although we are not aware of
any sampling bias, the selection of patients from the outpatient clinic
was not performed randomly. The difference in cigarette smoking between
groups was due to the fact that exposed patients are not able to smoke
as much as others due to their underlying respiratory problems. PFT results
in this article were analyzed according to GOLD criteria. We should take
into account that the cut off point of 70% for FEV1/FVC may
be inappropriate for special populations such as our study samples. Thus
inappropriate cut off point may affect the diagnostic value in patients
with special risk factors.
This study showed the value of chest HRCT in current smokers with symptoms
of emphysema. Even in asymptomatic subjects, significant air trapping
is probably pathological and once bronchial asthma has been excluded,
it may be related to cigarette smoking and indicates early inflammatory
bronchiolar damage (early smokers). Future studies on asymptomatic patients
will help us to diagnose emphysema in earlier phases. We should know more
about indications of performing chest HRCT in suspected patients prior
to developing symptoms or pulmonary dysfunctions.
In summary, smokers with additional risk factor, such as exposure to
respiratory toxins, develop emphysema at younger ages while they have
normal PFT. Chest HRCT should be regarded as a useful tool in the early
diagnosis of emphysema in smokers with history of exposure to toxic fumes.
This additional respiratory risk can accelerate the symptoms in early
stages. Diagnosis of emphysema may be possible prior to occurrence of
the symptoms; but future studies should focus on diagnostic values of
routine tests in asymptomatic patients.
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