PAT401 W6: Alterations of Pulmonary function

Why is infectious disease a significant cause of death and morbidity

• Reemergence of old infections thought to be controlled

• Emergence of previously unknown infections

• Development of infections resistant to multiple antibiotics

Capacity to cause disease terms

• Communicability

• Immunogenicity

• Infectivity

• Mechanism of action

• Pathogenicity

• Portal of entry

• Toxigenicity

• \Virulence

• ID50

Communicability (Capacity to cause disease terms)

• Ability to spread from person to person

Immunogenicity (Capacity to cause disease terms)

• Ability to produce an immune response

Infectivity (Capacity to cause disease terms)

• Ability to invade and multiply in the host

Mechanism of action (Capacity to cause disease terms)

• How microorganism damages tissue

Pathogenicity (Capacity to cause disease terms)

• Ability to produce disease

Portal of entry (Capacity to cause disease terms)

• Route microorganism takes

Toxigenicity (Capacity to cause disease terms)

• Production of toxins

Virulence (Capacity to cause disease terms)

• Capacity to cause severe disease

• potency

ID50 (Capacity to cause disease terms)

• Estimates number of organism or virus particles required to produce infection in 50% of a population

Endemic (how infectious disease can be classified)

• Diseases with relatively high, but constant, rates of infection in a population 

Epidemic (how infectious disease can be classified)

• Number of new infections in a population that greatly exceeds number usually observed

Pandemic (how infectious disease can be classified)

• An epidemic that spreads over a large area such as a continent or worldwide 

What does SARS-CoV-2 stand for?

Severe Acute Respiratory Syndrome - Coronavirus -2

SARS-CoV-2 (covid-19) Origin

• Outbreak of pneumonia in Wuhan, China in December 2019

• Led to identification of severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2)

SARS-CoV-2 (covid-19) Virus appearance

• distinctive spikes on its surface making it look like a solar corona

• Thus, its name coronavius

SARS-CoV-2 (covid-19) Virus origin

• may have originated in bats and may have been transferred to humans through exposure to an unidentified animal vector

• Genomic studies have identified related coronaviruses in bats in China, Cambodia, Thailand, and Laos

• global pandemic ensued

  • resulted in human-to-human transmission resulted in hundreds of millions of cases and millions of deaths

Structure of SARS-CoV-2

• Spike glycoprotein (S)

• Envelope glycoprotein (E)

• Membrane protein (M)

• Nucleocapsid protein (N)

• Lipid bilayer

Viral mutations lead to variants with…

Increased infectivity

Variants include (Viral mutations of SARS-CoV-2)

• B.1.1.7 (alpha) variant emerged in the United Kingdom,

• B.1.1.351 (beta) variant emerged in South Africa

• B.1.1.33 (P.1) variant emerged in Brazil

In 2021, two new variants emerged (Viral mutations of SARS-CoV-2)

• B.1.617.2 (delta) variant and the B.1.1.529 (omicron) variant

  • Have increased infectivity compared to previous forms of virus and have been cause of surges in new infections worldwide

  • More new variants are emerging!

Stages of viral infection of host cell

• Steps in viral life cycle of SARS-CoV-2 are same as for many other viruses

  • (1) Recognition and attachment of virus to host receptor or cell wall molecule

  • (2) Penetration into host cell by fusion or endocytosis

  • (3) Uncoating of viral genome within cell cytoplasm

  • (4) Replication of viral genome using host or viral transcriptases and polymerases

  • (5) Translation with viral structural protein synthesis in host cell endoplasmic reticulum and Golgi apparatus

  • (6) Assembly of virus

  • (7) Release of virus by budding or exocytosis, or by lysis of host cell

How many stages of a viral infection of the host cell are there?

7 stages

Stage 1: Recognition and attachment (Stages of viral infection of host cell)

• of virus to host receptor or cell wall molecule

Stage 2: Penetration (Stages of viral infection of host cell)

• into host cell by fusion or endocytosis

Stage 3: Uncoating (Stages of viral infection of host cell)

• of viral genome within cell cytoplasm

Stage 4: Replication (Stages of viral infection of host cell)

• of viral genome using host or viral transcriptase and polymerases

Stage 5: Translation (Stages of viral infection of host cell)

• with viral structural protein synthesis in host cell endoplasmic reticulum and Golgi apparatus

Stage 6: Assembly (Stages of viral infection of host cell)

• of virus

Stage 7: Release (Stages of viral infection of host cell)

• of virus by budding or exocytosis, or by lysis of host cell

Transmission of COVID-19

• Levels are highest in sputum, pharyngeal swabs, feces

• Transmitted via droplets, released during cough, sneezing, talking etc

• asymptomatic infected person is rare —> presymptomatic transmission is major contributor to spread of virus

• 3-7 days between infection & symptoms, shedding of virus can be high from resp tract (but infected person wont know they are ill)

• Transmission of virus from surfaces to hands then mouth/nose/eyes/ infected surfaces is inefficient

Viral shedding (Transmission of COVID-19)

• peaks during early symptomatic illness (3-5 days after symptom onset) 

• then declines approx. 5 to 7 days after onset of symptoms

  • No longer readily transmissible 

Risk of transmission (Transmission of COVID-19)

• is greatest in indoor environments with poor ventilation and close contact (less than 6 ft) with infected individuals

COVID-19: Pathophysiology

• Virus evades early innate responses, especially interferons

• As disease progresses, neutrophil and natural killer cell dysfunction develops

• Once infection established, powerful inflammatory response is initiated, sometimes progressing to a “cytokine storm”

• Hyperinflammatory response causes endothelial injury, microangiopathic changes, and platelet activation

• Severe inflammation of lung tissue results in acute respiratory distress syndrome (ARDS)

• Inflammatory and immune changes in myocardium

• Neuroinflammation is common

• AKI may occur, especially in critically ill clients

What determines the severity of COVID- 19?

