Medicinomy

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Coronavirus disease 2019 (COVID-19)

Disease class: Coronavirus infections
Disease class: Respiratory tract infections
Disease class: Viral diseases

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.

 

Causative pathogen

• Severe acute respiratory syndrome coronavirus 2
  

 

Pathophysiology

 

Clinical profile

 

History

 

See also

• Severe Acute Respiratory Syndrome (SARS)
• Middle East Respiratory Syndrome (MERS)
• Influenza
• Dengue

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.
  

SARS-CoV-2 VUI-202012/01

Strain of: Severe acute respiratory syndrome coronavirus 2

 Also known as:

• Lineage B.1.1.7 
• Variant Under Investigation in December 2020
  

 

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.

 

Laconic

• A new strain of SARS-CoV-2 with significantly greater transmissibility.

 

Disease:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology

 

Probable origin:

• London, United Kingdom
• September 2020
  

 

Key mutations (compared to the first SARS-CoV-2 strain)

17 in total

• N501Y : point mutation from asparagine (N) to tyrosine (Y) in amino-acid site 501

 

Clinical consequences

• Significantly increased affinity for ACE2 receptor binding.
  
• Significantly higher viral load (on average).
• Over 70% increase in transmissibility.
• No obvious increase in morbidity or mortality.
  

 

See also:

• Severe acute respiratory syndrome coronavirus 2 (First detected in China)
  
• SARS-CoV-2 Cluster 5 (First detected in Denmark)
  
• SARS-CoV-2 501.V2 Variant (First detected in South Africa)
  

COVID-19 pandemic

History of medicine: Pandemics

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.

 

Causative agent:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)
  

 

Disease:

• Coronavirus Disease 2019 (COVID-19)

Timeline

• 1st December 2019: Patient zero experiences symptoms in Wuhan.
• Day 23: An unsolved medical case is investigated by bronchoalveolar lavage. The specimen is sent for metagenomic massive parallel sequencing analysis. 
• Day 26: SARS-CoV2 is first identified from the specimen. 
• Day 41: Chinese state media report the first death from COVID-19.
• Day 49: First confirmed case outside Wuhan, in China.
• Day 50: The Chinese state media characterises the situation as an epidemic.
• Day 50: First confirmed cases in Singapore, Malaysia, South Korea.
• Day 52: First confirmed case in North America (Washington state).
• Day 52: First confirmed case in Europe (France).
• Day 56: First confirmed case in Oceania (Australia).
• Day 57: First confirmed case in Canada.
• Day 60: First confirmed case in India.
• Day 61: First confirmed case in Russia.
• Day 62: First confirmed case in United Kingdom.
• Day 76: First confirmed case in Africa (Egypt).
• Day 87: First confirmed case in South America (Brazil).
• Day 89: First confirmed case in Mexico.
• Day 91: First confirmed case in South Africa.
• Day 93: First confirmed case in Argentina.
• Day 101: The World Health Organisation characterises the situation as a pandemic.

• Day 365: Cumulative confirmed cases in the UK = 1,617,331 (2.38%)
• Day 365: Cumulative case fatalities in the UK = 58,245 (0.10%)
• Day 365: Cumulative confirmed cases in the world = 62,411,018 (0.79%)
• Day 365: Cumulative case fatalities in the world = 1,458,118 (0.02%)

• Day 386: United Kingdom announces that strain VUI-2020/01 appears significantly more transmissible than the first strain.

 

Consequences

• Significant increase in global morbidity and mortality.
  
• Significant increase in healthcare demands, leading to oversaturation, resource depletion and preventable harm to patients.
• Millions of infections and deaths amongst healthcare workers. 
• 2020 stock market crash
• COVID-19 recession
  
• Significant decrease in revenue for many businesses.
• Mass closure of businesses.
• Significant increase in unemployment.
• Significant increase in domestic violence.
• Significant increase in social isolation and loneliness.
  
• Significant increase in prevalence and severity of depression, stress, anxiety, and other mental health disorders (e.g. schizophrenia).
• Significant increase in social inequality and poverty.
  

 

Further reading

• World Health Organisation case tracker
• Public Health England case tracker

Severe acute respiratory syndrome coronavirus

Pathogen category: (+)ssRNA viruses

Also known as

• SARS-CoV-1
• SARS virus
  

 

Pathology

• Severe Acute Respiratory Syndrome (SARS)
  

 

Features

Exploits

• ACE2 (Angiotensin Converting Enzyme 2). An cell surface enzyme. The viral spike protein has evolved a Receptor Binding Domain, with high binding affinity for ACE2.
  
