o-Chlorobenzylidene Malononitrile (CS Riot Control Agent) Associated Acute Respiratory Illnesses in a U.S. Army Basic Combat Training Cohort

ABSTRACT

Acute respiratory illnesses (ARIs) are among the leading causes for hospital visits in U.S. military training populations and historically peak during U.S. Army Basic Combat Training (BCT) following mandatory exposure to the riot control agent o-chlorobenzylidene malononitrile (CS). This observational prospective cohort studied the association between CS exposures and ARI-related health outcomes in 6,723 U.S. Army recruits attending BCT at Fort Jackson, South Carolina from August 1 to September 25, 2012 by capturing and linking the incidence of ARI before and after the mask confidence chamber to CS exposure data. Recruits had a significantly higher risk (risk ratio = 2.44; 95% confidence interval = 1.74, 3.43) of being diagnosed with ARI following exposure to CS compared to the period of training preceding exposure, and incidence of ARI after CS exposure was dependent on the CS exposure concentration (p = 0.03). There was a significant pre-/postexposure ARI difference across all CS concentration levels (p < 0.01), however, no significant differences were detected among these rate ratios (p = 0.72). As CS exposure is positively associated with ARI health outcomes in this population, interventions designed to reduce respiratory exposures could result in decreased hospital burden and lost training time in the U.S. Army BCT population.

INTRODUCTION

Acute respiratory illnesses (ARIs), including the common cold, influenza, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, and other respiratory ailments, are a global medical concern. Lower respiratory tract infections alone account for over 429 million incident cases per year globally (second only to diarrheal diseases) and lead the world in disease burden.¹ ARIs are a primary contributor to health loss in the United States and are a significant source of morbidity in U.S. military training populations.^2,3 ARIs accounted for more hospital visits and lost work time than any other illness or injury in U.S. military recruits from 2010 to 2011 and were second only to injury and poisoning the following year.^4,–6

The occurrence of ARIs in military recruit populations has been well studied; however, understanding of causal factors is limited.^7,–10 A 1998 study of Army Basic Combat Training (BCT) at Fort Jackson, South Carolina found that nearly 50% of recruits sought medical care for ARI-related conditions and over 90% of participants self-reported ARI symptoms. Respiratory-related hospitalizations peaked during training weeks 4 and 5, whereas self-reported febrile illnesses peaked during the third week of training. Investigators attributed the rise in ARI rates to a lapse in availability of an effective adenovirus vaccine.⁷ Another study, conducted in 2004, investigated the effect of building design on ARI rates in the BCT population at Fort Jackson, South Carolina. Investigators determined that recruits living in 60-person rooms had a significantly greater ARI risk than those living in 8-person rooms, and that both febrile and afebrile ARI rates peaked during weeks 4 through 6 of the training cycle. Investigators concluded the week of training was significant at almost all levels, across genders, and for both febrile and afebrile ARI outcomes. The authors hypothesized the observed increase in ARI incidence was because of previously unencountered respiratory pathogen exposure, crowded living and training conditions, and decreased immune function because of physical and emotional stress related to entering military training. Immunity increased as the training cycle progressed and trainees adapted to their new environment. This study acknowledged the potential role of training in ARI trends, but did not identify specific training events that may have impacted the reported ARI rates.¹¹

In the early 1990s, British Surgeon Lieutenant Commander Pipkin described an ARI outbreak in a Royal Marines training population where cases of influenza peaked shortly following exposure to the riot control agent o-chlorobenzylidene malononitrile (CS).¹² CS has a profound effect on the respiratory system, causing immediate pain and irritation in the nose and mouth, excessive nasal discharge and salivation, and sometimes violent coughing spasms, damage to the respiratory epithelium, and pulmonary edema.^13,14 Pipkin speculated that a combination of these effects may have increased influenza incidence within the exposed Royal Marines.¹² The biological plausibility of this hypothesis is reasonable, as opportunistic respiratory infections (including those associated with ARI) have been shown to spread via direct and indirect contact, and to commonly occur following chemical irritation or injury.^11,15 Unfortunately, because of a small sample size, Pipkin's hypothesis could not properly be tested, and the question of whether CS exposure can increase ARI rates remains unanswered.

