Long-term pulmonary complications in combatants exposed to mustard gas: a historical cohort study

Karimi Zarchi, Ali Akbar1 and Kourosh Holakouie Naieni2

1 Medical Science University of Baghyatollah (a.s.), School of Health, Department of Epidemiology and Biostatistics
2 Medical Science University of Tehran, School of Health, Department of Epidemiology and Biostatistics

Correspondence: A Karimi Zarchi, Medical Science University of Baghyatollah (a.s.), PO Box, 1655737316, Tehran, Iran. E-mail: alikarimi_in{at}yahoo.com


    Abstract
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 
Background Sulphur mustard (mustard gas), the most widely used chemical agent in the Iran–Iraq war, affects many organs including the skin, the gastrointestinal and respiratory tracts, and the central nervous system. The aim of this study was to assess the cumulative incidence rate and annual incidence rate of pulmonary complications, and the rate ratio of related factors.

Methods In a retrospective cohort study of 1337 soldiers with a history of mustard gas exposure, factors such as age, smoking habit, number of exposure episodes, and the use of gas masks were determined, together with an assessment of their relationship to the occurrence of long-term pulmonary complications. All patients residing in the Tehran area were enrolled in the study. Data collection was based on the subjects' medical records and included clinical, spirometric, and in some cases histopathological findings.

Results The cumulative incidence rate of pulmonary complications was 31.6%; the lowest annual incidence rate was noted during the first year of follow-up (0.75/1000), and the highest rate recorded in the seventh year (76.9/1000). Estimated relative risks (RR) for various age groups are as follows: 1.13 (95% CI: 0.88, 1.46) for those aged 21–25 years; 1.49 (95% CI: 1.10, 2.01) for ages 26–30; 1.70 (95% CI: 1.20, 2.40) for ages 31–35; and 2.09 (95% CI: 1.57, 2.77) for subjects aged ≥36. RR with regard to other factors were: more than one versus single exposure 0.69 (95% CI: 0.42, 1.12); smoking versus non-smoking 1.08 (95% CI: 0.80, 1.45), and unprotected exposure versus protective mask use 3.04 (95% CI: 2.20, 4.20).

Conclusion The estimated risk of pulmonary complications from war exposure to mustard gas increased with age and for soldiers who had not worn masks.


Keywords Chemical injuries, mustard gas, pulmonary lesions, historical cohort study, incidence rate, rate ratio

Accepted 6 November 2003

Sulphur mustard (mustard gas), the most widely used chemical agent in the Iran–Iraq war,1 is a brownish yellow liquid with a garlic-like odour that boils at 228°C. It is unclear when this substance was first manufactured, but 1820, 1822, and 1845 have been cited by different authors.2,3 Mustard gas affects many organs including the skin, the gastrointestinal and respiratory tracts, and the central nervous system. The extent of tissue injury depends on the duration and intensity of exposure,4–6 and mortality is low (2–3%).7

To our knowledge, this is the first time that the annual incidence rate (AIR) and the cumulative incidence rate (CIR) for pulmonary lesions have being studied in terms of their relationship with factors such as age, exposure frequency, use of gas masks, and the victims' smoking habits.


    Materials and Methods
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 Abstract
 Materials and Methods
 Results
 Discussion
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For this retrospective cohort8 study, subjects were chosen from those attending the Kowsar Medical Center, where medical records of chemical victims (survivors of chemical attacks who have been transferred to hospital after chemical injuries) are kept. All patients residing in the Tehran area were enrolled in the study. Data collection was based on the subjects' medical records and included clinical, spirometric, and histological findings.

Data analysis
To obtain CIR, we divided the number of those with pulmonary lesions by the number of lesion-free individuals at the beginning of the study.9,10 For AIR, we divided the number of new cases in a year by the total person-years of follow-up in the same year.11 To compute relative risk (RR) for a particular factor, the incidence of lung lesions in the exposed group was divided by the incidence in the non-exposed group.12 We then used this approximative procedure,13 based on the error factor{exp [1.96 {surd}1/d0 + 1/d1]} to obtain 95% CI: multiplying and dividing the RR point estimate by this factor will yield the upper and lower confidence limits respectively. Data entry and analyses were made by Epi info (version 6.04) and Stata (version 4.0) software.14,15


    Results
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 Abstract
 Materials and Methods
 Results
 Discussion
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In all, 1337 men who had suffered mustard gas poisoning were studied with regard to factors such as age, smoking history, frequency and type of exposure (i.e. with or without protective masks), and the relationship between these factors and the incidence of pulmonary complications. Overall, 432 subjects (31.6%) were found to have at least one type of lung lesion.

Table 1 shows the frequency distribution of different age groups (mean age 25.5 years, SD 9.1 years). Some 1264 patients (94.5%) had been exposed only once, while 73 (5.5%) had experienced more than one exposure. The great majority (96.2%) were wearing gas masks at the time of poisoning, and 15.1% had a history of smoking cigarettes.


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Table 1 Age distribution of mustard gas victims

 
Incidence data are summarized in Table 2; the highest and lowest AIR were observed in the seventh and first post-exposure years, respectively.


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Table 2 Annual incidence rates of pulmonary complications in mustard gas victims (1983–1995)

 
Using the incidence in the ≤20 year old group as the common denominator, we present in Table 3 the estimated RR and 95% CI for different age groups: 1.13 (95% CI: 0.88, 1.46) for those aged 21–25 years; 1.49 (95% CI: 1.10, 2.01) for ages 26–30 years; 1.7 (95% CI: 1.2, 2.4) for ages 31–35 years; and 2.09 (95% CI: 1.57, 2.77) for subjects aged ≥ 36.


