Because a variety of factors – including infectious diseases, cancer, genetics, and environmental hazards – can cause or contribute to respiratory illness, the Department of Veterans Affairs’ (VA) respiratory and pulmonary research portfolio is broadly focused, including studies of the basic science of respiratory illnesses and how they might be prevented or treated.

One of the challenges of studying respiratory diseases or disorders is the number of ways they restrict breathing not only by themselves, but also as comorbidities associated with other conditions. Respiratory problems are the leading cause of death among those who have spinal cord injury (SCI), for example, and investigators at the VA’s Center of Excellence on the Medical Consequences of Spinal Cord Injury, in the Bronx, New York, are studying ways to prevent and treat these and other complications among veterans with SCI.

Among the most serious respiratory illnesses is chronic obstructive pulmonary disease (COPD), a broad term used to describe airflow restriction, usually progressive, that can be due to emphysema (damaged and enlarged air sacs in the lungs) or chronic bronchitis (excessive mucus in and inflammation of the bronchi or air passages within the lungs) – or a combination of both of these conditions. COPD is associated with an inflammatory response of lung tissue to harmful gases or particles, such as cigarette smoke. Tissue damage associated with COPD is irreversible, and treatments are minimally effective. A 2011 VA study, published in Military Medicine, suggested that COPD is more prevalent among veterans than among other Americans. One of a few likely reasons for this may be that compared to other Americans, higher percentages of active-duty military personnel and veterans smoke cigarettes.

COPD is a complex and multi-faceted disorder; while not an infectious disease, it nevertheless is often characterized by acute exacerbations, about half of which are caused by bacteria. The most common pathogen involved in COPD exacerbations, nontypeable Haemophilus influenzae (NTHi), causes much of the discomfort and distress associated with COPD, because it is capable of rapid mutation, adapting to individual hosts. NTHi is often directly linked to patients’ clinical outcomes.

The lungs of COPD patients contain higher levels of toxins associated with cigarette smoke, known as advanced glycation end products (AGEs). Investigators have revealed that these toxins interact with a receptor for advanced glycation end products (RAGE) that may promote inflammation, though the role of RAGE in emphysema is still unknown.

A recently completed 15-year study, a joint effort involving researchers at the University of Buffalo in collaboration with the VA Western New York Healthcare System, provided some insight into how NTHi lives and adapts to its host in real time over a period of months or years. Investigators collected samples among 192 COPD patients for a period of 15 years, yielding 269 different strains of NTHi. By sequencing the genome of the pathogen and tracking its changes over time, the team was able to see when, and in what ways, the NTHi organism was switching particular genes on and off – for example, in the nutrient-poor environment of the lower respiratory tract, the pathogen activates mechanisms that allow it to scavenge iron. Now that the team has revealed the organism’s mechanisms for survival, the team hopes further research will suggest targeted attacks for particular mechanisms, enabling eradication of NTHi in the airways.

Environmental hazards such as cigarette smoke, allergens, and viruses, activate immune receptors in cell membranes that sustain the airway inflammatory response in chronic disorders of the airways – and one of these receptors has become the focus of recent investigations. The lungs of COPD patients contain higher levels of toxins associated with cigarette smoke, known as advanced glycation end products (AGEs). Investigators have revealed that these toxins interact with a receptor for advanced glycation end products (RAGE) that may promote inflammation, though the role of RAGE in emphysema is still unknown.

Thanks to a research team led by John Hoidal, M.D., associate chief of staff for research with the VA Salt Lake City Health Care System, it is known that mice treated with a RAGE inhibitor are protected from emphysema in response to prolonged cigarette smoke exposure. Having established the importance of RAGE in the development of emphysema, the team now are engaged in further study of the receptor, aimed at discovering more specific information about the RAGE-induced response and how it propagates inflammation, oxidation, and cell death (apoptosis). More detailed knowledge of the pathways for developing emphysema may one day lead to treatments that reverse the inflammatory response and protect the lungs from COPD-related damage.

 

Deployment-Related Respiratory Hazards

Another important contributor to higher veteran rates of COPD may be the service-related exposures of military personnel to infectious agents or environmental hazards. The dioxin herbicide known as Agent Orange, for example, has created numerous health problems for veterans of the Korean and Vietnam wars. Establishing a link between Agent Orange exposure and disease has been notoriously difficult, as there is no way to quantify past herbicide exposure. COPD, typically a midlife-onset disease, has not been classified as one of the “presumptive diseases” the VA recognizes as being associated with exposure to Agent Orange or other herbicides during military service, and research on COPD and herbicide exposure among Vietnam veterans is limited.

