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Figure 2. Proposed approach to populating the five Targets of Support, across the four Phases of COVID-19 disease.

Immunological Framework (programmed cell death) in the infected T cells. In a
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Emerging evidence in COVID-19 suggests that the SARS-CoV-1 experimental model, robust virus replication
SARS-CoV-2 virus employs pathogen evasion strategies was accompanied by delayed type I interferon (IFN-I)
against macrophages, including delaying macrophage signaling, yielding inflammatory responses and lung
activation and infecting and killing macrophages. The immunopathology that diminished survival. Early IFN-I
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capacity to delay the innate immune response is consistent administration ameliorated immunopathology, suggesting
with the observation that host infection can occur two to that supporting efficient immune response early in the
fourteen days before the onset of symptoms. In a prospective infectious process might be useful.
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examination of patients stratified according to percentage In SARS-CoV-2 infection, if macrophages and DCs
of total lymphocytes (without differentiation of constituent are being destroyed by the virus before they can initiate
cells), those with the most marked lymphopenia (<5%) had effective antigen presentation to activate the adaptive
significantly higher mortality than those with total immune system, those with the highest viral loads might
lymphocytes <20%, measured at two time points. be expected to do most poorly. Higher viral loads would
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Lymphopenia linked to mortality implies that macrophages be expected to destroy more macrophages and DCs and to
and dendritic cells (DC’s) are failing to respond to epithelial more decisively inhibit the immune activation necessary
cell-derived pathogen associated molecular patterns to get ahead of the virus. This might contribute to
(PAMPs) and damage associated molecular patterns understanding of why health care workers, who are
(DAMPs) and hence achieve optimal maturation in order to potentially exposed to larger volumes of viral load, from
recognize and ultimately present antigen to naïve T cells, in repeated exposure to infected patients, would have greater
order to engage the adaptive immune system. Failure of risk of severe disease, as has been observed.
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clonal expansion of adaptive immune cells is a driver of In addition to appropriate measures aimed at social
lymphopenia. The weakness of the initial round of immune isolation, disinfection, and related approaches, this view
response may also make it more likely that when the suggests the importance of support for efficient activation
clonally expanded populations of T and B cells undergo of the innate immune system both pre-infection in
subsequent timed clonal contraction, there may often still susceptible individuals and as an early phase intervention
be enough virus left for a surge of disease symptoms in the in infected individuals.
so-called second wave of illness. However, every immune response against pathogens
SARS-CoV-2 has also been shown to infect but not carries with it, inherently, an incremental increase in
replicate in MT-2 experimental T cells in a lab setting. A inflammatory cytokine activation. In addition, damage to
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study of Middle Eastern Respiratory Syndrome (MERS) host tissues drives additional recruitment of neutrophils,
showed that the MERS coronavirus induced apoptosis macrophages, and other immune elements to the site of

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