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Table 3 Incidence rate and rate ratio in relation to various factors under study (1983–1995)

 
RR for patients exposed more than once as compared with one-time victims was 0.69 (95% CI: 0.42, 1.12) and that for cigarette smokers versus non-smokers was 1.08 (95% CI: 0.80, 1.45). Unprotected subjects were 3.04 (95% CI: 2.20, 4.20) times more likely to suffer lung injury compared with those wearing masks during the exposure episode.


    Discussion
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 Materials and Methods
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The effects of mustard gas on lung tissue vary with ambient gas concentrations and duration of exposure; high temperature is also believed to be a risk factor for pulmonary complications following exposure.

The histological features listed below are largely based on information from victims of chemical attacks in World War I; however, it should be borne in mind that because of the high prevalence of superimposed infections, it might be difficult to generalize these findings. Generally, light exposures only involve the upper respiratory tract but with more severe inhalation both the upper and lower tracts are affected.16

Clinical features, as summarized by Sohrabpour and Balali, include pulmonary/bronchial wheezing without consolidation, productive cough and, rarely, haemoptysis.17,18 In our study the low mortality rate meant that all patients were observed for the entire study period. The highest AIR of lung complications (76.9 per 1000) occurred in the seventh year, and the lowest (0.75 per 1000) in the first year. The risk appears to increase with age, with statistically significant elevations in all age categories except the 21–25 years age group. Use of protective masks was found to decrease the occurrence of lung complications, i.e gas masks exerted a protective effect.

Smoking history and frequency of gas exposure were not associated with a significant rise in the risk of lung injury; this may be explained by ambient gas concentrations and duration of exposure and temperature.4 Thus, smoking history and frequency of gas exposure may not be the only main risk factors, and the role of age and gas mask protection may be more important.


KEY MESSAGES

  • We determined cumulative incidence rate of pulmonary lesions following exposure to mustard gas.
  • Older age is associated with greater risk, but for unknown reasons, smoking does not seem to affect relative risk.
  • There have been no other studies of these risk factors so far.

 


    Acknowledgments
 
The research project has been ratified and sponsored by the School of Public Health, Tehran University of Medical Science. People who have helped with the organization and conduct of this study include Drs Abolhassan Nadim, Kazem Mohammad, Khosro Agin, Mahmood Mahmoodi-Farahani, Ali Shahidzadeh (English language editor), and Ms Mahmoodi.


    References
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 Abstract
 Materials and Methods
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 Discussion
 References
 
1 Forootan A. Medical notes on the chemical warfare: part I. Kowsar Medical Journal 1996;1:91–97.

2 West CJ. The history of mustard gas. Chem Metall Engin 1920;22:541–54.

3 Fredrick R et al. Sulfur Mustard: A Chemical Vesicant Model. New York: John Wiley & Sons, 1996.

4 Willems JL. Clinical management of mustard gas casualities. Ann Med Mill Belg 1989;3:S1–S61.

5 Balali M, Navaiean A. Clinical and practical findings in 232 patients with sulfur mustard poisoning. Proceeding of the Second World Congress on New Compounds in Biologic and Chemical Warfare. Ghent, Belgium, 1986, pp. 464–73.

6 Aasted A, Darre E, Wulf HC. Mustard gas: clinical, toxicological and mutagenic aspects based on modern experience. Ann Plastic Surg 1987;19:330–33.[ISI][Medline]

7 Gilchrist HL. Statistical consideration of gas casualities. In: Weed FW (ed.), Government office. Medical Aspects of Gas Warfare. Washington DC, 1926, pp. 273–79.

8 Gordis L. Epidemiology. Philadelphia: WB Saunders Co., 2000, pp. 31–33.

9 Szklo M, Nieto FJ. Epidemiology. Beyond the Basics. Gaithesberg, MD: Aspen Publisher Inc. 2000, pp. 55–58.

10 Rothman KJ, Greenland S. Modern Epidemiology, 2nd Edn. Philadelphia: Lippcott Williams & Wilkins, 1998, pp. 29–64.

11 Breslow NE, Day NE. Statistical Methods in Cancer Research. II. The Design and Analysis of Cohort Studies. Lyon: International Agency for Research on Cancer, 1987

12 Kahn HA, Sempos CT. Statistical Methods in Epidemiology. New York: Oxford University Press, 1989.

13 Armitage P. Statistical Methods in Medical Research. Oxford: Blackwell Scientific Publications, 1977.

14 EpiInfo: A Word Processing Database and Statistics Programme for Public Health. Version 6.0. Centers for Disease Controland World Health Organization, 1994.

15 Stata: Statistics, Data Analysis. Version 4.0. College Station, TX: Stata Corporation, 1995.

16 Easton DF. Cancers of the respiratory tract in mustard gas workers. Br J Indust Med 1988;19:529–36.

17 Sohrabpour H. Clinical manifestations of chemical agents on Iranian combatants during Iran-Iraq conflict. Arch Belg 1984;(Suppl.):291–97.[Medline]

18 Balali M. Clinical and laboratory findings in Iranian fighters with chemical poisoning. Arch Belg 1984;(Suppl.):254–59.[Medline]





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