COVID-19

COVID-19 - Risk factors

Risk factors → Older age → Male sex → Chronic pulmonary disease → Pre-existing cardiovascular disease → Cerebrovascular disease → Diabetes

SARS-CoV-2 - Aerosol and surface stability

Aerosol and Surface Stability → Aerosol = 3 hours or more → Steel = 72 hours or more → Plastic = 72 hours or more → Copper = no viable SARS-CoV-2 was measured after 4 hours → Cardboard = no viable SARS-CoV-2 was measured after 24 hours Holbrook et al., March 2020, NEJM

COVID-19 - Attack rate - Percentage of infected patients requiring hospitalization/ICU admission

Attack rate → 50 to 80% → Meaning that 50 to 80% of population will get infected Percentage of infected patients requiring hospitalization → Approximately 13% of infected patients require hospitalization → 6% of infected patients require ICU admission → Approximately 80% of cases are mild and don't need hospitalization (Verity et al., March 2020 Lancet)

COVID-19 - Cardiomyopathy

Cardiomyopathy → Troponin elevation is common with COVID-19 → Ruen et al. reported that 7% of patients die of fulminant myocarditis and this might also be a factor in 33% of deaths → Wang et al. reported that in 12% of patients arrhythmias was reason for ICU transfer

COVID-19 - Cause

Cause → SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2)

SARS-CoV-2 - Cell entry pathways - TMPRSS2 and furin in cell surface entry

Cell entry pathways Cell surface pathway → SARS-CoV-2 uses its spike (S) protein to mediate cell entry via the ACE2 receptor → Spike (S) protein is composed of two subunits (S1 and S2) → The S1 subunit contains a receptor-binding domain that engages with ACE2 on the surface of the host cell membrane → Upon binding of S1 to ACE2, the spike protein undergoes a conformational change from a pre-fusion to a post-fusion form and is cleaved at the S1/S2 junction → Cleavage is mediated by cell surface serine proteases such as TMPRSS2 → The newly liberated S2 N-terminal domain inserts into the target cell membrane mediating viral and plasma membrane fusion and resulting in transfer of the viral RNA into the host cell cytoplasm → The S2 subunit is highly conserved, the spike receptor-binding domain presents only a 40% amino acid identity with other SARS-CoVs Endocytic pathway → Endocytic/cathepsin-mediated entry pathway is preferred in case host cells don't express serine proteases TMPRSS2 and furin in cell surface entry TMPRSS2 → TMPRSS2 is a type II transmembrane serine protease which is localized to the plasma membrane via a single pass transmembrane helix near its N-terminus → TMPRSS2 expression on the surface of target cells (not virus producing cells) is critical for viral fusion → Two cleavage sites on S-protein (R667 located at the S1/S2 cleavage site and R797 located at the S2' cleavage site) have been proposed to be relevant sites of action of TMPRSS2 → Mutations at R797 abrogate TMPRSS2 dependent activation of the S-protein and is highly conserved Furin → Furin is a pro-protein convertase involved in processing and activating precusor proteins into their biological active form → For example: Furin is responsible for the proteolytic cleavage of HIV envelope polyprotein precursor gp160 to gp120 and gp41 prior to viral assembly → Processing of the spike protein by furin at the S1/S2 cleavage site is thought to occur following viral replication in the endoplasmic reticulum Golgi intermediate compartment (ERGIC) → Current available data support a plausible model for SARS-CoV-2 spike processing wherein furin-mediated cleavage at the S1/S2 site pre- primes the spike protein during biogenesis, facilitating subsequent activation for membrane fusion by a second cleavage event at S2' by TMPRSS2 following ACE2 receptor binding on target cells {Murgolo et al. 2021. SARS-CoV-2 tropism, entry, replication, and propagation: Considerations for drug discovery and development. PLoS pathogens 17: e1009225-e1009225.}

