Lecture 9.2 - COVID-19: Primary Care Perspective PDF

Coronavirus - ultrastructural morphology: ◦Transmission electron microscopy ◦Classical spikes on the outer surface of the virus - resemble the "corona" of the sun Coronavirus - history: ◦Human coronavirus first identified in 1965 ◦Later that decade, researchers found a group of...

Coronavirus - ultrastructural morphology: ◦Transmission electron microscopy ◦Classical spikes on the outer surface of the virus - resemble the "corona" of the sun Coronavirus - history: ◦Human coronavirus first identified in 1965 ◦Later that decade, researchers found a group of similar human and animal viruses and named them after their crown-like appearance ◦The spherical viral particles (coloured blue) contain cross-sections through the RNA viral genome, seen as black dots Classification of human coronaviruses: Naming Covid-19:  What we know about SARS-CoV-2: ◦SARS-CoV-2 is an enveloped beta-coronavirus ◦Has a genetic sequence very similar to SARS-CoV-1 (80%) and bat coronavirus RaTG13 (96.2%) ◦The viral envelope is coated by spike (S) glycoprotein, envelope (E), and membrane (M) proteins ◦Host cell binding and entry are mediated by the S protein ‣ Found on nasal and respiratory epithelia ◦The first step in infection is virus binding to a host cell through its target receptor ◦The S1 sub-unit of the S protein contains the receptor binding domain that binds to the peptidase domain of angiotensin-converting enzyme 2 (ACE 2) ◦In SARS-CoV-2 the S2 sub-unit is highly preserved and is considered a potential antiviral target Potential origin of SARS-CoV-2 - bats to humans?: ◦All human coronaviruses have animal origins (natural hosts) ◦Domestic animals can suffer from disease as Intermediate Hosts that cause virus transmission from natural hosts to humans ◦SARS-CoV-2 is highly identical (96.2%) at the whole-genome level to Bat-CoV RaTG13, which was previously detected in Rhinolophus affinis from Yunnan Province, over 1500km from Wuhan ◦Bats are likely reservoir hosts for SARS-CoV-2 ◦Inconclusive evidence if Bat-CoV RaTG13 directly jumped to humans or transmitted to intermediate hosts ◦No intermediate host sample was obtained by scientists in an initial cluster of infections of the Huanan Seafood and Wildlife Market in Wuhan, where the sale of wild animals may be the source of zoonotic infection ◦The earliest 3 patients with symptoms had no known history of exposure to the Huanan market ◦Metagenomic sequencing for samples from Malayan pangolins in Guangxi and Guangdong, China, suggests that pangolins might be the intermediate hosts between bats and humans because of the similarity of the pangolin coronavirus to SARS-CoV-2 SARS-CoV-2: ◦The virus binds to ACE 2, the host target cell receptor which is principally expressed in the airway epithelial cells and vascular endothelial cells ◦This leads to membrane fusion and releases the viral genome into the host cytoplasm ◦Subsequent steps of viral replication, leading to viral assembly, maturation and virus release Viral load dynamics and duration of infectivity: ◦Following initial exposure, patients typically develop symptoms within 5-6 days (incubation period) ◦The viral load peaks in the first week of infection, declines thereafter gradually  ◦The antibody response gradually increases and is often detectable by day 14 ‣ Virus doesn't cause illness - it causes a disease response that is relayed as symptoms Viral mutations, variants and strains: ◦Mutations are errors that occur during the process of duplicating viral RNA ◦Produces variants which are similar but not exact copies of the original virus "parental strain" ◦A new strain is when a variant (protein) displays distinct physical properties to the original virus Viral mutation and transmissibility: ◦"Viruses have to walk this fine line between stability and instability" ‣ This balancing act limits their transmissibility ◦A virus is essentially a microscopic box of genetic material: ‣ The box must be robust enough to keep the genetic material safe in the body and in the outside world ‣ But to infect cells, the box must open to let the virus' genetic material out ◦Too stable, and the virus can not open up and infect cells efficiently ◦ Too unstable, and the virus can not survive for long after being transmitted Viral mutation: ◦Viruses mutate to adapt to their surroundings and more effectively move from host to host ◦Mutations can help viruses to better evade the host's immune systems, treatments and vaccines ◦A mutation can help the virus gain traits that enable it to reproduce quickly or adhere better to the surface of human cells ◦Viruses can mutate so quickly that they do not develop traits that are advantageous to transmission. Hence some virus mutations seem to emerge and then die off ◦A typical SARS-CoV-2 virus accumulates only 2 single-letter mutations per month in its genome - a rate of change about 1/2 that of influenza and 1/4 that of HIV ◦Despite the virus' sluggish mutation rate, researchers have catalogued more than 12,000 mutations in SARS_CoV-2 genomes ◦Many mutations will have no consequences for the