The Role of Circadian Clock Proteins in Innate and Adaptive Immunity

Light Therapy in Patients Undergoing Appendectomy for Appendicitis, Colon Resection for Diverticulitis, or Treatment of Pneumonia

Our data suggest that modulating the characteristics of light carries the potential to modify the host response to injury and critical illness and thus, improve outcome. The ability to modify the host response to the stress of major operations and sepsis carries immense potential to improve patient care. This study is an experimental investigation of exposure to blue (480nm) light in the setting of appendectomy for appendicitis, colon resection for diverticulitis, or treatment of pneumonia The exposure of interest is blue light applied prior to surgery and during the 24 hour period after surgery. For the cohort with pneumonia, exposure of interest is blue light applied upon diagnosis of pneumonia for a 24 hour period after diagnosis and then for a 12 hour period on days 2 and 3 of treatment of pneumonia. The control group is comprised of controls that have undergone a similar operation or treatment for pneumonia but without exposure to blue light. The outcome of interest is change in the inflammatory response after surgery for appendicitis or diverticulitis as measured by the following parameters: white blood cell count, heart rate, the development of abdominal abscess, serum cytokine concentrations. The outcome of interest is change in the inflammatory response during pneumonia as measured by the following parameters: white blood cell count, heart rate, and serum cytokine concentrations.

Background and preliminary data: Our murine studies suggest that exposure to blue (480nm) light, by comparison to ambient white or amber (580nm) light, reduces the inflammatory response (i.e., cytokine concentration), risk of organ failure (i.e., kidney failure), and improves the clearance and control of the infectious focus (i.e., reduced abdominal and pulmonary bacterial counts and bacterial dissemination into tissues of the liver and spleen) in mice subjected to a model of cecal ligation and puncture (CLP) or a model of pneumonia. These data directly support the proposed project and experimentation. Exposure to blue light after a cecal ligation and puncture (CLP) model of sepsis reduces systemic inflammation, as evidenced by reduced serum TNF-alpha, IL-6 and IL-10 concentrations. These mice had reduced bacterial in the abdomen and reduced bacteremia. They also had reduced kidney failure after sepsis by comparison to mice subjected to ambient light. Similar data were observed in mice subjected to a model of Klebsiella pneumoniae: improved survival, reduced bacteria within the lung, reduced bacteremia and dissemination into the tissues of the liver and spleen, and reduced systemic inflammation in mice exposed to blue light. Significance: Our data suggest that modulating the characteristics of light carries the potential to modify the host response to injury and critical illness and thus, improve outcome. The ability to modify the host response to the stress of major operations and sepsis carries immense potential to improve patient care. Importantly, the risk of light is minimal. Thus, the intervention of exposing a patient to a characteristic spectrum of light carries a very large benefit:risk ratio. The results of these studies may be directly applicable to a more generalized population of critically ill patients. Approach: Subjects will receive the standard preoperative, intraoperative, and postoperative care for appendectomy or colon resection. All operations will be performed by one of the Trauma/Acute Care Surgery surgeons at PUH. Subjects with pneumonia will receive standard medical care for pneumonia. All medical care will be performed by one of the Critical Care Physicians at PUH. There are no deviations from the standard care received for subjects with these diagnoses. Discussions of the study, informed consent, and subsequent subject interaction will occur during the initial visit that occurs in the hospital at the time of diagnosis. There are 4 groups that are being evaluation: subjects undergoing appendectomy and exposed to Blue light: n=12 subjects undergoing appendectomy and NOT exposed to Blue light: n=12 subjects undergoing colon resection for diverticulitis and exposed to Blue light: n=12 subjects undergoing colon resection for diverticulitis and NOT exposed to Blue light: n=12 subjects with pneumonia and exposed to Blue light: n=12 subjects with pneumonia and NOT exposed to Blue light: n=12 Subjects that are to be exposed to Blue light will be provided by the research personnel (Dr. Rosengart) with a Day-Light Classic 10,000 lumen SAD light, a device that has been used in many of the previously listed published studies (Epilepsy Behav. 2012 Jul;24(3):359-64. doi: 10.1016/j.yebeh.2012.04.123. Epub 2012 May 30.) This light is fitted with a blue spectrum filter, such that it produces 2000 lumens of blue spectrum lighting at a distance of 12 inches. This intensity of light is 1/5 of what has been used in prior human studies. The comparative groups that are not exposed to Blue light do not receive this light, but otherwise, undergo identical standard of care and will have blood drawn for research purposes. At the time of enrollment subjects to be exposed to Blue light will be instructed in the use of the light, though during the period of light exposure the light will be managed by the investigative team. The light is small (4 X 16 X 21 inches) and weights less than a pound. It is UV filtered and glare free. There is a single "On/Off" switch. This study is one of effectiveness rather than efficacy. Thus, there are no rigid guidelines that are mandated regarding location or duration of lighting or other environmental restrictions. Surgical cohort: On the day of surgery, subjects that are to be exposed to Blue light will be exposed to the blue spectrum light after consent and prior to the operation. They will also be exposed to the light for a 24 hour period postoperatively. This light exposure will be initiated, maintained, and removed by Dr. Matthew Rosengart. The light will be positioned 12 inches from the subject for the period prior to and for 24 hours during postoperative day 1. At any time the subject may request the light to be removed. Preoperative and postoperative standard care, including blood sample analysis will be directed by the surgical team and performed at UPMC PUH hospital. Pneumonia cohort: On the day of diagnosis of pneumonia, subjects that are to be exposed to Blue light will be exposed to the blue spectrum light after consent. They will be exposed to the light for a 24 hour period after diagnosis. They will also be exposed to the blue light for 12 hours on days 2 and 3 of treatment of pneumonia. The light exposure will be initiated, maintained, and removed by Dr. Matthew Rosengart. The light will be positioned 12 inches from the subject for the period prior to and for 24 hours during postoperative day 1. At any time the subject may request the light to be removed. For ALL subjects we will abstract data from the electronic record regarding white blood cell count. An additional 2 samples of blood will be obtained for research purposes only to measure serum cytokine concentrations. These blood samples are obtain from ALL subjects in the study.

