COPD Due to Sulfur Mustard (Mustard Lung)

Sulfur Mustard (SM) is a potent toxic alkylating agent that has been used as a chemical warfare gas during the World War I and in the Iran-Iraq conflict between 1983 and 1988(1). SM can cause serious organ damages especially ocular, neurologic, cutaneous, bone marrow, and pulmonary complications (1). The previous studies have shown that the respiratory complications are the most common late complications of SM toxic exposure including chronic obstructive pulmonary disease (COPD), chronic bronchitis, bronchiolitis oblitrans, bronchiectasis, airway hyperresponsiveness, and lung fibrosis (2-6).The COPD which occur after SM exposure is known as "Mustard lung" (7 ). Since about 45000 patients are now suffering from long term complications of SM toxic exposure, the evaluation of its pathogenesis and finding the possible ways for treatment is necessary. During the last decade, especial attention to the possible underlying mechanism of COPD due to SM intoxications has been applied. Our previous studies have shown that in COPD patients due to SM exposure inflammatory markers (highly sensitive CRP, interleukin 6) are elevated and these markers have direct association with the severity of disease (8,9). The finding which recommends the role of systemic inflammation in the pathogenesis of COPD due to SM intoxication like the COPD due to other causes. In this chapter the historical points, probable pathogenesis, clinical manifestation, and diagnosis of mustard lung will be discussed.


Introduction
Sulfur Mustard (SM) is a potent toxic alkylating agent that has been used as a chemical warfare gas during the World War I and in the Iran-Iraq conflict between 1983 and 1988(1).SM can cause serious organ damages especially ocular, neurologic, cutaneous, bone marrow, and pulmonary complications (1).The previous studies have shown that the respiratory complications are the most common late complications of SM toxic exposure including chronic obstructive pulmonary disease (COPD), chronic bronchitis, bronchiolitis oblitrans, bronchiectasis, airway hyperresponsiveness, and lung fibrosis (2-6).The COPD which occur after SM exposure is known as "Mustard lung" (7 ).Since about 45000 patients are now suffering from long term complications of SM toxic exposure, the evaluation of its pathogenesis and finding the possible ways for treatment is necessary.During the last decade, especial attention to the possible underlying mechanism of COPD due to SM intoxications has been applied.Our previous studies have shown that in COPD patients due to SM exposure inflammatory markers (highly sensitive CRP, interleukin 6) are elevated and these markers have direct association with the severity of disease (8,9).The finding which recommends the role of systemic inflammation in the pathogenesis of COPD due to SM intoxication like the COPD due to other causes.In this chapter the historical points, probable pathogenesis, clinical manifestation, and diagnosis of mustard lung will be discussed.

Historical background
Mustard gas was possibly developed as early as 1822 by César-Mansuete Desperetez (1798-1863) (10).SM was used as the late 1880 for treating minor tumors (11).Mustard gas is the most widely -used vesicant chemical war agent in the past century (2).Unfortunately SM was first employed effectively as a weapon in World War by the Germans on the British at Ypres (3,11).It was then used during the Iran-Iraq war (1983)(1984)(1985)(1986)(1987)(1988)) and more than 100 000 military and civilian people were injured by SM gas (12).Now, over 45000 patients are suffering from the late complications of SM exposure (11,12) and now SM is included as a threat to both military and civilians (13).
cross" (it was a symbol means "skin damaging agent" during world war I) (11,12) .It is a colorless to yellowish-brown oily liquid at room temperature that converts to a gas with weapon system delivery (3,11).It has the odor of mustard, garlic, or onion (3 ).

Classification
Following the SM exposure, acute and late (long term) complications may occur.The long term complications of SM exposure are much serious than acute effects .Generally the long term effects of SM exposure occur several years after a mild contact and are totally different from continuous longtime exposure (mainly occupational exposure) (12,13).Several studies in Iran demonstrated that the most common late complication are respiratory problems, including chronic obstructive pulmonary disease (COPD), chronic bronchitis, bronchiolitis obliterans, bronchiectasis, airway hyperreactivity, and lung fibrosis (3-6).Ophthalmologic and cutenous problems are also seen in this period.Unfortunately, the respiratory problems usually exacerbate over time (12).A unique form of COPD known as" Mustard lung" is frequently seen as a long term complication (7).

