HIGH ALTITUDE MEDICINE & BIOLOGYVolume 12, Number 1, 2011ª Mary Ann Liebert, Inc. DOI: 10.1089/ham 2010.1033
Four-Year Prospective Study of Lung Function
in Workers in a High Altitude (4000 m) Mine
Denis Vinnikov,1 Nurlan Brimkulov,2 and Rupert Redding-Jones1
Vinnikov, Denis, Nurlan Brimkulov, and Rupert Redding-Jones. Four-year prospective study of lung function inworkers in a high altitude (4000 m) mine. High Alt. Med. Biol. 12:XXX–XXX, 2011.—The aim of this study was todetermine if work at high altitude is associated with accelerated lung function decline and if smoking couldfurther accelerate this decline. Subjects working at high altitude (3800 to 4500 m) in a gold mine on shift-rotationbasis were included, and 7320 spirometry reports were obtained throughout a 4-yr observation period (2005–2009). Out of 3368 selected reports with acceptable quality, for 842 patients aged 38.9 Æ 8.6 yr we analyzedannual decline in vital capacity (VC), forced vital capacity (FVC), and forced expiratory volume during the firstsecond (FEV1). VC was reduced by 46.5 mL, FVC by 67.8 mL, and FEV1 by 74.5 mL a year, greater than in
AU5 c historical controls. In those having initial FEV1/FVC below 70%, yearly VC decline was 59.4 mL, FEV1 À58.6 mL.
In long-term workers with no initial obstruction, FEV1 declined slower (67.2 vs. 101.3 mL/yr ( p < 0.001); but VCand FVC decline did not differ. Work at high altitude for years may be a factor that accelerates lung functiondecline, and the rate of decline along with confounding factors should be the subject of future studies.
Key Words: spirometry; lung function; intermittent hypoxia; high altitude; mining
pressure, low ambient temperature, and low air humidity(Hultgren, 1997; Luks and Swenson, 2007). People working at
Kyrgyzstan is a mountainous country with a great altitude are subjected to intermittent hypoxia, but studies of
number of constant residents at an altitude exceeding
the latter have mainly been made in mountaineers (Powel and
2500 m above sea level. It has one of the greatest burdens of
respiratory disease, including chronic respiratory disease
The effect of hypoxia on CRD and COPD patients has been
(CRD); mortality from CRD is 4 times greater compared with
studied widely (Moore et al., 1982; Bedu et al., 1996; Cogo
average European deaths (European Respiratory Society,
et al., 2004). In Kyrgyzstan there are a few open-pit mines at
2003). It has been demonstrated that, besides other reasons,
high altitude, and delivering medical service to people
living at high altitude plays a role in higher respiratory
working in one of them, we found some accelerated lung
morbidity and mortality, and strategies have been proposed
aging; however, not many of these people had contact with
to fight CRD, as in other high altitude countries (Bousquet et
the mine itself. We hypothesized that working at a high alti-
al., 2007). Further, residence at high altitude results in higher
tude mine could lead to accelerated annual lung function
mortality in chronic obstructive pulmonary disease (COPD)
decline, and thus aging of lungs. The aim of this study was to
patients (Cote et al., 1993); this is meaningful for Kyrgyzstan,
detect if work at high altitude is associated with accelerated
which has a very high smoking rate for males; standardized
lung function decline and if smoking could further accelerate
age male prevalence rate is 46.9% (Cote et al., 1993; Tobacco
Atlas, 2010). Given the remarkable number of local peopleworking in the mining industry (including gold mining) at
high altitude, for these subjects smoking may have a greater
potential negative effect, and this becomes a relevant localpublic health issue.
The study was conducted at a high altitude gold mine
It has been shown that high altitude has a diverse effect on a
operating at 3800 to 4500 m above sea level in the Issykul area
subject’s health owing to hypoxia, decrease in barometric
of Kyrgyzstan. Mining is performed in an open-pit mine.
1Kumtor Operating Company, Bishkek, Kyrgyzstan.