Several years ago the VA launched a study of Army Chemical Corps (ACC) soldiers who handled Agent Orange and other herbicides to explore relationships between their herbicide exposure and health conditions, such as high blood pressure and chronic respiratory diseases. The team examining COPD among ACC members, from the VA’s Post Deployment Health Epidemiology Program, have discovered a seeming contradiction, reported in summer 2018: Surveys of ACC personnel show a significant correlation between herbicide exposure and self-reported physician diagnoses of COPD – but no correlation between herbicide exposure and airflow obstruction as objectively measured through spirometry, a common diagnostic tool for diseases that affect breathing. The result suggests more research needs to be done to understand both the relationships between COPD and herbicide exposure, and how COPD is diagnosed among veterans.

The first wave of the National Health Study for a New Generation of U.S. Veterans, also known as the NewGen study, which examined the medical histories and survey data from more than 20,000 veterans, revealed some correlations between respiratory disease and multiple respiratory exposures among OEF/OIF veterans, including petrochemical fumes, emissions from local industry or burn pits, dust storms, and particulate matter.

Over the last decade, the respiratory health of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) veterans has become an issue of increasing concern, as a number of returning veterans have reported respiratory illnesses. Studies, both within and outside the VA research system, have shown that the air in Iraq and Afghanistan – both the ambient air and the smoke from the hundreds of open-air burn pits used to dispose of waste at forward facilities – contained toxic contaminants that presented health hazards to service members.

VA-commissioned studies have established that exposure to burn pit smoke may cause short-term reductions in lung function, but the research community hasn’t gathered enough data to make conclusions about their long-term consequences to veterans’ respiratory health. Several efforts at examining the link between deployment-related airborne contaminants and the long-term respiratory health of veterans are underway. Researchers from VA’s Airborne Hazards Center of Excellence at the New Jersey War Related Illness and Injury Study Center (WRIISC), for example, examine lung function among active-duty service members deployed to Iraq and Afghanistan, as well as among veteran volunteers, to better understand the effects of airborne hazards and compile data about the long-term effects of exposure.

The VA’s large-scale studies of respiratory illness among Iraq and Afghanistan have yielded data suggesting these military deployments may be associated with higher rates of respiratory illness: The first wave of the National Health Study for a New Generation of U.S. Veterans, also known as the NewGen study, which examined the medical histories and survey data from more than 20,000 veterans, revealed some correlations between respiratory disease and multiple respiratory exposures among OEF/OIF veterans, including petrochemical fumes, emissions from local industry or burn pits, dust storms, and particulate matter. The NewGen research team concluded that respiratory exposures “should be considered a hazard of military service in general, not solely deployment.”

“Correlation,” the study’s authors cautioned, is not a word that describes a causal effect. A greater accumulation of correlational data, acquired through epidemiological studies linking risk factors to respiratory illness, will be necessary. “Future research on this topic is needed,” wrote the NewGen team, “to determine if a causal relationship exists between these exposures and diseases, ideally including biological indicators, such as pre-military and pre-deployment lung capacity measurements.”

As the nation’s largest integrated health care system, the VA is in a unique position to coordinate such research. Its Cooperative Studies Program plans and conducts large multicenter clinical trials and epidemiological studies throughout VA facilities and those of federal, international, university, and private-industry partners. VA researchers are now recruiting for such a study – the Service and Health Among Deployed Veterans (SHADE) study – to be conducted at six VA sites, which are currently recruiting participants. Led by Dr. Eric Garshick, an epidemiologist and pulmonologist with the VA Boston Healthcare System and an associate professor of medicine at the Brigham and Women’s Hospital, the SHADE study aims to characterize the relationship between post-9/11 deployment-related exposures and current respiratory health, using standardized physiologic and epidemiologic measures. Among a cohort of 6,200 veterans who were deployed to Central Asia, Southwest Asia, or Africa, investigators will test hypotheses by combining data, primarily detailing cumulative exposures to fine particulate matter, with current measures of pulmonary function and medical record data.

In meticulously documenting and measuring the respiratory health of service members before, during, and after exposure to specific environmental hazards during post-9/11 deployments, the SHADE study, along with the work of other VA researchers, may begin to form definitive links between these exposures and long-term respiratory illnesses – and, ultimately, to produce treatments and bring relief to a new generation of service members with deployment-related respiratory illness.

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This article was originally published in the 2018 Fall edition of Veterans Affairs & Military Medicine Outlook By Faircount, LLC