Abstract
While the pathological mechanisms in COVID-19 illness are still poorly understood, it is increasingly clear that high levels of pro-inflammatory mediators play a major role in clinical deterioration in patients with severe disease. Current evidence points to a hyperinflammatory state as the driver of respiratory compromise in severe COVID-19 disease, with a clinical trajectory resembling acute respiratory distress syndrome, but how this ‘runaway train’ inflammatory response emerges and is maintained is not known. Here, we present the first mathematical model of lung hyperinflammation due to SARS-CoV-2 infection. This model is based on a network of purported mechanistic and physiological pathways linking together five distinct biochemical species involved in the inflammatory response. Simulations of our model give rise to distinct qualitative classes of COVID-19 patients: (i) individuals who naturally clear the virus, (ii) asymptomatic carriers and (iii–v) individuals who develop a case of mild, moderate, or severe illness. These findings, supported by a comprehensive sensitivity analysis, point to potential therapeutic interventions to prevent the emergence of hyperinflammation. Specifically, we suggest that early intervention with a locally acting anti-inflammatory agent (such as inhaled corticosteroids) may effectively blockade the pathological hyperinflammatory reaction as it emerges.
Highlights
SARS-CoV-2, the causative viral agent for COVID-19 illness, has infected tens of millions of people and caused many deaths worldwide
We (i) investigate which qualitative differences in inflammation levels can be observed in patients infected by SARS-CoV-2, and (ii) determine how inhaled corticosteroids (ICS) treatment can be employed to reduce inflammation in the lung epithelium, thereby preventing the onset of hyperinflammation and other severe damage associated with high levels of pro-inflammatory mediators
Using the current understanding of COVID-19 [5,6], we consider a mathematical modelling framework that describes the temporal evolution of five species at early timescales of SARS-CoV-2 viral infection: pro-inflammatory mediators, recruited immune system cells, freelymoving SARS-CoV-2 virus (V), cells susceptible to viral infection, and infected cells (I)
Summary
SARS-CoV-2, the causative viral agent for COVID-19 illness, has infected tens of millions of people and caused many deaths worldwide. As it has been recognized that COVID19 produces a ‘runaway’ train pattern of hyperinflammation [5,6], it can be postulated that early intervention with an anti-inflammatory, such as inhaled corticosteroids (ICS), could contain the illness [7] This hypothesis is supported further by the clinical finding that chronic respiratory diseases (such as asthma and chronic obstructive pulmonary disease, COPD) are not the most common co-morbidities seen in COVID-19 [8], indicating that ICS, a common treatment for asthma and COPD, could provide a protective response. We present a five-component mathematical model that describes inflammation kinetics, viral infection, and novel mechanisms that couple their dynamics Using this model, we (i) investigate which qualitative differences in inflammation levels can be observed in patients infected by SARS-CoV-2, and (ii) determine how ICS treatment can be employed to reduce inflammation in the lung epithelium, thereby preventing the onset of hyperinflammation and other severe damage associated with high levels of pro-inflammatory mediators
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