2Kyrgyz State Medical Academy, Bishkek, Kyrgyzstan.
Except for some occupations, local employees living in the
mL increase in FEV1 after bronchodilation, as advised by the
Issykul area work 2- or 3-week shifts at altitude and then
national guidelines, were classified as asthma and thus unfit
descend to their homes for 2 or 3 weeks in either Bishkek
to work at high altitude. They are not present in the datasheet.
(780 m) or Issykul (1600 m). Following local legislation, all
Quality control was performed by the technician: maximum
high altitude workers must undergo annual screening in a
visible muscle effort, flow–volume curve shape subsequent
specially designated clinic in Bishkek. Apart from clinical
analysis, and attainment of maximal PEF. Best curves were
examination and specialist counseling, as required by the
identified as those having maximal FEV1 þ FVC.
health-care regulations, clinical lab (blood cell count, urine
The spirometry datasheet included only prebronchodilator
analysis, and biochemistry) and instrument (electrocardiog-
raphy, cardiac ultrasonography upon indications, chest X-ray,and office spirometry) investigations were carried out. An-
nual screening normally took 2 days.
Initially, 7320 spirometries were analyzed, and only those
Smoking status and working history were recorded and
patients who had had four complete annual spirometry ses-
analyzed afterward. Smoking status was analyzed to distin-
sions were included. Patients having three or less spirometries
guish between current smokers (smoking daily), former
during the observation period were excluded. Reasons for the
smokers, and never-smokers. The number of cigarettes
missed sessions were vacations, sick leaves, work discontin-
smoked and smoking duration are expressed as pack-years.
uation, and the like. Also, all subjects working in other de-
Screening is done for both permanent and new employees.
partments of the company, such as the middle-altitude
Data for this prospective observational study were collected
Balychky and Bishkek offices, were excluded from analyses.
during 4 yr of screening, from August 2005 to August 2009.
Not all variables included had normal distribution; hence,
Hence, all permanent employees were ideally screened 4
nonparametric tests were used: a 2 by 2 test for differences
times at yearly intervals. During the observation period, 7320
between categorical data when w2 and p were calculated;
office spirometries were performed. The overall numbers of
otherwise, a Mann–Whitney test. Data are shown as
employees varied between 2000 and 2500. In general, people
mean Æ SD or as a percent for all the observations in a group.
working at the mine are healthy and fit, with no serious
All datasheets were analyzed using NCSS 2001 (PASS 2002)
chronic diseases, which would be contraindications to work at
and Statistica 7.0 (StatSoft, Tulsa, OK, USA).
high altitude. These contraindications are listed in Order 70 ofthe Ministry of Health of the Kyrgyz Republic dated 2000.
Only local subjects were included. These are either Kyrgyz
or Russian ethnic workers in all the different occupations of
When patients with irrelevant spirometry reports along
open-blast mining: drillers, mine truck drivers, engineers,
with those not working at altitude and those having three or
mine surveyors, foremen, metalworkers, gold factory opera-
less reports were excluded, a group of 842 patients was ob-
tors, kitchen workers, cleaners, security staff, and others. Only
tained with a total of 3368 spirometry reports. Demographic
a very few employees have direct contact with the mine.
characteristics and the smoking status of these subjects are
Many others work as engineers in separate and remote
buildings, cleaners in a living camp, kitchen staff, and other
The group in general had good lung function indexes.
occupations with no physical contact with the mine.
