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REVIEW OF EMERGING RESEARCH

Evidence Supporting a Phased Immuno-physiological

Approach to COVID-19 From Prevention Through Recovery

Yanuck SF , Pizzorno J , Messier H , Fitzgerald KN 4
1
3
2
1 Program on Integrative Medicine, Department of Physical Medicine and Rehabilitation, University of North Carolina School of Medicine; Yanuck Center
for Life & Health; Cogence Immunology; Chapel Hill, NC, USA. Corresponding author: syanuck@yanuckcenter.com
2 Editor-in-Chief, Integrative Medicine, A Clinicians Journal; Coauthor, Textbook of Natural Medicine; Chair, Board of Directors, Institute for Functional
Medicine; Founding President, Bastyr University; Seattle, WA, USA.
3 Medical Director, Altum Medical; Chief Medical Officer, Medical Intelligence Learning Labs; San Francisco, CA, USA.
4 Clinic Director, Sandy Hook Functional Medicine; Sandy Hook, CT, USA.
Abstract
This paper presents an evidence-based strategy for improving the timeliness, readiness, and robustness of
improving clinical outcomes in COVID-19. both the innate and adaptive immune responses.
Recommendations are based on the phases of the disease, At the other end of the disease pathology spectrum,
because optimal interventions for one phase may not be risk of fatality in COVID-19 is driven by excessive and
appropriate for a different phase. The four phases persistent upregulation of inflammatory mechanisms
addressed are: Prevention, Infection, Inflammation and associated with cytokine storm. Thus, the second
Recovery. clinical strategy is to prevent or mitigate excessive
Underlying this phased approach is recognition of inflammatory response to prevent the cytokine storm
emerging evidence for two different components of associated with high mortality risk.
pathophysiology, early infection and late stage severe Clinical support for immune system pathogen
complications. These two aspects of the disease suggest clearance mechanisms involves obligate activation of
two different patterns of clinical emphasis that seem on immune response components that are inherently
the surface to be not entirely concordant. We describe inflammatory. This puts the goals of the first clinical
the application of therapeutic strategies and appropriate strategy (immune activation) potentially at odds with the
tactics that address four main stages of disease goals of the second strategy (mitigation of proinflammatory
progression for COVID-19. effects). This creates a need for discernment about the
Emerging evidence in COVID-19 suggests that the time course of the illness and with that, understanding of
SARS-CoV-2 virus may both evade the innate immune which components of an overall strategy to apply at each
response and kill macrophages. Delayed innate immune phase of the time course of the illness.
response and a depleted population of macrophages can We review evidence from early observational
theoretically result in a blunted antigen presentation, studies and the existing literature on both outcomes and
delaying and diminishing activation of the adaptive mechanisms of disease, to inform a phased approach to
immune response. Thus, one clinical strategy involves support the patient at risk for infection, with infection,
supporting patient innate and adaptive immune responses with escalating inflammation during infection, and at
early in the time course of illness, with the goal of risk of negative sequelae as they move into recovery.

Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Immunological Framework. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Clinical Strategy for Patient Support in COVID-19 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Four Phases in the Time Course of COVID-19 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Five Targets of Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Tactics to Support the Clinical Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Assessment of Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Tactics for the Five Targets of Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
1. Foundational Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2. Natural Killer (NK) cell support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
3. Th1 cell support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
4. Anti-Inflammatory Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
5. Anti-Oxidant Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Appendix I - Drug – Nutrient Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

6 Integrative Medicine • Vol. 19, No. S1 • Epub Ahead of Print Yanuck—Immuno-physiological Approach to COVID-19