Evidence Supporting a Phased Immuno-physiological Approach to COVID-19 From Prevention Through Recovery

Abstract

This paper presents an evidence-based strategy for improving clinical outcomes in COVID-19. Recommendations are based on the phases of the disease, because optimal interventions for one phase may not be appropriate for a different phase. The four phases addressed are: Prevention, Infection, Inflammation and Recovery. Underlying this phased approach is recognition of emerging evidence for two different components of pathophysiology, early infection and late stage severe complications. These two aspects of the disease suggest two different patterns of clinical emphasis that seem on the surface to be not entirely concordant. We describe the application of therapeutic strategies and appropriate tactics that address four main stages of disease progression for COVID-19. Emerging evidence in COVID-19 suggests that the SARS-CoV-2 virus may both evade the innate immune response and kill macrophages. Delayed innate immune response and a depleted population of macrophages can theoretically result in a blunted antigen presentation, delaying and diminishing activation of the adaptive immune response. Thus, one clinical strategy involves supporting patient innate and adaptive immune responses early in the time course of illness, with the goal of improving the timeliness, readiness, and robustness of both the innate and adaptive immune responses. At the other end of the disease pathology spectrum, risk of fatality in COVID-19 is driven by excessive and persistent upregulation of inflammatory mechanisms associated with cytokine storm. Thus, the second clinical strategy is to prevent or mitigate excessive inflammatory response to prevent the cytokine storm associated with high mortality risk. Clinical support for immune system pathogen clearance mechanisms involves obligate activation of immune response components that are inherently inflammatory. This puts the goals of the first clinical strategy (immune activation) potentially at odds with the goals of the second strategy(mitigation of proinflammatory effects). This creates a need for discernment about the time course of the illness and with that, understanding of which components of an overall strategy to apply at each phase of the time course of the illness. We review evidence from early observational studies and the existing literature on both outcomes and mechanisms of disease, to inform a phased approach to support the patient at risk for infection, with infection, with escalating inflammation during infection, and at risk of negative sequelae as they move into recovery.

Figure 1.

Five Targets of Support as they apply to the four Phases in the time course of disease. It’s essential that if the patient moves from the Infection Phase to the Escalating Inflammation Phase, the emphasis shifts to downregulation of the potentially life-threatening inflammatory process.

Figure 2.

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

Figure 3.

Impact of Timing On Disease Course in COVID-19. Timely type 1 Interferon response yields antiviral response more likely to adequately suppress viral burden, leading to a milder clinical course. Delayed innate immune response, including delayed upregulation of type 1 interferons, may allow greater viral proliferation, leading to more extensive disease and poorer clinical outcomes. Adapted from Channappanavar et al and Klinker et al.

Figure 4.

The patient’s baseline level of pulmonary and systemic inflammation may in some cases impact their fatality risk. In A, the patient’s baseline level of inflammation at onset of infection is modest. As the immune response to the virus evolves, inflammatory cytokines are generated, moving the patient further up the vertical axis. However, the patient’s biology can accommodate this increase, as the incremental increase in inflammation is far from that which might risk moving the patient into manifesting ARDS, septic shock, heart or kidney failure, etc. In B, the patient’s baseline level of inflammation at onset of infection is higher. The same incremental additional inflammation associated with the immune system’s choreography of responding to the virus moves the patient correspondingly further up the vertical axis, moving the patient closer to the threshold of manifesting ARDS or other fatality risks. It’s noteworthy that, in some cases, inflammation may rapidly escalate from a low baseline to an excessively vigorous inflammatory response that puts the patient in jeopardy, for a host of reasons both known and unknown. So, a low starting inflammatory baseline may not be decisively protective. Nonetheless, moving the patient down the vertical axis, so that the crescendo of the inflammatory process inherent in killing virus doesn’t bring them across their threshold of fatality risk, is a worthy clinical goal that may improve the patient’s outcome.

Figure 5.

The relationships between TGF, GSH, ROS, fibrosis, alveolar inflammation, and NETosis in processes occurring at sites of local infection/inflammation. As with all such maps, the reality of the underlying biology is more deeply interconnected.

Figure 6.

The impact of MDSC / TGF / ROS interactions on T Cells and NK Cells.