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Tactics to Support the Clinical Strategy infiltrates, with increased macrophages in the alveoli and
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Assessment of Risk Factors interstitium. Inflammatory cytokine production by
Identifying whether the patient is at increased risk of macrophages would also induce vigorous neutrophil
severe disease course and poorer outcomes with chemotaxis to sites of inflammation, driving the NETosis

SARS-CoV-2 infection is critical. As an early robust referred to elsewhere in this paper. There is significant
immune response may be predictive of a milder form of ongoing discussion of senolytics for the treatment or
disease, patients at greater risk may be candidates for prevention of COVID-19. 137
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NK cell and Th1 cell support at baseline, rather than
waiting until they become infected. Patients With Known Comorbidities
The mechanisms underlying various risk etiologies The risk factors discussed earlier need to be identified,
may give perspective to the individual case and provide particularly including hypertension, diabetes,
clues as to how to treat the patient, with the goal of cardiovascular disease, malignancy, respiratory problems,
minimizing these risks. and obesity. Underlying upregulation of NLRP3 expression
in these diseases suggests that inhibition of the
Health Care Workers inflammasome, perhaps through greater emphasis on
Health care workers, who are potentially exposed to tactics in the Foundational and Anti-inflammatory Targets
larger volumes of viral load, from repeated exposure to of Support categories, starting at baseline, may be essential
infected patients, have been observed to be at greater risk in patients with these risk factors.
of developing more severe forms of COVID-19.
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Patients With Respiratory Problems
Older Individuals Fibrotic diseases like idiopathic pulmonary fibrosis,
Hospitalization rates for COVID-19 increase with hypersensitivity pneumonitis, and COPD may confer

age and are highest among older adults; the majority of significantly increased risk. An established fibrotic
hospitalized patients have underlying conditions. mechanism involving TGFβ suggests that, in addition to
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Immune function declines with age, particularly T cell- NLRP3 inflammasome inhibition, greater emphasis may
mediated activity, which increases morbidity and need to be placed on GSH and vitamin D, as both can
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mortality from infectious disease. Thymus involution is inhibit TGFβ. This may be appropriate early in the clinical
correlated with aging and loss of T cell activity. Select course of these cases, and/or as part of an overall prevention
nutrients recommended in the five Targets of Support strategy in cases with these features.
and elsewhere including zinc and vitamins A and D have Patients With Genetic Susceptibilities. As part of the
recognized benefit on thymus function and T cell status, assessment of patient risk factors, genotype testing to
and may therefore be especially beneficial for older assess patient GSH functional capacities may be clinically
individuals. 131,132 useful. For example, patients with exaggerated
Older age carries with it the likelihood of onset of inflammatory neutrophil response to inhaled ozone were
Immunosenescence. Immunosenescence may increase 13x more likely to carry the GSTM1null genotype. If
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the risk of contracting an infection and may also make it infected, these patients might more readily enter the
harder to clear infections. In older humans, macrophages Escalating Inflammation Phase of COVID-19. Higher
become less efficient, phagocytize less, and secrete more doses of GSH and NAC may be appropriate in these cases,
inflammatory cytokines. This age-associated low-level to compensate for the genotypic disadvantage.
inflammatory upregulation is termed “inflammaging.” See also the discussion of polymorphisms related to
Inflammaging may contribute to poorer immunological zinc and IL-6 in the discussion of zinc.
outcomes, manifesting as both less efficient macrophage
pathogen clearance and greater macrophage production of Tactics for the Five Targets of Support
inflammatory cytokines. Inflammaging is consistent This section describes the tactics associated with each
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with the description of macrophage activation syndrome of the five Targets of Support. It’s important to understand
(MAS), described as contributing to increased COVID-19 which tactics to apply throughout, and which ones to
age-related mortality. In MAS, macrophages produce emphasize during specific Phases of the disease process.
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excessive amounts of inflammatory cytokines. This is Information in the tables and text, along with the clinician’s
consistent with the inflammaging model. Inefficient unfolding work with the patient, form the basis for that
macrophage mediated pathogen clearance would perhaps discernment.
explain the observation that, early in the disease process,
the innate immune system fails to adequately suppress 1. Foundational Support
proliferation of the virus, and yet there is copious To address foundational support, clinicians can
infiltration of innate immune cells in the lungs of patients consider addressing factors that impact immunological
with progressed disease. In an autopsy study of six integrity as well as factors that drive non-purposeful
SARS-CoV-1 patients, four were found to have giant cell inflammation.

Yanuck—Immuno-physiological Approach to COVID-19 Integrative Medicine • Vol. 19, No. S1 • Epub Ahead of Print 17