SARS-CoV-2 - Classification - Virus characteristics - Cell entry

Classification → Order = Nidovirales → Family = Coronaviridae → Subfamily = Orthocoronavirinae → Orthocoronavirinae subfamily is classified into four genera → Genera = Alphacoronavirus, Betacoronavirus, Deltacoronavirus, and Gammacoronavirus → Only alpha and beta coronaviruses are known to infect humans Virus characteristics → SARS-CoV-2 is an enveloped, positive-sense, single stranded, RNA Beta-coronavirus (+ssRNA) of the family Coronaviridae → SARS-CoV-2 shows a crown-like appearance under an electron microscope (coronam is the Latin term for crown) due to spike (S) glycoproteins on the envelope → Homotrimers of S proteins compose the spikes on the viral surface

Attack rate - Definition - c Calculation

Definition → Attack rate is the percentage of the population which contracts the disease, in an at risk population Calculation → Attack rate is calculated by dividing the number of new cases in the population by the number of persons at risk in the population

Case fatality rate - Definition - Infection fatality rate (IFR)

Definition → Case fatality rate is the proportion of deaths from a certain disease compared to the total number of people diagnosed with the disease Infection fatality rate (IFR) → Infection fatality rate (IFR) tries to additionally account for asymptomatic, undiagnosed infections → Infection fatality rate will always be lower than the case fatality rate

Epidemic doubling time - Definition

Definition → Doubling time (T2) = natural logarithm of 2 (ln (2)) divided by exponent of growth (in percent) → Natural logarithm of 2 is approximately 72

Infectious dose (ID) - Definition

Definition → Infectious dose is the minimum number of microbes necessary to cause an infection to proceed

Basic reproduction number (R0) - Definition - Factors influencing R0 - Use

Definition → R0 is the average number of secondary infections produced by a typical infectious individual that is introduced into a population where every host is susceptible Factors influencing R0 → R0 is not a biological constant for a specific pathogen → R0 is affected by environmental conditions and the behaviour of the infected population → Factors include duration of infectivity, the infectiousness of the organism and the number of susceptible people in the population that the affected patients are in contact with Use → R0 is used to determine if an emerging infectious disease can spread in a population and what proportion of the population should be immunized through vaccination to eradicate the disease → When R0 > 1 the infection will be able to start spreading in a population, but not if R0 < 1 → Proportion of the population that needs to be effectively immunized to prevent sustained spread of the infection has to be larger than 1 − 1/R0 → Conversely, the proportion of the population that remains susceptible to infection in the endemic equilibrium is 1/R0

SARS-CoV-2 - Delta variant

Delta variant → The delta variant is characterized by a unique P681R mutation which plays an important role in its fitness advantage and improved S-protein processing → The improved S-protein processing is most likely due to an improved furin cleavage (at the S1/S2 cleavage site) when newly assembled virions egress the trans-Golgi network → The original SARS-CoV-2 virus has a functioning furin cleavage site, however adjacent residues influence the cleavage efficiency → Improved S-protein processing (priming for S2' cleavage mediated by TMPRSS2) leads to enhanced viral cell entry and replication {Liu, Yang, Liu, Jianying, Johnson, Bryan A., Xia, Hongjie, Ku, Zhiqiang, Schindewolf, Craig, Widen, Steven G., An, Zhiqiang, Weaver, Scott, Menachery, Vineet D., Xie, Xuping & Shi, Pei-Yong. 2021. Delta spike P681R mutation enhances SARS-CoV-2 fitness over Alpha variant. bioRxiv 2021.08.12.456173. doi: 10.1101/2021.08.12.456173. http://biorxiv.org/content/early/2021/08/13/2021.08.12.456173.abstract}

