LR18- COVID-19, SARS-CoV-2

early transmission dynamics in Wuhan, China, of Novel Coronavirus- Infected Pneumonia -mean incubation period= -early stages epidemic doubled every _____ days -basic reproductive number, Ro=

-5.2 days -7.4 Ro ~ 2.2 ​

SARS illness

-Can range from classic resp. symptoms to respiratory distress and death​ -Begins with high fever greater than 38˚C (100.4˚F)​ -Chills, headache, body aches​ -Diarrhea in 10-20% of patients (possible spread in feces)​ -2-7 days later = dry, nonproductive cough, progressing to low oxygen in blood​ -10-20% may require mechanical ventilation (breathing problems)​

More serious long-term complications are less common but can affect different organ systems in the body including:

-Cardiovascular: inflammation of the heart muscle (myocarditis)​ -Respiratory: lung function abnormalities​ -Renal: acute kidney injury​ -Dermatologic: rash, hair loss​ -Neurological: smell and taste problems, sleep issues, difficulty with concentration, memory problems​ -Psychiatric: depression, anxiety, changes in mood

common cold

-Infectious rhinitis​ -Rhinorrhea (runny nose) and nasal obstruction are the most prominent complaints​ -Usually lasts approximately 7-10 days​ -Usually occurs without a fever, unless secondary bacterial infection

respiratory transmission of disease

-Inhalation of respiratory droplet​ -Respiratory Secretions: Mucus, Saliva, Sputum​ -Portal through eyes, mouth, nose​ -Fomite Transmission​

COVID-19: viral infection

-attachment protein: spike -cellular receptor: Angiotensin Converting Enzyme II (ACE2)​

lower respiratory infections

-bronchitis -bronchiolitis -pneumonia (fluid accumulation in alveoli) -influenza-like illness (flu-like symptoms)

upper respiratory infections

-common cold -pharyngitis -tonsillitis, laryngitis -Laryngotracheobronchitis (croup in infants)

COVID-19 pathophysiology

1. SARS-CoV-2 enters the body and reaches lower respiratory tract​ 2. SARS-CoV-2 binds ACE2 on airway epithelial cells​ Virus replicates and is released from airway epithelial cells​ 3. Virus reaches alveoli and types I & II pneumocytes ​ 4. Neutrophil and macrophage driven innate immune response begin​ 5. Inflammatory cytokines recruit additional leukocytes to the site of infection, amplifying the inflammatory response​ 6. Virus leaks into circulation, significant system-wide release of cytokines

SARS-CoV-2 entry mechanisms

1. endocytosis 2. cell surface

SARS-CoV-2 entry mechanisms 1. endocytosis

1. endocytosis: cathepsin proteases in endosome get activated at low pH (acidified)--> trigger activity of endosomal proteases (cleave off segment of spike protein)--> triggers conformational change into the fusion state (allows membrane of virus to fuse with endosomal membrane)

Retrospective seroprevalence study of a convenience sample of residual blood specimens of persons aged <18 years in Mississippi​ -____% tested positive for SARS-CoV-2 antibodies -after adjustment for race/ethnicity, estimated seroprevalence....

10.9% tested positive for SARS-CoV-2 antibodies After adjustment for race/ethnicity, estimated seroprevalence increased from 2.5% in May to 16.3% in September ​

coronavirus disease 2019 (COVID-19) -incubation period

2-14 days, average 5 days​

SARS-CoV-2 genome

29,891 nucleotides, encoding 9,860 amino acids​ -CoVs have the largest genomes of known RNA viruses​ -89% homology with bat SARS-like-CoVZXC21​ -82% homology with human SARS-CoV​

Long Term Complications in Children

53% of children were reported to have one or more symptoms 120 days or more after diagnosis​ (Insomnia, respiratory symptoms (chest tightness and pain), nasal congestiona, tiredness, difficulty concentrating, muscle pain, headaches, palpitations)

according to a web survey taken by patients with long COVID/PASC

80% were female 25% reported lab diagnosis of COVID-19 half couldn't work full time, 6 months later most frequent symptoms: fatigue, post-exertional malaise, cognitive dysfunction relapses most commonly triggered by exercise, mental activity, stress

droplets can remain suspended for ______

>10 mins

MERS-CoV first reported in

April 2012 in Saudi Arabia

COVID-19 disease severity

Asymptomatic/minimally symptomatic infections Symptomatic infections

Rationale for symptom-based criteria rather than requiring negative test to return to school or work​ Criteria:

At least 10 days have passed since symptom onset and at least 24 hours have passed since resolution of fever without the use of fever-reducing medications and other symptoms have improved

stopping transmission

Avoid infected people -Problem: SARS-CoV-2 is frequently transmitted BEFORE symptoms appear​ -Testing can identify infected people, but only starting 4-5 days after the infection begins​ -Infectiousness declines rapidly within 7 days​

complications of common colds

Bacterial sinusitis​ Bacterial otitis media​ Worsening of asthma​ Acute bronchitis (chest cold)​ Sore Throat, tonsillitis​ Pneumonia

disease nomenclature

COVID-19: CO = corona​ VI = virus​ D = Disease​ 19 = first emerged in 2019​

SARS-CoV first identified in... origin?

China in November 2002 ​ Origin linked to fruit bats in Southeast Asia

COVID-19: attachment protein: spike

Composed of two subunits, S1 and S2​ Assembles into homotrimers on surface, bind to receptor

COVID 19: in adults, some emergency warning signs

Difficulty breathing or shortness of breath​ Persistent pain or pressure in the chest​ New confusion or inability to arouse​ Bluish lips or face​

other reported long-term symptoms

Difficulty with thinking and concentration ("brain fog"), Depression, Muscle pain, Headache, Intermittent fever, heart palpitations​ More serious long-term complications are less common but can affect different organ systems in the body

estimated that ______ of all transmission occurs during _____

Estimated that at least half of all transmission occurs during the pre-symptomatic phase

Respiratory viruses: Most have an RNA genome

Except adenoviruses Most have multiple serotypes except RSV Allows higher mutation and escape from immune surveillance

cold viruses: coronaviruses

Family Coronaviridae "Crown"​ -Enveloped RNA viruses​ -Second most prevalent cause of common cold (10-15% of Upper Respiratory Tract Infections)​ -Some have caused outbreaks of severe respiratory disease

cold viruses: rhinoviruses

Family PicoRNAviridae "small RNA"​ -Non-enveloped RNA virus​ -30-50% of common colds

COVID 19: symptoms

Fever or chills, Cough, Shortness of breath or difficulty breathing​ Fatigue, Muscle or body aches, Headache​ New loss of taste or smell​ Sore throat, Congestion or runny nose​ Nausea or vomiting, Diarrhea​

lower respiratory infections: influenza-like illness (flu-like symptoms)

Fever, Headache, Body aches (myalgia), Chills, Cough

viral RdRp: High homology between SARS-CoV-2 and SARS-CoV

Genetic inactivation of the coronavirus ExoN results in a 21-fold decrease in replication fidelity compared to wild type SARS-CoV

prevention of common colds

Handwashing and environmental disinfection ​ Avoid touching face with unwashed hands​ Covering coughs and sneezes

Laryngotracheobronchitis (croup in infants)

Hoarseness, "Barking" cough, wheezing, fever​ Risk of choking (croup) in infants

SARS-CoV-2 chain of infection

If any link in this chain is broken, disease transmission is slowed or stopped​ -Avoidance of infection sources, masks, hygiene, immunity from a previous infection, antiviral drugs, vaccination​

Problem: SARS-CoV-2 is frequently transmitted BEFORE symptoms appear​

Infectiousness starts 2.3 days before symptom onset and peaks at 0.7 days before symptom onset​ Makes isolation difficult​

Influenza and influenza related complications kill 12,000-61,000 Americans every year, why don't we shut down for that?

Influenza vaccines and antivirals are readily available​ Influenza only results in hospitalizations in 1-2% of cases​ -10-fold-less than COVID-19​ Average hospital stay for COVID-19 = 11 days, Average hospital stay for influenza = 5-6 days​ COVID-19 is at least 10x more lethal than influenza

different sizes of droplets

Large droplets (>5µM): fall quickly (3ft) get stuck in mucus in URT​ Droplet nuclei (<5µM): spread further, can enter lungs easier​

basic reproductive number, Ro ~2.2

Likely to be somewhere between 2-3​ Outbreak likely to continue spread until it drops below 1.0​

hCoVs compared to rhinovirus

Longer incubation period​ May have fever, malaise frequent

The most commonly reported long-term symptoms include:​

Loss of taste and smell, Fatigue, Shortness of breath, Cough, Joint pain, Chest pain​