• TMPRSS2 (Transmembrane protease, serine 2): A transmembrane enzyme. SARS-CoV1 and SARS-CoV2 have evolved to initiate cell entry when they interact with this enzyme on the cell surface.

 

Taxonomy

• Category: Virus     
• Realm: Riboviria
• Kingdom: Orthornavirae
• Phylum: Pisuviricota
• Class: Pisoniviricetes
• Order: Nidovirales
• Family: Coronaviridae
• Genus: Betacoronavirus
• Subgenus: Sarbecovirus
• Species: Severe acute respiratory syndrome–related coronavirus

 

See also

• Severe acute respiratory syndrome coronavirus 2 (a later strain.)
  

TYK2

Also known as

• Tyrosine kinase 2
  
• Non-receptor tyrosine-protein kinase TYK2 
• EC 2.7.10.2
• JTK1
  

 

Physiology

Activated by:

• IFNAR2
  
• Type I interferon signalling
• Type III interferon signalling
  
• IL-6 (Interleukin 6)
• IL-10 (Interleukin 10)
• IL-12 (Interleukin 12)
• IL-23 (Interleukin 23)

Molecular actions

1. IFNAR1 (subunit 1) and IFNAR2 (subunit 2) form a cell surface receptor called IFNAR (Interferon-alpha/beta receptor).
2. IFNAR1 associates with the enzyme TYK2. 
3. IFNAR2 associates with the enzyme JAK1.

Interferon signalling

1. IFNAR1 or IFNAR2 binds an IFN to form a binary complex.
2. The interferon-subunit complex recruits the other IFNAR subunit to form a ternary complex.

JAK/STAT signalling

1. JAK1 and TYK2 are brought into close proximity and phosphorylate the 2 IFNAR subunits.
2. IFNAR recruits proteins called STATs (Signal transducer and activator of transcriptions). The STATs are activated by phosphorylation.
   
3. pSTATs form homodimers (e.g. STAT1-STAT1) or heterodimers (e.g. STAT1-STAT2). 
4. pSTAT dimers enter the cell nucleus and bind to the DNA.
5. Transcription is blocked or reduced in some target genes (repression).
6. Transcription is activated in some target genes (expression).

 

Biological functions

• Immunity
  
• Antiviral responses
• Pro-inflammatory responses

 

Clinical significance

Disorders associated with TYK2 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology
• Chronic hepatitis C infection
• Immunodeficiency 35 (IMD35)
• Hyperimmunoglobulin E syndrome (HIES)
• Lymphomatoid Papulosis
• Primary cutaneous anaplastic large cell lymphoma
• Polycythemia vera

These disorders suggest an increased susceptibility to severe infections and malignancies, possibly due to cytokine signalling deficiencies. 

 

Protein profile

• Size = 1187 amino acids
• Molecular mass = 133,650 Da
• Quaternary structure: Interacts with JAKMIP1. IFNAR1 interacts with TYK2. IFNAR2 interacts with JAK1.
• Protein family = Enzyme > Tyrosine kinase > Janus kinase

 

Genetic profile

• Species: Human
• Chromosome: 19
• Band: 19p13.2
• Starts at base pair: 10,350,529
• Ends at base pair: 10,380,572 
• Sequence length (base pairs): 30,043

 

See also

• genecards.org
  
• Interferon
  

IFNAR2

Also known as

• Interferon-alpha/beta receptor beta chain
• Interferon Alpha And Beta Receptor Subunit 2
• Interferon (Alpha, Beta And Omega) Receptor 2
• Type I Interferon Receptor 2
• IFNABR

 

Physiology

IFNAR2 is activated by:

• Type I interferons
  
1. IFN-α
2. IFN-β
3. IFN-ε
4. IFN-κ 
5. IFN-ω
• Type III interferons
1. IFN-λ1
2. IFN-λ2
3. IFN-λ3
4. IFN-λ4

 

Molecular actions

1. IFNAR1 (subunit 1) and IFNAR2 (subunit 2) form a cell surface receptor called IFNAR (Interferon-alpha/beta receptor).
2. IFNAR1 associates with the enzyme TYK2. 
3. IFNAR2 associates with the enzyme JAK1.

Interferon signalling

1. IFNAR1 or IFNAR2 binds an IFN to form a binary complex.
2. The interferon-subunit complex recruits the other IFNAR subunit to form a ternary complex.