COVID-19 - Differential diagnosis

Differential diagnosis → Influenza or other respiratory viruses →

COVID-19 - Estimated case fatality rate - Estimated infection fatality rate

Estimated case fatality rate → Overall case fatality rate is approximately 2.6% → 1.4% [0.4-3.5] in those aged <60 years → 4.5% [1.8-11.1] in those aged ≥60 years → up to 13.4% (11.2-15.9) in those aged 80 years or older Estimated infection fatality rate → 0.66% (0.39-1.33), with an increasing profile with age {Verity et al., March 2020 Lancet} {Murgolo et al. 2021. SARS-CoV-2 tropism, entry, replication, and propagation: Considerations for drug discovery and development. PLoS pathogens 17: e1009225-e1009225.}

COVID-19 - Typical imaging findings - Imaging findings typically not seen

Imaging findings CXR → Bilateral, diffuse opacities in all lung zones CT-chest → Patchy, ground glass opacities, predominantly peripheral and basal Findings typically not seen with COVID-19 → Pleura effusion → Lymphadenopathy → Cavitation or masses

COVID-19 - Incubation period - Duration from onset of symptoms to dyspnea - Duration from onset of symptoms to hospitalization - Duration from onset of symptoms to ICU admission - Duration from onset of symptoms to death - Duration from onset of symptoms to hospital discharge

Incubation period → Incubation period is approximately 5 days but can be as long as 14 days Laurer et al. February 2020 Duration from onset of symptoms to dyspnea → 5 days Duration from onset of symptoms to hospitalization → 7 days Duration from onset of symptoms to ICU admission → 9 to 10 days Murthy et al. March 2020 JAMA Duration from onset of symptoms to death → 17.8 days (95% credible interval [CrI] 16.9-19.2) Verity et al., March 2020 Lancet Duration from onset of symptoms to hospital discharge → 24.7 days (22.9-28.1) Verity et al., March 2020 Lancet

COVID-19 - antiviral therapy - Indications (when, who) - Agents and combinations used in current trials

Indications → Data from SARS and influenza suggest that antiviral therapy needs to be initiated early in the disease course to work → The vast majority of patients will do fine without any therapy → Waiting for patients to get critically ill before administrating therapy may cause us to miss the early treatment window → Therefore markers that allow us to predict who will get critically ill are necessary Agents and combinations used in current trials → Remdesivir → Lopinavir/ritonavir → Chloroquine → Olsetamavir & other neuraminidase inhibitors → So far Remdesivir is the only FDA approved agent (IV use in critically ill COVID-19 patients) → However, a multicenter evaluation of 4 repurposed antiviral drugs (remdesivir, hydroxychloroquine, lopinavir, and interferon β 1a) reported by the WHO noted no effect on overall mortality, initiation of ventilation and duration of hospital stay {Murgolo et al. 2021. SARS-CoV-2 tropism, entry, replication, and propagation: Considerations for drug discovery and development. PLoS pathogens 17: e1009225-e1009225.}

COVID-19 - L2ab findings

Lab findings → WBC tends to be normal → Lymphopenia tends to be common, seen in 80% of patients → Mild thrombocytopenia, platelet count less than 100 000 is rare → Elevated D-dimer is common → Procalcitonin does not appear to be elevated → CRP is elevated in COVID-19, CRP levels track with disease severity and prognosis

COVID-19 - PCR sensitivity -

PCR sensitivity → PCR sensitivity seems to be around 75%

ACE2 - Physiologic function

Physiologic function → ACE2 catalyzes the degradation of angiotensin II to angiotensin-(1-7) → By aiding the degradation of ATII, ACE2 attenuates the effect of angiotensin II on vasoconstriction and sodium retention

RNA viruses - Positive vs negative sense

Positive-sense → Positive-sense (5'-to-3') viral RNA signifies that a particular viral RNA sequence may be directly translated into viral proteins → Therefore, in positive-sense RNA viruses, the viral RNA genome can be considered viral mRNA, and can be immediately translated by the host cell Negative-sense → Negative-sense (3'-to-5') viral RNA is complementary to the viral mRNA → Therefore a positive-sense RNA (= mRNA) must be produced by an RNA-dependent RNA polymerase from it prior to translation → Negative-sense viruses must carry an RNA polymerase inside the virion

COVID 19 - Predictive markers (laboratory)

Predictive markers → Markers for poor prognosis are → Lymphopenia trend (prolonged or worsening predicts poor outcome) → Neutrophil/lymphocyte ration, NLR > 3 suggest a worse outcome → Lower platelet count → High troponin → High CRP → High ferritin??? (data??)