Picornaviruses: Rhinoviruses disease

Major Cause of the Common cold ​ -Upper Respiratory Tract Infection​ -Localized infection​

fomite transmission

Mechanical vehicle of transmission (inanimate)​ Doorknobs, clothing, keyboards, cell phones, drinking glasses, sink handles

MERS-CoV

Middle East respiratory syndrome coronavirus​ MERS: SARS-like illness, pneumonia, resp. distress​ -Fever, Cough, Shortness of breath​ Zoonotic - Associated with camels and bats​

Seroprevalence from banked samples was extrapolated to state population​ -infected individuals vs confirmed and probable cases by end of sept 2020

Might be as much as 13x the number of cases in young populations​ -undertested, less symptomatic cases, shorter time period of symptoms/positivity of nucleic acid test

respiratory viruses:

Most have an RNA genome rhinovirus coronaviruses seasonality

coronaviruses: replication

Most human coronaviruses (hCoV) cannot replicate at physiological temperature​ -Restricted to upper respiratory tract (33°C - 35°C), like rhinoviruses​ Animal coronaviruses, MERS-CoV and SARS-CoV, can replicate at 37°C​ -Can cause severe viral pneumonia​ -Acute Respiratory Distress​

viral RdRp: ExoN, 3'-5' exonuclease contained in the amino terminal portion

Mutation frequency is much lower than other RNA virus polymerases​ ExoN is not essential for viral replication, but mutants have a greatly enhanced mutation rate

common cold: usually lasts approx 7-10 days

Nasal and pharyngeal symptoms usually subside beginning on the 3rd or 4th day​ May last up to 2 weeks, lingering cough

common cold: Rhinorrhea (runny nose) and nasal obstruction are the most prominent complaints​

Nasal secretions clear watery, then thicken and turn cloudy, greenish​ Cough and hoarseness may occur​

long term complications of COVID-19 aka

Post-acute sequelae of COVID-19 (PASC) -Previous terms: Long-COVID, Long-COVID syndrome, COVID Long Haulers​

lower respiratory infections: bronchiolitis

Predominantly in infants & younger children​ Wheezing, Cough, Dyspnea (shortness of breath)​ Tachypnea (rapid breathing)​

coronaviruses: transmission

Respiratory Droplet, Secretions, fomites, fecal-oral​

coronavirus disease 2019 (COVID-19) -transmission

Respiratory droplet, secretions, fomites​ -Not thought to circulate in air like measles or smallpox​

Picornaviruses: Rhinoviruses permissive cells

Respiratory epithelial cells​ -Replicates best at 33 C (Upper respiratory tract)​ -Cannot replicate in the gastrointestinal tract like enteroviruses, labile to low pH​

Picornaviruses: Rhinoviruses transmission

Respiratory secretions, droplets, fomites​ -Survive on skin and environmental surfaces for several hours​ -Infectious dose as little as 1 viral particle​ -Nasal secretions may contain concentrations of 500-1000 virions/mL​

hCoVs: seen primarily in fall and winter

Responsible for ~15% of adult colds​ Reinfections are common

URT: common cold

Rhinitis, cough, sneezing, pharyngitis​

virus nomenclature

SARS-CoV-2: SARS = Severe Acute Respiratory Syndrome​ CoV = Coronavirus​ 2 = Related to, but different from the coronavirus responsible for the 2003 SARS outbreak​ ​

coronavirus disease 2019 (COVID-19) -causative agent

SARS-CoV-2​ Previously named 2019 novel coronavirus (nCoV-19)​

respiratory viruses: seasonality

Several peak in winter​ Usually diagnosed clinically​ Conduct epidemiology, new emerging​ Multiple tests at the same time

SARS-CoV

Severe-acute respiratory syndrome (SARS)-associated coronavirus​

symptomatic infections

Symptom onset to symptom resolution: Highly variable​ -3 days to 3 weeks​ Mild disease is the most common outcome of infection​

SARS-CoV-2 entry mechanism: 2. cell surface:

TMPRSS2 cleaves spike protein at cell surface--> trigger fusion state in virus and fuses directly at the cell surface

transmission: -Inhalation of respiratory droplet​

Talk, laugh, sing, cough, sneeze: Discharge microorganisms in liquid​ -Different sizes of droplets​

responsible viruses- "cold viruses"

Two major ones - responsible for most colds​ -Rhinoviruses -Coronaviruses Numerous other viruses may cause "colds" in adults:​ -Influenza viruses, Parainfluenza viruses, RSV, Adenoviruses, other