Currently, no ARI studies have considered exposure to CS as a covariate in analyses. All U.S. Army BCT soldiers are exposed to CS in the first 3 weeks of BCT. A 2012 study of over 6,500 soldiers participating in mask confidence training (MCT) during BCT at Fort Jackson, South Carolina showed that unmasked soldiers were exposed to CS concentrations over 125 times the American Conference of Industrial Hygienist Threshold Limit Value Ceiling and over 25 times the National Institute for Occupational Safety and Health Immediately Dangerous to Life and Health (IDLH) level.¹⁶ These limits were established to protect against irreversible health effects and prevent damage to the respiratory epithelium.¹⁷ High levels of acute CS exposure in Army BCT before the observed increase in ARI rates make it temporally plausible that CS exposure experienced during MCT could induce chemical damage and irritation to the respiratory tract. These effects could be diagnosed as ARI or increase susceptibility to respiratory infection, both of which would result in an increase in observed ARI incidence rates. It is also possible that CS-induced expectoration promotes the spread of pathogens responsible for ARIs in this population.

This study examines the association between CS exposure concentrations and ARI health outcomes during Army BCT. The study protocol was approved by the U.S. Army Training and Doctrine Command and the Uniformed Services University of the Health Sciences and was deemed non-human subject research by the Uniformed Services University of the Health Sciences Institutional Review Board because of the observational nature of the study and lack of personal identifying information available to the investigators.

METHODS

This study used an observational, prospective cohort design in a gender integrated cohort of 6,723 exposed soldiers attending U.S. Army BCT at Fort Jackson from August 1 to September 25, 2012 to capture the incidence and distribution of ARI before and after completion of the mandatory MCT portion of their initial military training.

Army training units, designated as approximately 200-person “Companies,” scheduled for the MCT were identified by Unit Identification Code through coordination with staff at the chemical, biological, radiological, and nuclear (CBRN) training range. Data on the type of barracks and training week were captured from administrative records provided by Fort Jackson training officials.

Upon arrival to the training site, training units were divided into four ad hoc exposure groups consisting of approximately 50 personnel to proceed through the mask confidence chamber. Exposure group assignment, composition, and size were determined by training officials and were not influenced by investigators.¹⁶ CBRN staff aerosolized 10 CS capsules to establish an initial concentration of CS inside the chamber; the first exposure group entered, conducted a series of exercises, removed their protective masks, and exited the chamber. CBRN staff then aerosolized one additional CS capsule for every 10 people that exited the chamber and the next exposure group entered.¹⁶ This process continued until all four exposure groups completed the training event.

Officials from each training unit used a personnel roster to document trainee attendance, exposure group (1–4), and completion of the chamber exercise. Trainees who completed the MCT with their assigned training unit were enrolled in the cohort; absent soldiers or those who completed the training but were from a different training unit were excluded. Count data specifying the number of trainees that completed the chamber exercise and the number of trainees in each exposure group were provided to the investigators after each training event. CS concentrations were obtained for each exposure group from a concurrent industrial hygiene study.¹⁶ Exposure groups were categorized as one of four exposure categories: 0 to 2 mg/m³, 2 to 5 mg/m³, 5 to 10 mg/m³, and greater than 10 mg/m³ based on the IDLH value (2.0 mg/m³) and the incapacitating range (5.0–10.0 mg/m³) outlined in U.S. Army manuals.^18,19

Clinically diagnosed and documented inpatient and outpatient ARIs (both febrile and afebrile) were the outcomes of interest. Medical staff queried the Composite Healthcare Computer System for ARI encounters within companies that completed the MCT using the following International Classification of Diseases Version 9 (ICD-9) codes: 079.99 Viral infection, not otherwise specified (NOS); 382.9 Otitis media, NOS; 460 Nasopharyngitis, acute; 461.9 Acute sinusitis; 465.8 Acute upper respiratory infections of other multiple sites; 465.9 Acute upper respiratory infections of unspecified site; 466.0 Bronchitis, acute; 486 Pneumonia, organism NOS; 487.0 Influenza with pneumonia; 487.1 Influenza with respiratory manifestation, not elsewhere classified (NEC); 487.8 Influenza with manifestation, NEC; 490 Bronchitis, NOS; 784.1 Pain, Throat; and 786.2 Cough.

Surveillance count data by training unit were provided by local preventive medicine personnel as part of the existing acute respiratory disease surveillance program.²⁰ No personal identifying information was provided to the investigators. The surveillance period began 7 days before CS exposure and ended 7 days after exposure (including the day of the exposure). Occurrence of one or more of the ARI-related ICD-9 codes as the primary or secondary diagnosis in a trainee's electronic medical record during the surveillance period was designated as case. This case definition captured both febrile and afebrile ARI cases. Febrile ARI cases had oral temperature of 100.5°F or higher and at least one sign or symptom of acute respiratory tract inflammation (i.e., sore throat, cough, runny nose, chest pain, shortness of breath, headache, tonsillar exudates, or tender cervical lymphadenopathy).²⁰ All cases not meeting this definition were categorized as afebrile. Cases were further divided into pre- and postchamber ARI cases. A prechamber ARI case was defined as occurring with a training unit in the 7-day period before CS exposure. A postchamber ARI case was a case that occurred during the 7-day surveillance period beginning with exposure to CS in the mask confidence chamber.