COVID-19 - Prognosis once hospitalized (ICU, intubation, death)

Prognosis → 10-20% of hospitalized patients require ICU → 3-10% of hospitalized patients require intubation → 2-5% of hospitalized patients die

Basic reproduction number (R0) - Values of R0 for Measles - Values of R0 for COVID-19

R0 for Measles → 12-18

COVID 19 - Signs and symptoms

Signs and symptoms Constitutional symptoms → Fever (77-98) → Myalgia (11-15%) → Headache (6-34) Upper respiratory symptoms → Rhinorrhea (4-24%) → Sore throat (5-14%) Lower respiratory symptoms → Dyspnea (3-64%), silent hypoxemia (some patients may develop hypoxemia and respiratory failure without dyspnea) → Chest tightness (24%) → Cough (68-82%) → Sputum (14-56%) → Hemoptysis (1-5%) Gastrointestinal → Nausea/Vomiting (1-10%) → Diarrhea (2-8%)

COVID-19 - Stage of illness

Stage of illness → There seem to be different stages of illness that patients may move through Replicative stage → Viral replication occurs over a period of several days → Innate immune response occurs but fails to contain the virus → Relatively mild symptoms may occur due to direct viral cytopathic effect and innate immune responses Adaptive immunity stage → An adaptive immune response eventually kicks into gear → This leads to falling titres of virus, however, it may also increase levels of inflammatory cytokines → Increase levels of inflammatory cytokines may cause tissue damage and clinical deterioration → Some patient may respond to COVID-19 with a cytokine storm → This progression through different pathogenic stages may explain the clinical phenomenon wherein patients are relatively OK for several days, but then suddenly deteriorate when they enter the adaptive immunity stage

COVID-19 - Steroids - Ascorbic acid

Steroids → Steroids should not generally be used → Steroids haven't demonstrated benefits in prior SARS or MERS epidemics and may increase viral shedding (Lee 2004) → Nearly all articles recommend against the use of steroid → A recent subgroup analyses suggested that early glucocorticoid use in patients with markedly elevated C-reactive protein levels (≥20 mg/dL) was associated with a significant reduction in mortality or mechanical ventilation → Glucocorticoid treatment in patients with lower C-reactive protein levels was associated with worse outcomes {Murgolo et al. 2021. SARS-CoV-2 tropism, entry, replication, and propagation: Considerations for drug discovery and development. PLoS pathogens 17: e1009225-e1009225.} Ascorbic acid → Ascorbic acid did appear to improve mortality in the multi-center CITRIS-ALI trial → Problems with survivor ship bias in CITRIS-ALI trial make data interpretation difficult → Administration of a moderate dose of IV vitamin C could be considered (e.g. 1.5 grams IV q6 ascorbic acid plus 200 mg thiamine IV q12) → This dose seems to be safe, however, there is no high-quality evidence to support ascorbic acid in viral pneumonia

SARS-CoV-2 - Transmission

Transmission → Transmission may occur via droplets, aerosols, contamination of surfaces and possibly through fecal-oral route Symptomatic transmission → Direct transmission from symptomatic individual Pre-symptomatic transmission → Direct transmission transmission from individual that occurs before individuals experiences symptoms Asymptomatic transmission → Direct transmission transmission from individual who never experiences symptoms Environmental transmission → Indirect transmission

SARS-CoV-2 - Variants

Variants → WHO has classified variants of concern and variants of interest Variants of concern → Alpha, Beta, Gamma, Delta Variants of interest → Eta → Iota → Kappa → Lambda