JAK/STAT signalling

1. JAK1 and TYK2 are brought into close proximity and phosphorylate the 2 IFNAR subunits.
2. IFNAR recruits proteins called STATs (Signal transducer and activator of transcriptions). The STATs are activated by phosphorylation.
   
3. pSTATs form homodimers (e.g. STAT1-STAT1) or heterodimers (e.g. STAT1-STAT2). 
4. pSTAT dimers enter the cell nucleus and bind to the DNA.
5. Transcription is blocked or reduced in some target genes (repression).
6. Transcription is activated in some target genes (expression).

 

Biological functions

• Immunity
  
• Antiviral responses
• Pro-inflammatory responses
  

 

Clinical significance

Disorders associated with IFNAR2 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology
• Measles as a result of MMR vaccination
  
• Severe HHV6 infection
  
• Immunodeficiency 45 (IMD45)

These disorders suggest an increased susceptibility to severe viral infections, possibly due to an interferon signalling deficiency.

 

Protein profile

• Size (amino acids) = 515
• Molecular mass (Daltons) = 57,75
• Quaternary structure: Heterodimer with IFNAR1. Isoform 1 interacts with the transcriptional factors STAT1 and STAT2. IFNAR1 interacts with TYK2. IFNAR2 interacts with JAK1.
• Protein family: Cell surface receptor.

 

Genetic profile

• Species: Human
• Chromosome: 21
• Band: 21q22.11
• Starts at base pair: 33,229,901
• Ends at base pair: 33,265,675
• Sequence length (base pairs): 35,775
  

 

See also

• genecards.org
• Interferon
  

COVID19 Clinical profile

Disease: Novel coronavirus disease 2019 (COVID-19)

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.

 

Causative pathogen

• Severe acute respiratory syndrome coronavirus 2
  

 

Symptoms

• Anosmia
• Pyrexia
• Shortness of breath
• Cough (dry)
• Chest pain
• Muscle ache
• Weakness
• Fatigue
  
• Abdominal pain
• Nausea
  
• Diarrhoea
• Confusion

 

Clinical manifestations

• Pneumonia
• Pleuritis
• Pneumonitis
• Acute Respiratory Distress Syndrome
• Delirium
• Acute Kidney Injury
• Sepsis
• Septic shock
• Pneumatosis intestinalis
• Pericarditis
• Myocarditis
• Myositis
• Enteritis
• Infarction
• Stroke
• Myocardial infarction
• Hepatitis
• Disseminated Intravascular Coagulation

Differential diagnosis includes:

• Acute heart failure
• Hypersensitivity pneumonitis
• Influenza

 

Management

• Isolation / Quarantine
• Contact tracing
  
• Nasopharyngeal swabbing and testing for viral RNA by PCR
  
• Blood tests
• Chest radiograph
• Arterial Blood Gas analysis

Interventions

• Supportive management
• Oxygen therapy 
• Continuous Positive Airway Pressure
• Prone positioning
• Intubation
• Mechanical ventilation
• Anti-coagulation therapy
• Anti-inflammatory therapy
  
• Corticosteroid treatment may reduce mortality in the population with severe disease.
• Intravenous infusions of tocilizumab OR sarilumab may reduce mortality in the population with severe disease.
• Vitamin D supplementation may reduce morbidity and mortality.
• Antibiotic therapy may help to reduce any element of opportunistic bacterial infections (e.g. viral pneumonia with secondary bacterial pneumonia).
  

 

CCR2

Also known as

• C-C Chemokine Receptor Type 2
• C-C Motif Chemokine Receptor 2  
• CD192
• Cluster of differentiation 192
  
• Monocyte Chemoattractant Protein 1 Receptor
• Monocyte Chemotactic Protein 1 Receptor
  

 

Biological functions

• Immunity
  
• Antiviral responses
• Pro-inflammatory responses

 

Clinical significance

Disorders associated with CCR2 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology
  

 

Protein profile

• Size (amino acids) = 374
  
• Molecular mass (Daltons) =  41,915
• Quaternary structure: Interacts with ARRB1. Interacts (via extracellular N-terminal region) with beta-defensin DEFB106A/DEFB106B. Interacts with NUP85; the interaction is required for CCR2 clusters formation on the cell membrane and CCR2 signaling.
  
• Protein family = Cell surface receptor.

 

Genetic profile

• Species: Human
• Chromosome: 3
• Band: 3p21.31
• Starts at base pair: 46,353,734
• Ends at base pair: 46,360,928
• Sequence length (base pairs): 7195

 

See also

• Chemokines 
• genecards.org