Cytocentric Visionaries dg02

Cytocentric Visionaries: Dr. David Gozal, MD

Part 2: COVID-19 Research, Prone Positioning, and Chronoadequacy

Alicia Henn, PhD MBA, Chief Scientific Officer, BioSpherix
David Gozal, MD, MBA, PhD (Hon) is the Marie M. and Harry L. Smith Endowed Chair and Chairperson of the Department of Child Health, and Pediatrician-in-Chief, MU Women’s and Children’s Hospital, both at the University of Missouri School of Medicine. He is an expert in pediatric sleep disorders and the effects of hypoxia resulting from sleep apnea.
In Part One, we talked with Dr. Gozal about his recent publication in the European Respiratory Journal, “Putative contributions of circadian clock and sleep in the context of SARS-CoV-2 infection”, published in April of this year. [1]  Here we go into more depth with the concept of chronoadequacy and COVID-19 Research. This interview was edited for length and clarity.
I am in love with the term “chronoadequacy” from this paper. That seems to me like a large concept embodied in a single word. Can you describe it for me?
I did not make it up, somebody else did, but I love this term as much as you do because I think it illustrates two major elements of the field.  One is the importance of time as a function of the world and environment in which we live, and the other implies the importance of being aligned with that environment. That’s essentially living within your time in the best possible way.
One of the issues of chronoadequacy followed work on chronotherapy. When is the best time to give, for example, a chemotherapeutic drug? There are very nice studies, for example, in breast cancer. Tailoring the administration of the specific therapy at the time that would be the most favorable from their circadian clock specific status led to better results. We have been talking about the chronotherapy of hypertension. In what phase of the Circadian Cycle is it most optimal to give medication to achieve optimal control of blood pressure with that specific dose of the medication?
These aspects reflect a unique wave of implementation of personalized medicine. In order to have personalized medicine, you need to know what major determinant systems are operational and then tailor those to achieve the optimal therapy for that individual. Chronotherapy, and chronoadequacy if you wish, are as important in the scheme of things as your body weight or your genotype or phenotype to optimize both the diagnostics as well as the management. 
I think chronoadequacy is here to stay. However, it is not yet pervasively implanted in the mind of most of the physicians. But with the spread of wearable technologies to look at sleep, maybe this will open the window. Maybe algorithms within the software could provide not only the quality of your sleep, but also the possibly provide recommendations for chronoalignment or circadian phenotyping. Say you're taking Medication X. Based on your wearables you should probably be taking it at let's say 10:00AM as opposed to taking it at 6:00AM. I think technology will open the way for chronoadequacy to establish itself as part of the personalized medicine armamentarium. 
How about in the hospital environment where you have patients being monitored 24/7? 
It's more complicated because it's not just about circadian, it's also about insufficient sleep or interruption of sleep. In the hospital do I need to measure blood pressure every 2 or 4 hours? Well you may need to. If you don't, can we safeguard sleep in a hospital setting in order to optimize outcomes of those patients? The data is still very early, but there are advantages of doing this. I think that we still have a ways to go. We started when I was at the University of Chicago to work with Dr. Vineet Arora on the children's component. On the adult side, Dr Vineet Arora and others have done very nice work showing that sleep disruption was tremendous even in the regular ward. Attention to some of these details could lead to less stress levels and better recovery. 
I think that we're seeing a trend of moving away from the standard rigid approach to disrupting sleep, as safeguarding sleep is a way to facilitate patient recovery.
And in the lab, working with lab animals in our daytime means working with them in their nighttime.
Yeah, it does. Mice sleep through the day and night, they just have different densities of sleep. They sleep much more during the daylight and then during the night they have shorter naps. We did a study that we never published. We found that to do certain behavioral testing in mice during the daylight, which would be convenient to us, had different results when done during the night. Obviously, their level of commitment and interest was going to be different. We now routinely do our behavioral work in their active phase, not in their rest phase.
