COPD, Sleep Disorders Studies Involving Veterans Funded

Sanjay Sethi, MD, professor of medicine and chief of pulmonary, critical care and sleep medicine, is principal investigator on a U.S. Department of Defense study on COPD.

The three-year, $1.9 million study is titled “The Network Biology of Pathogen-Host Interactions Driving Exacerbation in Chronic Obstructive Pulmonary Disease.”

The study will test the hypothesis that using an integrated systems-based approach to host-pathogen interaction in COPD will reveal key relationships and interactions in the complex networks of microbes, immune cells, immune mediators and structural lung cells that directly impact clinical manifestations.

Sethi says the hope is that knowledge of these underlying networked interactions will inform on illness-specific immune response programs supporting exacerbation susceptibility and disease progression.

The project’s specific aims are to:

• isolate mechanisms of homeostatic regulation in COPD by isolating host-pathogen immune mechanisms within and between airway mucosal and peripheral circulatory compartments that support infection-related inflammation in stable COPD and confer susceptibility to exacerbations
• isolate mechanisms underlying onset and recovery from exacerbation by developing a mechanistic understanding of host-pathogen interactions in the airway and synergistic host peripheral immune response during the onset pathogenesis, clinical course and resolution of exacerbations

The study will leverage a biorepository of biological samples collected in a 20-year prospective longitudinal cohort study of bacterial infection in veterans with COPD at the Buffalo VA Medical Center.

“We will validate our observations in a prospective collection of biological specimens from COPD in stable state and during exacerbation episodes,” Sethi says.

Proteomic analysis and immune-inflammatory profiling will be used to evaluate sputum and serum samples. Sputum will also undergo genomic sequencing to understand host gene expression and the microbiome.

The resulting profiles will then be analyzed by combining a prior-knowledge informed mechanistic modeling of regulatory networks with high-dimensional empirical network modeling.

“Together, these complementary approaches will make maximal use of documented mechanistic knowledge where such knowledge exists and infer undocumented causal relationships from the data in areas of the host-pathogen network where prior knowledge is especially sparse or uncertain,” Sethi says.

The two-pronged approach will also be used to identify early biosignatures of exacerbation pathology and support the identification and numerical simulation of immune response components active at various phases of infectious exacerbation.

Gordon Broderick, PhD, director of the Center for Clinical Systems Biology at Rochester General Hospital, is co-principal investigator on the study.

Co-investigators on the study from UB are:

• Manoj J. Mammen, MD, assistant professor of medicine in the Division of Pulmonary, Critical Care and Sleep Medicine
• Jun Qu, PhD, professor of pharmaceutical sciences in the School of Pharmacy and Pharmaceutical Sciences

Ali A. El Solh, MD, professor of medicine in the Division of Pulmonary, Critical Care and Sleep Medicine, is principal investigator on a four-year, $644,000 VA Merit Award study on insomnia funded by VA Clinical Science Research and Development.

The study focuses on comorbid insomnia and obstructive sleep apnea (OSA) a condition originally labeled as “complex insomnia.”

It has emerged as one of the most challenging sleep conditions to manage, especially when the co-occurrence of OSA and insomnia is associated with significant morbidity, according to El Solh.

He explains that patients with this condition may have more diffi­culty wearing a continuous positive airway pressure (CPAP) mask because of increased awareness of the mask due to frequent awakenings and an inability to initiate or return to sleep with the mask in place. 

“Fortunately, there are effective treatments for each of these sleep disorders,” El Solh says. “Traditional treatment models consist of treating OSA first, followed by adjunctive or concurrent treatment for insomnia only if the response to CPAP is deemed unsatisfactory.”

However, the suboptimal response from such an approach in terms of quality of life, and CPAP adherence highlights the need to examine alternative modalities of treatment, he notes.

At present, there are no general guidelines on the best strategy to treat complex insomnia.

Prior studies have shown that cognitive behavioral therapy (CBT) is effective for treating insomnia when compared with hypnotic agents. Whether combination therapy offers a therapeutic advantage over CBT alone for complex insomnia is yet to be determined, El Solh says.

“The overarching theme of our study is to conduct a pragmatic, randomized, parallel clinical trial comparing the effectiveness of brief behavioral therapy for insomnia (BBTI-MV) plus eszopiclone, a non-benzodiazepine hypnotic, versus BBTI-MV alone in 52 OSA patients at the Buffalo VA Medical Center with coexisting insomnia on global sleep quality of life, symptoms and CPAP adherence,” he says.

El Solh says the study addresses several key areas of unmet needs for veterans with sleep-disordered breathing.

Among these are:

• the association between complex insomnia and post-traumatic stress disorder on global sleep quality of life
• the effectiveness of combined treatment of CBT and eszopiclone versus CBT alone in improving sleep quality
• the impact of each treatment regimen on CPAP adherence

“By establishing the most effective therapy in alleviating insomnia that complicates the presence of OSA, higher CPAP adherence will ultimately translate into improved cognitive function, reduced burden of cardiovascular diseases and enhanced quality of life,” El Solh notes.

“The long term benefit of this trial will also lead to opportunities for more personalized treatment, including delivery method via mobile health technologies which will allow greater assimilation of results across several domains,” he adds.

Co-investigators on the study from UB’s School of Public Health and Health Professions are:

• Gregory P. Beehler, PhD, research assistant professor of community health and health behavior; and clinical research psychologist at the Buffalo VA Medical Center
• Gregory G. Homish, PhD, professor and interim chair of community health and health behavior; and research associate professor of family medicine in the Jacobs School of Medicine and Biomedical Sciences
• Gregory E. Wilding, PhD, professor and chair of biostatistics