Pathogenesis
The exact mechanism of late pulmonary complication of SM exposure are not fully defined (14).Although the pathogenesis of COPD has completely determined and is mainly dependent on chronic inflammation and oxidative stress following activation of airway inflammatory cells, but there are few studies about the inflammatory basis of mustard lung (8,9,15).The pathological studies have shown that mustard lung is a neutrophilic / lymphocytic disorder (16,17).Also bronchiolar disease with varying degrees of inflammation as the main pathological finding, was demonstrated in a recent pathologic study in patients with sulfur mustard injury (18 ).According to the previous pathological studies, it seems that activation of inflammatory cells and generation of reactive oxygen species resulting in oxidative stress be involved (16,17).It has been shown that decreased glutathione and increased serum malondialdehyde levels in mustard lung patients can be an indicator of oxidative-antioxidative system imbalance (16).The previous animal model studies have mentioned that the activation of inflammatory cells are involved in the pathogenesis of SM lung injury (19,20).It is well documented that oxidative antioxidative imbalance may result in oxidative stress and triggering inflammatory process (21).
Despite the accepted role of inflammatory cytokines in acute pulmonary complications of SM, there are limited studies on the level of cytokines in the long term complications of SM injury .Our recent studies (8,9) on 50 stable mustard lung patients with all stages according to GOLD (Global Initiative for Chronic Obstructive Lung Disease) classification (Fig. 2) (22),showed that despite the exclusion of smoking, cardiovascular diseases, infections, and other important inflammatory conditions, serum level of highly sensitive c reactive protein (hs-CRP) and interleukin 6 (IL-6), as inflammatory markers, are elevated in mustard lung patients in comparison of normal controls and are directly related to severity of COPD according to spirometry findings (Fig. 3,4)(8,9).It is clearly documented that IL-6 has an important part in reduced forced expiratory volume in one second (FEV1), impaired functional capacity, and worsening the underlying inflammatory condition by release of acute phase proteins (23,24).Also the previous studies in COPD patients have shown that the serum hs-CRP is related to severity of airflow obstruction (25,26).Additionally increased levels of IL-8 in the bronchoalveolar lavage fluid of patients with sulfur mustard poisoning and late pulmonary complications have been demonstrated (15) Despite these studies, few studies reported that inflammatory mediators probably do not have any major role in the pathogenesis and persistence of pulmonary complications of sulfur mustard exposure (27).
These findings provide evidence of the possibility of an inflammatory basis for the late pulmonary complications of sulfur mustard exposure and is in accordance with previous studies in other COPD patients which pointed out that, even during the stable phase of COPD, serum levels of inflammatory markers, including IL-6, may be raised (8,9)

Clinical manifestations
The most common compliant of mustard lung patients is chronic cough (12).A study showed that a triad of cough, expectoration and dyspnea was found in more than 80% of Iranian veterans 3 years after the exposure (1,28).
On physical examination, crackles, wheezing, and rhonchi depending to the state of the patient, can be seen (12,29).The attacks of COPD exacerbation with increasing the severity of dyspnea, cough, and discoloration of sputum, is a common clinical presentation (12,30).
The late pulmonary complications of SM injury may occur in patients who had not developed acute symptoms (12).A study on patients who did not have acute symptoms showed that 38% of these patients had air trapping on high resolution CT (HRCT) of chest (31).
Our previous studies on exercise tolerance of mustard lung patients have shown that the mean exercise capacity of these patients measured by 6 minute walk distance test (6MWD) has been decreased in comparison of normal population (8,9 ).Also the evaluation of quality of life in mustard lung patients showed significant impairment in this assessment by saint George respiratory questionnaire (SGRQ) (8,9,32).Additionally ,in our study the BODE (body mass index, obstruction, dyspnea, and exercise capacity) index had significant correlation with the serum level of inflammatory markers (8,9).

Pulmonary function tests
Spirometry is a common diagnostic way for staging the severity of pulmonary impairment.Like to COPD due to other causes, generally an obstructive pattern is present in patients.A study showed that FEV1 is decreased at a rate of 50 ml/year in mustard lung patients (11,33).
In body plethysmography, total lung capacity (TLC) and residual volume (RV) are markedly increased and Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) remains normal (11,34).

Chest x-ray
Since the majority of mustard lung patients have normal or near normal chest x-ray (CXR) , some authors believe that CXR is not a reliable diagnostic imaging modality in these patients (12,35).Increased bronchovascular markings, and hyperinflation, pulmonary hypertension can be seen in CXR (12,36).

HRCT
Chest HRCT has became a imaging modality of choice in SM patients (12).Air trapping and airway abnormal wall thickening are the most common HRCT finding (12,37).

Treatment
Unfortunately, there are no cure for mustard lung disease (11 ).Bronchodilators, inhaled steroids, long-term oxygen therapy, and pulmonary rehabilitation are different therapeutical strategies which are used in these patients (11 ).The combination of longacting beta agonists (LABAs) and inhaled steroids has been shown to be effective (11,38,39 ).
In mustard lung patients, systemic steroid is only recommended during exacerbations (11).The prolonged use of systemic steroids should be avoided because of severe complication (39).
As we mentioned earlier, the oxidative -antioxidative imbalance may be an underlying mechanism in mustard lung patients.So the potent antioxidant agents are tried for this purpose.N-Acetylcysteine is an antioixidat and mucolytic drug that in double-blind clinical trial, improved dyspnea, cough, and sputum after 4 months of treatment (11,40).

Conclusion
SM can cause serious late pulmonary complications.A unique form of COPD, known as mustard lung, is frequently encountered in patients .Systemic inflammation may be involved in pathogenesis of mustard lung.Unfortunately there is no cure for these patients.

Fig. 1 .
Fig. 1.Molecular structure of sulfur mustard SM is absorbed by different ways: inhalation, through the skin, eyes, and gasterointestinal tract due to consumption of contaminated food (3 ).In large amount exposure, it can cause damages in rapid proliferating tissues particularly bone marrow (3 ).SM can cause different biochemical reactions and alterations in DNA structure ( 1).

Fig. 4 .
Fig. 4. The correlation of FEV1 and IL-6 in mustard lung patients (9) Furthermore, the BODE (body mass index, obstruction, dyspnea, and exercise capacity) index, that is more reliable parameter of COPD morbidity and mortality, was significantly correlated with the serum IL-6 level (Fig 5) (9).