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role of the NLRP3 inflammasome in organ fibrosis and its of the focus on therapeutic downregulation of IL-6
follow-on consequences for substantial subsequent in COVID-19. Of note, CXCR2 antagonism, which
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mortality risk. TGFβ is known to drive fibroblast and inhibits neutrophil migration to sites of infection, plays a
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fibrocyte transformation into myofibroblasts, the cells down-regulatory role in circulating neutrophil NET
responsible for the development of tissue fibrosis. TGFβ formation in COPD. Therefore, therapeutics that can
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and ROS reinforce each other’s activation. Production of slow/prevent neutrophil migration may be of clinical
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(ROS) can further drive lung fibrosis and can also benefit as another mode of dampening inflammation-
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promote further NLRP3 inflammasome upregulation, 33,40,41 based processes that contribute to COVID-19 morbidity.
completing a positive feedback loop.
Inflammasome activation is the driver of Phase 4 - Recovery
autoinflammatory disease. There is a noteworthy association Disease sequelae, including persistent organ
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between autoimmune diseases and autoinflammatory dysfunction, are a significant concern, particularly related
disease, with inflammasome activation driving inflammation to acute lung injury and fibrosis. In SARS-CoV-1, 20% of
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in many autoimmune diseases. 43,44 This suggests that patients recovered patients had fibrotic disease nine months post
with autoimmune disease in outpatient clinical settings may infection. Given the apparent role of the NLRP3
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need to be followed with heightened discernment regarding inflammasome in COVID-19, and the role of NLRP3 in
their risk of shifting into a course of disease process that driving TGFβ-mediated fibrosis mentioned already, it
enters the Escalating Inflammation Phase. becomes essential to attend to the patient’s potential need
NETs, Thrombosis, Sepsis, and Fibromyxoid for persistent downregulation of inflammasome biology,
Exudates. Increased risk of thrombosis and septic with the goal of mitigating risk of additional consequences
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shock have been described in COVID-19. At autopsy, the from non-lethal but nonetheless life changing sequelae
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alveoli are described as containing cellular fibromyxoid related to lingering inflammatory and fibrotic effects that
exudates. In February, a Chinese respiratory expert occur in the tail of the curve after the crescendo of disease
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described COVID-19 as involving a “large amount of very has passed. As mentioned above, because patients have
sticky mucus in their small airways.” 47 been observed to relapse into the Escalating Inflammation
Thrombosis, sepsis, and thick mucous secretions share Phase, it is essential for clinical surveillance to continue
neutrophil extracellular traps as a common causal agent. In well into what may appear to be the Recovery phase.
addition to phagocytosis and degranulation, neutrophils These Phases and their corresponding clinical
can kill pathogens by extruding neutrophil extracellular imperatives are interconnected and bidirectional. There is
traps (NETs), a process termed NETosis. NETs have been both a sequencing as the patient transitions between them
identified in the lungs of cystic fibrosis (CF), acute lung and an order of importance of tactics to address each of
injury (ALI), allergic asthma, and lungs infected with them, addressed in the tables that describe the tactics. If the
bacteria, virus, or fungi. NETs have been shown to predict patient becomes infected, the very same clinical goals that
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adverse outcomes in community acquired infections such are appropriate to the Prevention Phase (avoiding infection
as pneumonia. A NET is a chromatin mesh, adorned and early virus clearance) will continue to apply as in the
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with anti-microbial peptides and enzymes like neutrophil Infection Phase. The key tactical transition occurs if the
elastase. 50,51 With increased ROS, a shift toward excessive patient enters the Escalating Inflammation Phase.
NETosis drives a significantly exaggerated inflammatory
response. Exaggerated NETosis has been described in Five Targets of Support
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diabetes and cardiometabolic disease, risk factors that There are five types of clinical support that target
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drive greater mortality in COVID-19. specific patient immune functions. Some forms of support
The NETosis response in acute infection can trigger are appropriate to all Phases in the time course of the
thrombosis. This has been termed immunothrombosis. disease. Others need to be emphasized or deemphasized,
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NETs have been shown to drive death of epithelial cells depending upon the Phase. Taken together, the five Targets
and endothelial cells, through a histone-dependent of Support represent a strategy that can be deployed across
mechanism. Extracellular histones, the primary protein the four Phases in the time course of the patient’s illness.
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of the chromatin mesh of NETs, have been shown to
contribute to mortality in sepsis. NETosis contributes to Target 1 - Foundational Support
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the picture of septic shock. 48,57 In addition to core approaches involving isolation,
NETosis is involved at the site of lung infection, where disinfection, and other such factors, foundational support
it increases mucous viscosity, and in the circulation, involves several key components:
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where it can promote clot formation. 59,60 NETs appear to
provide a third form of clot-forming scaffold, in addition a. Eliminating factors that can drive non-purposeful
to fibrin and vonWillebrandt Factor (vWF). 60 inflammation and related dysregulatory impacts
Interleukin-6 (IL-6) is a potent inducer of NET on immune function. The patient’s inflammatory
formation. This is particularly interesting, in light baseline status is influenced by pre-existing
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12 Integrative Medicine • Vol. 19, No. S1 • Epub Ahead of Print Yanuck—Immuno-physiological Approach to COVID-19