High illuminance (1000lux), blue spectrum (peak 441 nm) light for an initial 24 hour photoperiod and then a 12 hour photoperiod for days 2 and 3 after randomization.

High illuminance (1000lux), blue spectrum (peak 441 nm) light for an initial 24 hour photoperiod after surgery for diverticulitis

High illuminance (1000lux), blue spectrum (peak 441 nm) light for an initial 24 hour photoperiod after surgery for diverticulitis

Standard ambient hospital lighting (~300 lux) for an initial 24 hour photoperiod and then a 12 hour photoperiod for days 2 and 3 after randomization.

Standard ambient hospital lighting (~300 lux)for an initial 24 hour photoperiod after surgery for diverticulitis.

Standard ambient hospital lighting (~300 lux) for an initial 24 hour photoperiod after surgery for diverticulitis.

Subjects that are to be exposed to blue light will be provided by the research personnel with a Day-Light Classic 10,000 lumen SAD light, a device that has been used in many of the previously listed published studies (Epilepsy Behav. 2012 Jul;24(3):359-64. doi: 10.1016/j.yebeh.2012.04.123. Epub 2012 May 30.) The light is small (4 X 16 X 21 inches) and weights less than a pound. It is UV filtered and glare free. There is a single "On/Off" switch. It will be attached to a rolling stand. This light is fitted with a blue spectrum filter (peak 441 nm) such that it produces 1000 Lux of blue spectrum lighting when positioned at a distance of 12 inches from the subject.

Inclusion Criteria: All patients greater than or equal to 18 years old and undergoing 1) appendectomy for appendicitis, 2) colon resection for diverticulitis,, and 3) treatment of pneumonia. Exclusion Criteria: traumatic brain injury, blindness, immunocompromised or immunosuppressed state