To prevent counting multiple encounters by an individual and ensure the most severe health outcomes were captured, first diagnosis of ARI during the surveillance period was used to establish pre- or postchamber ARI status. However, if a later febrile ARI diagnosis occurred, it took priority and was used to establish pre- or postchamber ARI case status. Those designated as prechamber cases were treated as nonsusceptible for postchamber ARI risk calculations. Cases were cross-referenced with training rosters to determine their cohort and exposure group status. Local preventive medicine personnel provided case counts by training unit, febrile/afebrile, exposure group, and date of encounter.

These counts, along with previously gathered information, were entered into SPSS Statistics for Windows (Version 19, IBM, Chicago, Illinois) for data management. χ² analyses, stratified risks, risk ratios (RR), and their 95% confidence intervals (95% CI) were calculated using Open Source Epidemiologic Statistics for Public Health (Version 3.01, www.openepi.com, 2013). SPSS was used to conduct a Poisson regression analysis to examine the relationship between CS exposure concentration and available daily ARI count data allowing the use of ARI diagnoses following CS exposure as variables in the analysis. Power calculations determined a minimum of 64 exposure groups were required to detect a 0.5 difference in risk at 80% power.

RESULTS

There were a total of 6,723 soldiers divided into 134 exposure groups during the surveillance period. All members of the cohort were exposed to CS in the first 3 weeks of training and lived in one of three building types: (1) starship barracks (SS)—fixed facilities consisting of 60-person rooms, (2) relocatable barracks (RL)—movable facilities that can accommodate up to 50 soldiers per room, or (3) rolling pin barracks (RP)—fixed facilities consisting of 8-person rooms. Over half (55.9%) of the cohort completed the mask confidence chamber during their second week of training and most (58.0%) lived in the SS style barracks. Only one training unit consisting of 165 soldiers was housed in the RP style barracks. There were a total of 161 clinically diagnosed cases of ARI in the study population; 47 occurred before CS exposure and 114 after (Table I). Only four (2.48%) of these cases were coded in Composite Healthcare Computer System as febrile ARI cases; all of which occurred postchamber. Figure 1 shows the distribution of postchamber ARI cases by day.

TABLE I

ARI Incident Cases by Chamber Week and Building Type

	Prechamber ARI	Postchamber ARI	Total Population
	N (%)
Overall	47 (0.70)	114 (1.70)	6,723 (100)
Chamber Week
1	7 (0.66)	20 (1.89)	1,065 (100)
2	26 (0.70)	60 (1.62)	3,693 (100)
3	14 (0.71)	34 (1.73)	1,965 (100)
Building Type
SS	30 (0.77)	72 (1.86)	3,900 (100)
RL	16 (0.60)	42 (1.58)	2,658 (100)
RP	1 (0.61)	0 (0.00)	165 (100)

FIGURE 1

Distribution of postchamber ARI by postchamber surveillance day.

Table II shows the overall risk of developing ARI after exposure to CS was significantly higher than the risk of developing ARI in the surveillance period before completion of the mask confidence chamber (RR = 2.44; 95%CI = 1.74, 3.43). Increased ARI risk was observed regardless of training week the mask confidence chamber was conducted or building the soldier lived in. The Breslow-Day test for interaction of RR over strata did not suggest interaction; stratum specific Mantel–Haenszel adjusted rate ratios were not significantly different than the overall rate ratio suggesting a lack of confounding by chamber week or building type. Overall ARI, prechamber ARI, and postchamber ARI incidence rates were not observed to be different across chamber week (p = 0.98, p = 0.98, p = 0.85, respectively) or building type (p = 0.18, p = 0.72, p = 0.17) (Table II). A χ² analysis suggested postexposure ARI cases are dependent on CS exposure concentrations (p = 0.03) (Table III). A Poisson regression analysis showed a significant pre-/postchamber ARI difference across all concentrations higher than the referent level (0–2 mg/m³) (p = 0.006); however, no significant differences were detected among these rate ratios (p = 0.72) (Figure 2).

