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specific system processes may be irrelevant. For those for For higher risk patients, it may be appropriate to
whom SARS-CoV-2 infection may create a substantial consider early initiation of tactics that appear in the
morbidity and/or mortality risk due to more aggressive or Infection Phase. This lets the high-risk patients get a head
extensive disease, excessive inflammatory activation is a start on immune activation.
concern which requires consistent, high level clinical
attention. Since there are cases in which young, fit, healthy Phase 2 - Infection
patients have died of COVID-19, this discernment must In this Phase, the patient has symptoms that may be
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be applied in every case. presumed to be related to the SARS-CoV-2 virus that
causes COVID-19 disease. They may have tested positive
for the virus. They may have respiratory or GI symptoms,
Clinical Strategy for Patient Support in fever, or other onset of new symptoms. The focus in this
COVID-19 Phase is on supporting the components of immune system
This section describes strategy. The section that function that are essential to the patient’s ability to fight
follows populates the strategy with tactics. the infection.

Four Phases in the Time Course of COVID-19 Phase 3 - Escalating inflammation
We propose four phases in the time course of the COVID-19 can enter a dangerous phase in which
disease, requiring different points of emphasis in the extreme upregulation of inflammatory cytokines can pose
clinical support strategy. mortal danger. The clinical goal in this Phase is to help
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the patient stay away from manifesting the excessive
Phase 1 - Prevention inflammatory cytokine production and tissue destruction
In the Prevention Phase, in addition to guidance associated with sepsis, ARDS, and cardiovascular
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about social distancing, masks, stress reduction, etc., the events. 14,29,30 Natural approaches here are supportive, not
task is to support the patient in anticipation of the primary. The unfolding disease process can escalate
possibility that they’ll contract the virus. This is rapidly. 31
accomplished by A) identifying and addressing ways to The current prevailing hypothesis is that a substantial
reduce baseline inflammation, and B) identifying and component of the inflammatory process in COVID-19 is
addressing deficiencies in key nutrients that are central to driven by activation of the nucleotide binding domain
healthy, robust immune system activation. (NOD)-like receptor protein 3 (NLRP3) inflammasome. 32,33
Part of the clinical task in this Phase is to triage patients Inflammasome-mediated lung inflammation has
as to risk factors for developing severe course of COVID-19. previously been described as steroid-resistant. Current
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The main non-pulmonary risk factors identified thus far are observations from inpatient settings describe steroids as
hypertension (HTN), diabetes, cardiovascular disease 14-16 having equivocal evidence in early acute circumstances,
and malignancy. Pulmonary risk factors include asthma, and being ineffective in progressed severe forms of
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COPD, and other respiratory diseases that would suggest COVID-19. 34
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the patient would be more likely to enter the Escalating It’s noteworthy that, in addition to asthma and
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Inflammation Phase if they become infected. Environmental COPD, non-respiratory risk factors like cardiovascular
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inflammatory stressors like air pollution have been shown disease, obesity, diabetes, and chronic kidney disease, that
to increase lung inflammation affect patients with present greater mortality risk in COVID-19, share the
respiratory disorders. 17,18 Two cases of early COVID-19 feature of having NLRP3 inflammasome activation as a
have been described in patients undergoing lobectomy for key component of their etiologies. 23,35 This connection
adenocarcinoma. Liver and kidney injury are also seems relevant, though whether the greater risk in patients
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mentioned. Obesity has also been reported as a risk with these diseases is a consequence of greater tendency to
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factor In the H1N1 epidemic, obesity and severe obesity vigorous epigenetic expression of NLRP3 or some other
.20
were significant risk factors. 21 mechanism is not clear. Given the speed with which these
Furman, et al, found that patients over the age of 85 cases can decline (<24 hrs), it becomes essential to discern
who had greater expression of specific inflammasome the inflection point at which more vigorous measures
gene modules had markedly greater all-cause mortality. must be taken to address declining function.
The same paper also showed an inflammasome mediated Particular attention may be usefully focused on the
activation of platelet aggregation that may not be age relationship between NLRP3, transforming growth factor
related. That’s important, given concerns about beta (TGFβ), reactive oxygen species (ROS, and glutathione
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thrombotic events in COVID-19. It is useful to notice that (GSH). In SARS-CoV-1, the virus upregulated TGFβ via
biology of inflammasomes, a key intracellular mechanism the ROS/p38 MAPK/STAT3 pathway, which correlated
that drives inflammation, plays a central role in diabetes, with upregulation of profibrotic responses in vitro and in
CVD, and obesity, in renal disease, in liver disease, vivo. The role of NLRP3 in inducing TGFβ-mediated
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23
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and in pulmonary inflammation. 12,26 activation of fibroblasts has been reviewed, as has the
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Yanuck—Immuno-physiological Approach to COVID-19 Integrative Medicine • Vol. 19, No. S1 • Epub Ahead of Print 11