SARS-CoV-2: Synthesis

Viral RNA-dependent RNA polymerase -ExoN, 3'-5' exonuclease contained in the amino terminal portion -All of these properties support the model that ExoN provides a proofreading function for the coronavirus RdRp. Such a corrective activity may be essential for maintenance of the stability of the exceptionally large coronavirus genome -High homology between SARS-CoV-2 and SARS-CoV

infection

Viral infection: Replication within a host cell​ Example: SARS-CoV-2 infects lung epithelial cells​ We are infected with viruses all the time without even knowing it

SARS-CoV-2: Infectiousness declines rapidly within 7 days

Viral nucleic acid can be detected longer, but this is remnants of dead virus or abortive infections which are not contagious​ Rationale for symptom-based criteria rather than requiring negative test to return to school or work​

lower respiratory infections: bronchitis

Wheezing, coughing, usually viral

viral infectious disease

When a viral infection prevents the body from functioning normally​ Example: SARS-CoV-2 infects lung epithelial cells leading to signs and symptoms of COVID-19​ Viral infection can result in no symptoms, mild symptoms, severe symptoms or even death​

SARS-CoV-2: disease symptoms

Wide range of symptoms characterized by fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, diarrhea​

URT: pharyngitis

With or without resp. symptoms​ -May have fever​

SARS-CoV-2 genome -probably evolved from

a strain in bats

coughs and sneezes: spray ______

aerosols up to 18ft and 23ft

coronaviruses can infect _____

animals and humans -some coronaviruses can cause severe disease Most coronaviruses infect only a single animal species, but SARS-CoV and MERS-CoV infect humans as well as other animals

respiratory viruses: coronaviruses

cause common colds, some can cause severe lower respiratory disease

SARS-CoV-2 genome -mutation in the original strain could have

directly triggered virulence towards humans​

Picornaviruses: Rhinoviruses -infection stopped by

innate and adaptive immunity (can spread to ears, sinuses, or lower respiratory tract)​

COVID-19 cases by age group

largest percent 18-64

SARS-CoV: early in infection....

little virus present and low probability of transmission​ -Viral numbers surge within a week and transmissibility soars​ -After 3 weeks, viral levels decrease, and symptoms subside​

SARS-CoV-2 cannot _____

live/replicate on its own -Rely on cellular machinery to grow and replicate​ -SARS-CoV-2 needs to infect new cells in the infected person or move on to another susceptible person​

COVID-19: disease ranges from

mild symptoms to severe illness and death​

respiratory viruses: rhinovirus

most common cold cases

SARS-CoV-1 was contagious....

only after symptoms appeared

COVID cases and deaths by sex

pretty even (cases slightly more in women and deaths slightly more in men)

SARS- CoV-2 entry mechanism: -reason hydroxychloroquine didn't work:

prevented endosome acidification --> prevent activity of cathepsins so spike proteins are not cleaved however this does not limit cell surface fusion pathway- primary path of COVID (if both cathepsin L and TMPRSS2 were blocked it would prevent replication of cells)

COVID-19 deaths by age group

primarily >65

Asymptomatic/minimally symptomatic infections

rates range from 4-32% 57% asymptomatic infections showed lung inflammation and damage on CT scans (generally minor/walking pneumonia)

common cold: symptoms due to

release of cytokines and histamine​

human coronaviruses (hCoVs)

ssRNA (+), Enveloped​ -CoVs have the largest genomes of known RNA viruses​ Mild to moderate upper respiratory illnesses (common cold)​ -Able to withstand GI tract (Possible fecal-oral transmission)​ asymptomatic infections common seen primarily in fall and winter

Picornaviruses: Rhinoviruses

ssRNA (+), non-enveloped​ -More than 100 serotypes​

Picornaviruses: Rhinoviruses -immunity is...

transient, wanes within 18 months

_________, was estimated to account for more than half of all COVID-19 transmission

transmission from asymptomatic individuals

common cold: not a good candidate for ____

vaccines

symptomatic treatment of common colds

(Don't make the disease go away faster)​ -First-generation antihistamine​ -NSAID - non-steroidal anti-inflammatory drugs​ -Decongestants if needed (oral preferred to nasal)

lower respiratory infections: pneumonia

(fluid accumulation in alveoli)​ -Cough, Chest pain​ -Lack of oxygen getting to blood