(103.8 Æ 13.5%); FVC: 4.78 Æ 0.84 L (103.8 Æ 13.5%); FEV1:3.81 Æ 0.73 (104.6 Æ 13.2%); PEF: 563 Æ 113 L/min (107.7 Æ
17.6%); FEV1/FVC: 79.9 Æ 7.0% (99.3 Æ 8.2% to predicted
Office spirometry was performed with MicroMedical Mi-
value), and MEF50: 4.31 Æ 1.41 (88.8 Æ 26.7%). We found no
croLab (United Kingdom) at fasting in the morning after at
differences in lung function indexes (percent of predicted
least 3 h since the last cigarette smoked, with the patient
values) in daily smokers compared to never-smokers. When
standing, as recommended by the national guidelines on
compared to a group of recently employed people entering
spirometry (Brimkulov et al., 2005). Because suspected or di-
the company and having their first spirometry, those working
agnosed bronchial asthma is a contraindication to work at
for years had poorer FEV1 (103.9 Æ 13.2% vs. 107.7 Æ 13.0%).
high altitude, there were no subjects with this disease in the
Over the 4 yr of the observation period, we observed a
company except for one man and one woman, and they were
reduction of all lung function indexes in the entire group,
except for PEF (which is a marker of good muscle effort
In accordance with national guidelines (Brimkulov et al.,
during forced expiration). VC was reduced from 4.692 to
2005), at least one tidal volume maneuver followed by twovital capacity (VC) maneuvers with reproducibility less than
Table 1. Demographic Data and Smoking Status
4% and three forced vital capacity (FVC) maneuvers with
reproducibility less than 4% were accomplished. VC, FVC,(FEV1), Tiffeneau index (FEV1 to VC or FVC ratio, whichever
is larger), peak expiratory flow (PEF), and maximal instan-
taneous forced expiratory flow at 50% FVC (MEF50) were
measured. The European Community for Steel and Coal
(ECSC) II reference set for all indexes was used, and the actual
index ratio to reference reading was calculated. To exclude
reversible obstruction, all patients having FEV
tion to 70% were subjected to a bronchodilation test with two
doses of salbutamol with spacer. Patients having a 15% or 200-
LUNG FUNCTION IN WORKERS IN A HIGH ALTITUDE MINE
Annual FEV1 and VC decline in the whole group. Data shown as means with 95% confidence intervals.
4.506 L (46.5 mL/yr), FVC from 4.779 to 4.508 L (67.8 mL/yr),
from 4.650 to 4.472 L (44.5 mL/yr), FVC from 4.717 to 4.481 L
FEV1 from 3.815 to 3.517 L (74.5 mL/yr), and MEF50 from 4.314
(58.9 mL/yr), FEV1 from 3.798 to 3.529 L (67.2 mL/yr), PEF
to 3.860 L (113.5 mL/yr). FEV1 declined gradually, but not
from 568 to 554 L/min (3 L/yr), and MEF50, 102 mL/yr.
F1 c equally, throughout the observation period (Fig. 1), as did VC.
The opposite group of subjects entering the company at the
At baseline, 66 (7.83%) patients in this group had FEV1/
beginning of the current study and not having bronchial ob-
FVC below 70% (with all other indicators of good-quality
struction had an almost similar lung function decline: VC was
maneuver attained, such as high PEF, maximum muscle ef-
reduced by 41.5 mL/yr and FVC by 67.3 mL/yr; but FEV1 was
fort, and others), 90.9% (n ¼ 60) of which were males. At the
reduced much greater in this group (101.3 mL/yr, p < 0.001).
end of the observation, there were 81 (9.6%) patients withsuch a reduction. In those having initial FEV1/FVC below
70% (COPD or other obstructive syndrome), yearly decline in
The purpose of our study was to determine if work on a
VC was 59.4 mL, and in FEV1 it was 58.6 mL. PEF did not
shift-rotation basis at an altitude of 4000 m could lead to sig-
change; its decline was 3.2 L. In this group there were 36
nificant changes in lung function, first of all to an accelerated
(54.5%) daily smokers in the beginning; however, this number
was reduced insignificantly to 27 (40.9%) by the end of ob-
prevalence of bronchial obstruction as measured by FEV
servation. Number of smoked cigarettes did not change ei-
FVC reduction to less than 70%. Bronchial obstruction in our
ther. This group of obstructive patients had a longer work
subjects was likely to have the same prevalence as in the
duration (8.4 Æ 6.0 yr vs. 6.5 Æ 5.1, p < 0.001) compared with
general population in other studies (Halbert et al., 2006).
the entire group in the beginning of the study and was older
When measured with the use of spirometry, but not based on
(45.0 Æ 7.6 vs. 38.9 Æ 8.6 yr, p < 0.001).
subjects’ complaint questionnaires, meta-analysis showed
We found no correlation of age, work duration, or body
mass index with annual decline in any of the indexes: VC,
prevalent in 9.2% (patients’ reported prevalence was 4.9%).