virus' ability to spread or cause disease, because they do not alter the shape of a protein, whereas those mutations that do change proteins are more likely to harm the virus than improve it ◦Spike proteins (s) on SARS_CoV-2 bind to receptors enabling the virus to enter the host ◦A spike protein is made up of 3 smaller peptides in the OPEN or CLOSED orientations ◦The more that are open, the easier for the protein to bind  ◦The D614G mutation is caused by a single letter change to the viral RNA code. This makes more conformations more likely, hence increasing the chance of infection SARS-CoV-2 variants: SARS-CoV-2 vaccines - bluffing the body: ◦Pfizer - BioNTech BNT1662b2 and Moderna mRNA-1273 vaccines: ‣ Contain the genetic code (mRNA) of the spike protein. Once inside the body, the spike protein is produced, causing the immune system to recognise it and initiate an immune response ‣ If the body later encounters the spike protein of the coronavirus, the immune system will recognise it and destroy it before an infection is caused ‣ These vaccines can not cause COVID-19 disease, as there is no whole or live virus involved. The mRNA is naturally degraded after a few days ‣ Safety and efficacy: Pfizer - BioNTech vaccine: Clinical trials including 44,000 people in 6 countries. Can prevent 95% of COVID-19 cases Moderna vaccine: Clinical trials including 30,000 people across the US: Can prevent 94% of COVID-19 cases, and prevented all severe cases of COVID-19 ◦Oxford-AstraZeneca ChAdOx1 nCoV-19 (AZD1222): ‣ Made from a virus that is a weakened version of a common cold virus known as an adenovirus. This adenovirus has been genetically changed (engineered) so that it can not cause infections in humans. ChAdOx1 has been engineered to make the spike protein of the SARS-CoV-2 virus ‣ The immune system recognises the spike protein as foreign, forms antibodies and then attacks the SARS-CoV-2 virus, preventing an infection ‣ Safety and efficacy: Clinical trials including 23,000 people in UK: 82.4% effective after second vaccine Pathogenesis - Asymptomatic phase: ◦Respiratory aerosols bind to epithelial cells in the upper respiratory tract ◦Main host receptor is the ACE 2 (nasal epithelial ++) ◦Local replication and propagation ◦This stage lasts a couple of days. Limited immune response generated ◦Despite having a low viral load, individuals are highly infectious, and the virus can be detected via nasal swab testing Pathogenesis - upper respiratory tract involvement: ◦Non-specific symptoms - fever, malaise, dry persistent cough ◦Can cause transient damage to olfactory epithelial cells, leading to olfactory dysfunction (loss of smell and taste) ◦Greater immune response generated during this phase (involving the release of C-X-C motif chemokine ligand 10 (CXCL-10) and interferons  (IFN-beta and IFN-gamma) from the virus-infected cells ◦The majority of patients do not progress beyond this phase as the mounted immune response is sufficient to contain the spread of infection Pathogenesis - lower respiratory tract involvement: ◦~1/7 of all infected patients progress to this stage and can develop severe symptoms ◦Can ultimately lead to ARDS (acute respiratory distress syndrome) ◦Stipulated mechanism in brief: ‣ Virus invades and enters the type 2 alveolar epithelial cells via the host receptor ACE-2 ‣ Undergoes replication to produce more viral nucleocapsids ‣ The virus-laden pneumocytes now release many different cytokines and inflammatory markers "Cytokine storm": Interleukins (IL-1, IL-6, IL-8, IL-120 and IL-12), tumour necrosis factor-alpha (TNF-alpha), IFN-gamma and IFN-beta, CXCL-10, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) ‣ This "cytokine storm" acts as a chemoattractant for neutrophils, CD4 helper T cells and CD8 cytotoxic T cells, which then begin to get sequestered in the lung tissue ‣ These cells are responsible for combating the virus, but in the process they cause subsequent inflammation and lung injury ‣ The host cell undergoes apoptosis with the release of new viral particles, infecting adjacent type 2 alveolar epithelial cells in the same manner ‣ Sequestered inflammatory cells -> persistent injury -> loss of both type 1 and type 2 pneumocytes -> diffuse alveolar damage -> ARDS Clinical spectrum: COVID-19 - assessment and management: ◦Approximately 80% of patients can be managed effectively at home with conservative measures for viral infection ◦Remote assessment and risk stratification is a clinical dilemma ◦Hence the set up of Covid-19 "red sites" across the country: ‣ To support resilience in primary care ‣ To provide a clinically safe and effective face-to=face assessment service for patients that can not be seen at their base practices due to the current coronavirus pandemic restrictions ‣ To stratify the clinical risk and offer appropriate management  Covid-19 - pulse oximetry: Covid-19 - red site outcomes: ◦Home management - supportive advice +/- prescribing, with specific attention to SAFETY NETTING: ‣ What/when/where ◦CMS (Covid management service) review appointment ◦Hospital admission (A+E/SPOA according to clinical urgency)