TABLE II

ARI Rates (Per 100 Person-Weeks) by Chamber Week and Building Type

	Prechamber ARI	Postchamber ARI	ARI Incidence	Pre/Post Rate Ratio
	ARI Rates (95% CI)
Overall	0.70 (0.52, 0.93)	1.71 (1.42, 2.05)	1.20 (1.03, 1.40)	2.44 (1.74, 3.43)
Chamber Week
1	0.66 (0.29, 1.38)	1.89 (1.21, 2.92)	1.27 (0.86, 1.85)	2.88 (1.22, 6.77)
2	0.70 (0.48, 1.03)	1.64 (1.27, 2.10)	1.17 (0.95, 1.44)	2.32 (1.47, 3.67)
3	0.71 (0.41, 1.20)	1.74 (1.24, 2.43)	1.23 (0.92, 1.63)	2.45 (1.32, 4.54)
Mantel–Haenszel Risk Ratio				2.44 (1.74, 3.43)
Breslow-Day Test for Interaction				p = 0.91
Building Type
SS	0.77 (0.54, 1.10)	1.86 (1.48, 2.34)	1.31 (1.08, 1.59)	2.42 (1.58, 3.69)
RL	0.60 (0.36, 0.98)	1.59 (1.17, 2.15)	1.09 (0.85, 1.41)	2.64 (1.49, 4.69)
RP	0.61 (0.00, 3.70)	0	0.30 (0.00, 1.88)	0
Mantel–Haenszel Risk Ratio				2.44 (1.74, 3.43)
Breslow-Day Test for Interaction				p = 0.61

TABLE III

χ² Test for Independence of Pre- and Postchamber ARI Cases by CS Concentration

Variable	Prechamber ARI				Postchamber ARI
	Non-Case	Case	χ2	p Value	Non-Case	Case	χ2	p Value
CS Concentration (mg/m3)			6.60	0.09			8.87	0.03
0–2	131	3			128	3
2–5	1,852	9			1,832	20
5–10	2,773	23			2,712	61
>10	1,920	12			1,890	30

FIGURE 2

Relative incidence of postchamber ARI by CS concentration and 95% CIs.

DISCUSSION

The results of this study suggest that within our study population, exposure to CS resulted in nearly 2.5 times greater ARI diagnosis risk after MCT compared to the period of training preceding this event. Elevated ARI risk was independent of both the week of training in which CS exposure occurred and barracks building type.

Over 95% of the cohort was exposed to CS in excess of IDLH (2.0 mg/m³), with the majority of the population (70.0%) exposed at levels greater than 2.5 times IDLH.¹⁶ The risk of being diagnosed with a postchamber ARI compared to being diagnosed prechamber was significantly elevated in all exposure concentration levels exceeding IDLH. These risks were not statistically different from each other, thus a dose–response relationship could not be established (p = 0.72); however, postchamber ARI incidence was dependent on CS exposure concentrations (p = 0.03).

The incidence of both prechamber ARI (2.24%; 95%CI = 0.47, 6.81) and postchamber ARI (2.29%; 95%CI = 0.48, 6.81) were elevated in exposure concentrations below IDLH when compared to other groups. However, it is important to note the lack of statistical significance may be because of the sparseness of data at this lowest exposure group (N = 134). Also, ARI present in the prechamber (unexposed) population cannot be temporally linked to CS exposure. One possible link could be mixing of the population with CS exposed cases returning to a military unit before it attends the mask confidence chamber, but this was not observed during the conduct of this study.

The increased risk observed at concentrations above IDLH suggests that there may be a threshold concentration in the range of 0.00 to 2.0 mg/m³ above which promotes symptoms that could result in an ARI diagnosis. It may also suggest that the IDLH value (2.0 mg/m³) set by National Institute for Occupational Safety and Health is protective against ARI. A decreased risk (RR = 1.02; 95%CI = 0.21, 4.98) was observed at concentrations below IDLH; however, because only 134 (2%) of the entire cohort was exposed at levels below IDLH, it is difficult to determine whether this decreased risk was observed by chance alone. Future studies are needed to better characterize the ARI risk associated with this CS concentration range.

Week of training and living environment have been associated with increased risk of both febrile and afebrile ARI outcomes in a BCT population.^7,11 The results of this study, however, suggest that these covariates do not play a significant role in ARI outcomes during the first 3 weeks of BCT. Prechamber, postchamber, and overall ARI incidence rates did not vary by week or building type and the pre-/postchamber ARI rate ratio was the same across these strata.

One potential explanation for the lack of significance of these covariates is seasonality. Previous studies were conducted in close proximity to the cold and flu season.^7,11 These populations may have been exposed to a greater number of infectious ARI causing pathogens whose transmission (via direct and/or indirect mechanisms) could be influenced by living and sleeping arrangements. Furthermore, in this scenario, it would take time for infectious ARI to build within a training unit, thus making week of training a relevant factor. This study was well removed from the cold and flu season and observed ARI cumulative incidence of only 2.40% (0.06% febrile, 2.34% afebrile) over the study period.