Our subjects were also likely to have the same prevalence of
The entire group on study commencement also included
obstructive ventilation defect (OVD). When subjects over 39
people who had had their first screening and were entering
yr old were screened for OVD in a large study in Poland
the company at that moment. We hypothesized that their
(11,027 subjects), bronchial obstruction was found in 24.3%
decline during the following 4 yr would be different from that
(Zielinski and Bednarek, 2001). In that study, 9.6% was the
of those already working in intermittent hypoxia for years.
prevalence of only moderate OVD and, in general, obstruction
Thus we separated a group of 616 subjects who met both
was found to be more prevalent than we had believed.
criteria: (1) at inclusion had already been working at high
The obvious limitation of the present study was the use of
altitude for a certain number of years, and (2) had FEV1/FVC
prebronchodilator spirometry for the analysis. The screening
above 70%. In this group we found overall declines for VC
procedures and time allowed hampered us from performingbronchodilation in all subjects, and we could perform it onlywith those patients having OVD.
Table 2. FEV1 Decline in Different Categories
In population studies of healthy adult never-smokers, FEV1
declined slowly over time (20 to 30 mL/yr), with some ac-celeration with age (Fletcher et al., 1976; Kerstjens et al., 1996;
James et al., 2004). In smokers developing chronic obstructive
pulmonary disease (COPD), the rate of decline in FEV1 was
larger; but after smoking cessation, the decline slowed to the
normal rate (Tashkin et al., 1984). A recent TORCH study in
which postbronchodilator FEV1 readings were used revealed
slower lung function decline (55 mL in a placebo group), and
smokers had accelerated decline; but the COPD treatment had
Controls are subjects from Busselton Health Surveys from 1966 to
1981 up to 1994 ( James et al., 2005).
an opposite effect (Celli et al., 2008). Different data were
obtained in an UPLIFT study with COPD patients: pre-
bronchodilator annual FEV1 decline was 37 mL/yr (Decramer
Workers at a high altitude gold mine in Kyrgyzstan have
et al., 2009), but was also slower than in our patients.
accelerated age-related lung function decline. The greatest
In this prospective 4-yr study, we found annual FEV1 de-
rate of decline is in new workers just starting their work at the
cline was around 70 mL/yr in both smoking and nonsmok-
ing patients. To draw scientific conclusions about therelevance of this annual decline, there should be a historical
control group in the Kyrgyzstan population, but no studies ofthis kind have ever been conducted. Although not ultimately
Authors express their gratitude to the former medical ad-
relevant, we have attempted to compare our data on lung
visor of Kumtor Operating Company, Dr. Hans LeRoux, for
function decline with historical controls; these are the sub-
aid in conducting this study. This study would not have been
jects of the Busselton Health study ( James et al., 2005). This
possible without the help of all the other staff of the medical
comparison clearly shows that our subjects have an almost
clinic of the company in Bishkek, including doctors and nurses.
double annual lung function decline. We believed that highaltitude itself could be a factor accelerating lung function
decline; however, it cannot explain the full range of possible
This study was conducted as part of a planned medical
mechanisms, among which could be some kind of chronic
screening procedure for company employees and was funded
inflammation, some cellular mechanisms, and others. It is
by the company. The authors have no conflicts of interest or
well documented that other exposures at the workplace can
lead to an accelerated decline, such as coal mining (Beeckmanet al., 2001) and farming (Dalphin et al., 1996; Iversenand Dahl, 2000), as can hereditary conditions such as a1-
antitrypsin deficiency (Seersholm et al., 1995). In manyrelated studies, accelerated decline was associated with self-
American Thoracic Society, Standardization of Spirometry, 1994
Update (1995). Am. J. Respir. Crit. Care Med. 152:1107–1136.
