COVID19 Pathophysiology

Disease: Novel coronavirus disease 2019 (COVID-19)

 

This article concerns the "host side" of the infection. 

To learn more about the "viral side" (e.g. viral characteristics and virulence factors) see here: 

Severe acute respiratory syndrome coronavirus 2

 

Disclaimer:

At the timing of writing, COVID-19 has been a known clinical entity for just over one year. 

This is an area of intense active research. 

The information presented herein is likely to change many times as new evidence is gathered and reported.

 

Risk factors associated with cases of severe COVID-19:

• Advancing age
  
• Tobacco smoking
  
• Cancer
• Organ dysfunction
  
• Respiratory dysfunction
• Chronic Obstructive Pulmonary Disease
• Cystic fibrosis 
• Asthma (severe)
  
• Heart failure
• Chronic Kidney Disease 
• Chronic liver disease
• Vascular dysfunction
• Hypertension
• Cerebrovascular disease
• Endocrine/Metabolic dysfunction
• Obesity
• Type 1 Diabetes Mellitus
• Type 2 Diabetes Mellitus 
• Haemoglobinopathies
  
• Sickle cell disease
• Thalassaemia
  
• Pregnancy
  
• Immunosuppression
• Immunosuppressive therapy

 

There is evidence to suggest that a large spectrum of chronic diseases may increase the probability of severe disease and death.

• Complex metabolic derangements such as obesity and Diabetes Mellitus may cause a generalised dysfunction of immunity, predisposition to inappropriately severe inflammation, or reduced physiological reserve.
• Some pathophysiological abnormalities may interact with SARS-CoV2 directly, to cause dysfunction unique to COVID-19.
  
• Chronic organ dysfunction is associated with severe disease and death. This may result from decompensation (a vulnerable organ fails to meet rising demands during an infection). There may exist a three-way dynamic interaction between increasing organ failure (failure to meet demand), an intensifying global inflammatory response, and a rising viral load.

 

Pathological findings associated with cases of severe COVID-19:

• High blood viral load.
• Lymphocytopoenia
• Relatively low numbers of NK cells.
• Relatively low numbers of T cells.
• Monocytosis (high numbers of monocytes).
• Hypercytokinaemia
• High serum levels of NF-kB, CXCR2, CCL2, CCR2, TNF-alpha, IL-6.
• Deficiencies in interferon signalling
• Relatively low levels of Interferon-alpha
• Relatively low expression of Interferon-Stimulated Genes.

 

The findings in severe COVID-19 appear consistent with a downward spiral of rising viral load, accumulating viral-mediated tissue damage, rising inflammatory signals, accumulating host-mediated tissue damage, depleting physiological reserves, and immune exhaustion. 

Genes with variants associated with cases of severe COVID-19:

• DPP9
• Enzyme
• Healthy variant: Many potential uses. Plays a role in cell adhesion.
  
• Disease variant: Potential cell surface vulnerability for viral entry.
• IFNAR2
• Receptor
• Healthy variant: Component of interferon signalling pathway. Antiviral function.
• Disease variant: Ineffective antiviral function.
  
• TYK2
• Enzyme
• Healthy variant: Component of interferon signalling pathway. Antiviral function.
• Disease variant: Ineffective antiviral function.
  
• CCR2
• Receptor
• Healthy variant: Component of chemokine signalling pathway. Antiviral function.
• Disease variant: Ineffective antiviral function.
  
• OAS1
• Enzyme. Induced by interferon signalling.
  
• Healthy variant: Promotes viral mRNA degradation. Antiviral function.
• Disease variant: Ineffective antiviral function.
  

 

There is evidence to suggest that specific genetic vulnerabilities in a host's antiviral defences increase the probability of severe disease and death.

 

The battle against every virus

• The spread of a viral infection throughout a host's body can be imagined as a battle. A successful virus is achieving three primary goals:
• It is invading new host cells at a greater rate than the rate of virus-infected cell destruction.
  
• It is replicating at a greater rate than the rate of viral destruction.
• It is spreading to new host bodies at a greater rate than the rate of host death or viral clearance.
  
• A host who survives and clears a virus has achieved several goals:
• They identified viral-infected cells, suppressed replication, and destroyed them.
• They coordinated trafficking of immune cells to virus-infected tissues.
• They destroyed virions at a rate faster than they could replicate or spread until no active virus remained.
  
• They maintained sufficient immune function to avoid death from other infections.
• They maintained vital physiological function (e.g. metabolism, organ function).
• The hosts who are most likely to lose this battle are:
• Incapable of destroying the virus at a sufficient rate.
• Failures of a specific antiviral defence (e.g. IFNAR2) .
• Generalised immune system dysfunction (e.g. immunosuppression).
• Incapable of suppressing viral replication sufficiently. 
• Failure of a specific antiviral defence (e.g. OAS1).
  
• Incapable of vital physiological function while burdened with the infection.
• Decompensated organ failure (e.g. heart failure).
• Respiratory failure.
• Sepsis
• Septic shock
  

 

Another hypothesis

• By causing down-regulation of ACE2 receptors throughout the body, SARS-CoV2 may interact harmfully with RAAS or the kinin–kallikrein system.
  
• This may be advantageous to the virus, but it is more likely to be an unfortunate coincidence for the host.

 

Challenges in modelling COVID-19

• Severe COVID-19 is associated with a large number of factors, which can interact with each factors in many ways.
  
• This is undoubtedly a complex system. 'Complex' features include:
  
• A network of interacting components (e.g. virus-cell interactions, cytokines, metabolism, organ function).
• Feedback loops (e.g. secretion of inflammatory factors to attract cells which secrete more inflammatory factors, without resolution of the infection).
• Emergent phenomena (e.g. the impact on the function of each organ).
  
• Nonlinearity (e.g. two hosts with identical physiologies and identical risk factors may have a dramatically different course of pathophysiology on a sub-cellular, cellular, and macroscopic level)
  
• Stochastic processes (e.g. intra-host virus-cell dynamics).

 

Summary

• There is already a wealth of information available about COVID-19. Many congenital factors, and acquired factors, appear to influence the probability of severe COVID-19 and death.
• We can expect a great deal more research over the coming years. Further research should reveal synergistic or antagonistic interactions between various combinations of factors. 
• Advances in technology may facilitate predictive modelling.