The paper also focuses on sleep apnea or sleep disorders because you cannot explicate one from the other completely. If you are a shift worker or if you are circadianly-challenged your sleep is going to be affected as well. You don't sleep as many hours, you have insufficient sleep, and you have fragmented sleep. You wake up many more times when you are sleeping during a circadian misalignment. 
Also remember that sleep apnea affects a billion people in the world at least, based on historical estimates. Hypoxia and intermittent hypoxia can lead to changes in ACE2 expression. The corollary of these facts is obvious.  
And that is critical for COVID-19-19 research.
In the context of intermittent hypoxia, and of sleep apnea models, ACE2 expression, and therefore an immune dysregulation, could trigger both higher susceptibility to infection as well as higher susceptibility to spread and replication of the disease within the cells. Ultimately, it could lead to more severe outcomes, both in COVID-19 patients that just have sleep apnea, and those that have more underlying morbidities. 
But let's think of all the people that have sleep apnea who are in risk groups, for example, the obese. We know that they have more severe disease with COVID-19-19. Patients with chronic lung disease, they have it more severe. Well, chronic lung diseases such as COPD or asthma are also at much higher risk of having sleep apnea and having intermittent hypoxia. People with cardiovascular diseases, hypertension, or diabetes; all of these high-risk groups with highest mortality happen to be people where one of the underlying high prevalence diseases happens to be sleep apnea or intermittent hypoxia. So we made the inference of that in the editorial as well, even though we didn't want to push it since we don't have enough evidence.
It's very difficult to show because nobody’s screening for sleep apnea in all the patients with COVID-19. Then you have to stratify for severity and how do you adjust for confounders? You would need a very large cohort. Nonetheless, I think that is another area that we need to be cognizant. 
One of the interesting things is prone positioning of the patient is improving their breathing substantially. Well prone positioning also removes upper airway obstruction and optimizes the interdependencies between the upper airway and the lungs. Therefore, as we try to get away from ventilating patients and move to putting them in prone position and on CPAP, it’s remarkable to me that we are not thinking that sleep apnea and intermittent hypoxia may be contributors to some of the variance in infection rates and outcomes. So we put it in the article as well, but it's something that we need to talk about. 
The other one is insufficient and disrupted sleep. Insufficient sleep may alter the immune system. We know it. We showed with interrupted sleep or disrupted sleep or fragmented sleep that there is clearly activation of innate immunity. We know that COVID-19 is involved in both the activation of the innate immunity as the first stage, but also an exhaustion of T-cells. In insufficient sleep, all of these elements that have to do with defense mechanisms against the virus may also be altered. 
So on one side are the cell receptors that propagate the virus. On the other side is immune recognition and immune processing and the ability to overcome the virus. All these can be put into an envelope that says, rather shouts “circadian and sleep”. 
All this is critical for COVID-19 Research
We need to put all this in context. We cannot separate ourselves. We are in Mother Earth and Mother Earth is regimented by the light and dark, and from the dawn of life we developed systems that regulate the clock. This affects all functions of the body. To understand any threats such as COVID-19-19 or its solution we need to make sure that we control for the clock. 
Thank you for your time and your thoughts. We look forward to seeing how hypotheses like these could produce studies that might reduce COVID-19 infection rates and improve the community’s care for COVID-19 patients.

This concludes our interview series with Dr. David Gozal, MD.

 If you would like to be featured in our Cytocentric Visionary Series, contact us. We would love to hear about your work.

  1. Meira, E.C.M., M. Miyazawa, and D. Gozal, Putative contributions of circadian clock and sleep in the context of SARS-CoV-2 infection. Eur Respir J, 2020: p. 2001023.
  2. Tufik S., D. Gozal D, I.A. Ishikura, G.N. Pires, and M.L. Andersen. Does obstructive sleep apnea lead to increased risk of COVID-19 infection and severity? J Clin Sleep Med. 2020 May 22. doi:  10.5664/jcsm.8596. Epub ahead of print. PMID: 32441246.


alicia author iconAbout the Author

Alicia D Henn, PhD, MBA

Alicia Henn has been the Chief Scientific Officer of BioSpherix, Ltd for two years. Previously, she was a researcher at the Center for Biodefense Immune Modeling in Rochester, NY. Alicia obtained her PhD in molecular pharmacology and cancer therapeutics from Roswell Park Cancer Institute in Buffalo, NY and her MBA from the Simon School at University of Rochester in Rochester, NY.