Subjects in the current study were not subjected to a pure
Bedu M., Giraldo H., Janicot H., Fellmann N., and Coudert J.
intermittent hypoxia, but instead worked in a gold mine,
(1996). Interaction between cold and hypoxia on pulmonary
where dust could be a contributing factor to their accelerated
circulation in COPD. Am. J. Respir. Crit. Care. Med. 153:1242–
lung function decline. This is certainly one limitation of the
Beeckman L.F., Wang M.L., Petsonk E., and Wagner G. (2001).
study; however, only a very few people working there had
Rapid declines in FEV1 and subsequent respiratory symp-
contact with the mine itself (mine truck drivers and drillers).
toms, illnesses, and mortality in coal miners in the United
Many employees work in service departments and never have
States. Am. J. Respir. Crit. Care Med. 163:633–639.
contact with the mine itself, but they have the same lung
Bousquet J., Dahl R., and Khaltaev N. (2007). Global alliance
function decline indexes as those working in this open-pit
against chronic respiratory diseases. Eur. Respir. J. 29:233–239.
mine. Probably, it may be long-term work in conditions of
Brimkulov N., Vinnikov D.V., Davletalieva N.E., Nyholm J.,
intermittent hypoxia that leads to accelerated lung aging.
Uchkempirova B., and Erhola M. (2005). Guidelines on
Besides, all employees at the mine strictly follow safety reg-
Spirometry for Medicals of Kyrgyzstan. Bishkek, Kyrgyzstan
ulations and wear personal protective equipment to minimize
Celli B.R., Thomas N.E., Anderson J.A., Ferguson G.T., Jenkins
As reported by internal agencies, silicon content in this
C.R., Jones P.W., Vestbo J., Knobil K., Yates J.C., and Calverley
mine’s dust is very low, and throughout this 4-yr observation
P. (2008). Effect of pharmacotherapy on rate of decline of lung
we did not have a case of respiratory occupational disease; all
function in chronic obstructive pulmonary disease: results
this together probably minimizes the role of the mine in lung
from the TORCH study. Am. J. Respir. Crit. Care Med.
Data obtained in the current study demonstrate that people
Cogo A., Fischer R., and Schoene R. (2004). Respiratory diseases
working shifts at high altitude have accelerated lung function
and high altitude. High Alt. Med. Biol. 5:435–444.
decline compared with healthy never-smokers reported in the
Cote T.R., Stroup D.F., Dwyer D.M., Horan J.M., and Peterson
D.E. (1993). Chronic obstructive pulmonary disease mortality:
reported healthy nonsmokers, both in those who had initial
a role for altitude. Chest. 103:1194–1197.
normal lung function with no evidence of obstruction and
Dalphin J.C., Maheu M.F., Dussaucy A., Pernet D., Polio J.C.,
Dubiez A, Laplante J.J., and Depierre A. (1996). Six year lon-
those having obstruction. Noteworthy is the finding of the
gitudinal study of respiratory function in dairy farmers in the
current study that long-term workers had slower decline
Doubs province. Eur. Respir. J. 11:1287–1293.
compared with new people in the company working for the
Decramer M., Celli B., Kesten S., Lystig T., Mehra S., Tashkin
first 4 yr. We hypothesize that this accelerated decline of FEV1
D.P., for the UPLIFT investigators. (2009). Effect of tiotropium
in new healthy employees is a result of acute stress reaction
on outcomes in patients with moderate chronic obstructive
and that gradually, with time, annual FEV1 decline will not be
pulmonary disease (UPLIFT): a prespecified subgroup analy-
so fast. Working at high altitude must be also considered an
sis of a randomised controlled trial. Lancet. 9696:1171–1178.
occupational exposure, and studies must focus of the effect of
European Respiratory Society, European Lung Foundation.
this exposure on respiratory function, first with respect to age-
(2003). European Lung White Book. The First Comprehensive
related decline in FEV1. Very few studies have reported an-
Survey on Respiratory Health in Europe. European Re-
nual ventilation indexes for a decline in people constantly
spiratory Journal Ltd., Sheffield, UK.
living at high altitudes, and even fewer for those subjected to
Fletcher C.M., Peto R., Tinker C.M., and Speizer F.E. (1976). The
intermittent hypoxia owing to work at altitude.