A more likely reason for the disparity in relevant covariates in this study when compared to previous work is the implementation of a new vaccine in November, 2011, which targeted adenovirus types 4 and 7 and significantly decreased ARI incidence in the BCT populations across all military services.^5,21,22 The impact of the vaccine was evident in this study with only four febrile ARI cases and both febrile and afebrile incidence rates considerably lower than the historic incidence rates.^7,11 The majority of febrile cases (3 of 4) resided in the SS style barracks, which was consistent with previous research.¹¹ All four cases occurred after completion of the mask confidence chamber at exposure concentrations greater than 2.5 times the IDLH, suggesting that exposure to elevated CS concentrations may increase febrile ARI risk. The low febrile case count, however, could suggest that CS-induced respiratory tract injury rather than infection may have contributed to the number of postchamber ARI diagnoses in this population. However, as symptoms associated with CS exposure are generally short-lived and resolve themselves as time from exposure increases, one would expect CS injury–induced ARI diagnoses to occur immediately following exposure. Our data show that only three (2.6%) postchamber ARI cases were diagnosed the day of the chamber and only 19 (17.7%) were diagnosed the following day. This may suggest that infection rather than CS-induced injury was more prevalent in postchamber ARI diagnoses.

There are several limitations associated with this study. To begin with, it was strictly observational and did not allow for the collection of personal characteristics (e.g., body mass index, prior smoking status, and sex) that have been shown to influence ARI outcomes. Another potential confounder was reuse of protective masks by trainees during MCT. Midway through the study period, investigators witnessed soldiers exit the chamber and transfer their protective mask to waiting soldiers whose originally issued masks were defective. Most masks were exchanged after quickly wiping with one antibacterial wipe; however, some masks were not wiped at all. This practice introduced a potential avenue for the spread of ARI causing pathogens and was not controlled for in the study. Another limitation is that it relied on ARI incidence estimates based on ICD-9 codes in the soldier's electronic medical records, and did not include laboratory-confirmed ARI diagnosis. Without laboratory-confirmed pathogen-specific diagnosis, CS-induced injury of the respiratory tract could have been misdiagnosed as infection. However, the small number of ARI cases on the day of the chamber exposure makes this less likely. In addition, the follow-up period may not have been long enough to identify these misdiagnosed cases or other afebrile ARI that may have progressed to febrile ARI later in the training cycle. A combination of these factors makes it difficult to determine whether the cases captured in this study are a result of infection or injury. Finally, exposure concentrations were assigned based on an area sampling methodology that assumed that CS was evenly dispersed in the mask confidence chamber.¹⁶ Although this is considered an acceptable method for estimating exposures, it is not as precise as individual monitoring and could have impacted the results observed here.

CONCLUSION

This is the first study to consider CS exposure as potential risk factor for ARI diagnoses in a BCT population. Regardless of the cause for diagnosis (injury or infection), ARIs have a significant impact on the health care system and on the readiness of today's fighting force. This study showed that those exposed to CS in the mask confidence chamber had nearly 2.5 times greater risk of being diagnosed with ARI after completion of this training event. It also suggests that postexposure ARIs are dependent on the CS exposure concentration. As ARI is positively associated with CS exposure in this population, interventions designed to reduce or eliminate the exposure could result in decreased hospital burden, health care costs, and lost training time within the BCT population. It is also possible that this study could have broader implications to other military populations and law enforcement personnel.

Preliminary results of this study were provided to medical and training officials at Training and Doctrine Command, through the Army Public Health Command, resulting in an Army-wide intervention by the U.S. Army Safety Office targeting CS exposure levels to mitigate the risks reported here. This intervention, All Army Activities message 051/2013, was implemented in March 2013 mandating lower CS concentrations, shorter exposure times, semiannual industrial hygiene surveys, and periodic wet cleaning of all Army mask confidence chambers.²³ Ongoing research is being conducted at the Uniformed Services University of the Health Sciences to determine the efficacy of this intervention in lowering CS exposure concentrations and mitigating the risks reported here. Future research is required to determine intervention impact on a soldier's perception of the protective nature of their assigned CBRN protective equipment and to determine if this intervention reduced lost training time, health care costs, and hospital burden.

ACKNOWLEDGMENT

This work was sponsored by the U.S. Army Medical Command, Office of the Surgeon General, Falls Church, Virginia.

Author notes

1

The views expressed in this article are those of the authors and do not reflect the official policies or positions of the Uniformed Services University of the Health Sciences, the Department of the Army, the Department of Defense, or the U.S. Government.