Natural History of Chronic Bronchitis and Emphysema: An
LUNG FUNCTION IN WORKERS IN A HIGH ALTITUDE MINE
Eight Year Study of Early Chronic Obstructive Lung Disease in
tization near home? Early respiratory changes after short-term
Working Men in London. Oxford University Press, Oxford, UK.
intermittent exposure to simulated altitude. Wilderness En-
Halbert R.J., Natoli J.L., Gano A., Badamgarav E., Buist A.S., and
Mannino D.M. (2006). Global burden of COPD: systematic
Seersholm N., Kok-Jensen A., and Dirksen A. (1995). Decline in
review and meta-analysis. Eur. Respir. J. 28:523–532.
FEV1 among patients with severe hereditary a1-antitrypsin
Hultgren H. (1997). High Altitude Medicine. Hultgren Publica-
deficiency type PiZ. Am. J. Respir. Crit. Care Med. 152:1922–
Iversen M., and Dahl R. (2000). Working in swine-confinement
Tashkin D.P., Clark V.A., and Coulson A.H. (1984).The UCLA
buildings causes an accelerated decline in FEV1: a 7-yr follow-
population studies of chronic obstructive respiratory disease.
up of Danish farmers. Eur. Respir. J. 16:404–408.
VIII. effects of smoking cessation on lung function: a pro-
James A.L., Palmer L.J., Kicic E., Maxwell P.S., Lagan Sh.E., Ryan
spective study of a free-living population. Am. Rev. Respir.
G.F, and Musk A.W. (2005). Decline in lung function in the
Busselton Health Study: the effects of asthma and cigarette
smoking. Am. J. Respir. Crit. Care Med. 171:109–114.
Kerstjens H., Brand P., and Postma D. (1996). Risk factors for ac-
2368-table-a-the-demographics-of-tobacco.html. Accessed July
celerated decline among patients with chronic obstructive pul-
monary disease. Am. J. Respir. Crit. Care Med. 154:S266–S272.
Zielinski J., and Bednarek M. (2001). Early detection of COPD in
Luks A.M., and Swenson E.R. (2007). Travel to high altitude
a high-risk population using spirometric screening. Chest.
with pre-existing lung disease. Eur. Resp. J. 29:770–792.
Moore L.G., Rohr A.L., Maisenbach J.K., and Reeves J.T. (1982).
Emphysema mortality is increased in Colorado residents athigh altitude. Am. Rev. Respir. Dis. 126:225–228.
Nanduri R., and Prabhakar Kline D. (2002). Ventilatory changes
during intermittent hypoxia: importance of pattern and du-
ration. High Alt. Med. Biol. 3:195–204.
Powel F.L., and Garcia N. (2000). Physiological effects of inter-
mittent hypoxia. High Alt. Med. Biol. 1:125–136.
Ricart A., Casas H., Casas M., Pages T., Palacios L., Rama R.,
Rodriguez F.A., Viscor G., and Ventura J.L. (2000). Acclima-
accepted in final form October 4, 2010.
AUTHOR QUERY FOR HAM-2010-1033-VINNIKOV_1P
AU1: Pls.give city name. AU2: Punctuation thruout this listing OK?AU3: Pls. clarify. 1966 to 1994?AU4: Update, if necessary. AU5: OK?AU6: How many cigarettes in a pack?AU7: Pls. cite Table 2 in text. AU8: Pls. cite this ref in text or delete here.
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