It is primarily the host response, rather than the virulence of the virus, that determines the progression and severity

Intubation period of COVID-19 (Clinical manifestations of COVID-19)

• Approx. 6 days from exposure to symptoms onset

Clinical manifestations of COVID-19

• About 25% of all cases remain asymptomatic

• Most infected individuals have only mild symptoms

• Many organ systems affected

• Additional symptoms result from neurologic, cardiac, endocrine, hepatic and renal injury 

• Most recover within 3 to 4 weeks after infection

• But, nearly 1/3 of affected persons have persistent symptoms lasting for many weeks,  even months

Common symptoms (Clinical manifestations of COVID-19)

• Fever, cough, shortness of breath, myalgias, fatigue, loss of smell and taste 

Complications (Clinical manifestations of COVID-19)

• Thrombotic issues linked to increased risk for stroke and venous thromboembolism 

• Respiratory failure and septic shock are primary causes of mortality

Prolonged syndrome of covid is called

• Post-acute COVID-19 or long COVID

Clinical Manifestations of Acute COVID-19

• Receptor-binding portion of spike protein binds with high affinity to ACE2 receptor on cells

  • ACE2 receptor is highly expressed in lung, brain, and fat, and to a lesser extent in heart, kidney, pancreas, and intestine

• Affects: Eyes, ears, liver, GI tract, Pancreas, Heart, Brain and olfactory neurons , Kidney, vasculature

Eyes (Clinical Manifestations of Acute COVID-19)

• Irritation and photophobia

Ears (Clinical Manifestations of Acute COVID-19)

• Hearing loss and vertigo

Liver (Clinical Manifestations of Acute COVID-19)

• Elevated liver enzymes

Gastrointestinal tract (Clinical Manifestations of Acute COVID-19)

• Nausea, anorexia, diarrhea, abdominal pain

Brain and olfactory neurons (Clinical Manifestations of Acute COVID-19)

• Stroke

• encephalitis

• loss of smell and taste

• confusion

• memory loss

• brain fog

• anxiety

• depression

Heart (Clinical Manifestations of Acute COVID-19)

• heart failure

• palpitations

• chest pain

• shortness of breath

Pancreas

• Abdominal pain

• Hyperglycemia

Kidney (Clinical Manifestations of Acute COVID-19)

• Acute renal failure

Vasculature (Clinical Manifestations of Acute COVID-19)

• Thrombosis with ischemic symptoms in multiple organs

COVID-19 infection in children: emerging science

• most show no/very mild symptoms during acute SARS-CoV-2 infection

• significant number develop serious illness occurring days to few weeks after initial infection

  • Multisystem inflammatory syndrome in children (MIS-C)  

• SARS-CoV-2 serves as a superantigen causing overwhelming immune response

• Approx. 60% require intensive care

  • 15% require mechanical ventilation

Hyperinflammation results (Covid infection in children: superantigen causing overwhelming immune response)

• Cardiac, pulmonary, renal, GI, neurological injury

• Thrombotic complications

• Shock 

Post-Acute Covid-19

• Continuation of COVID-19 symptoms or complications after 3-4 weeks post acute infection

• Continued viral toxicity, microvascular injury, immune system dysregulation, and persistent hyperinflammatory state

• Underlying comorbidities, recurrent infections also play role

Rate of occurrence (Post Acute COVID-19)

• Approx. 1/2 of those infected with SARS-CoV-2 develop some post-acute symptoms within 12 months after acute infection

• Can occur in those after hospital discharge and in those who suffered only mild-moderate acute illness

Post acute Covid-19 symptoms

• Fatigue and dyspnea (reduction in diffusion capacity in lung) are most common persistent symptoms

• Neurologic disorders constitute second most common sequelae

• Muscular weakness, joint pain, anxiety, hair loss, and sleep disturbances also common

• Risk of thromboembolic events increased

• Overall QOL significantly reduced

• Worsening abnormalities in physical, cognitive and psychiatric health after critical illness compound symptoms 

Covid-19 is a syndrome which means…..

it is a group of diseases

Screening for Acute COVID-19

• Respiratory, psychiatric and thromboembolic sequelae at 4–6 weeks and again at 12 weeks after discharge

Fatigue and Dyspnea (Post Acute COVID-19 Symptoms)

• Occurs in 50%–75% of individuals at 2–3 months

• Persists 6 months after acute illness in approximately 25% of individuals 

Neurologic disorders (Post Acute COVID-19 Symptoms)

• constitute second most common sequelae

• Persistent neuroinflammation associated with cognitive and behavioral changes, decreased memory and ability to concentrate

Two types of viral tests are used (Testing for COVID-19)

• Polymerase chain reaction (PCR)

• Rapid antigen tests

Testing for covid-19 is for….

those with symptoms, known exposures, or who are required to be tested for community or employment purposes

Polymerase Chain reaction (PCR) (Testing for Covid-19)

• Most sensitive test

• Can test for new reaction at day 91

  • checking at day 90 can give false positive of new infection due to previous infection still being present

How long can Post viral RNA persist?

• For up to 90 days

Rapid antigen test (Testing for Covid-19)

• single negative finding does not indicate negative for disease 

• recommended that retest is taken 8 hours later to confirm or deny illness

Laboratory findings (Testing for Covid-19)

• Are supportive not diagnostic

• Decreased lymphocytes in blood

• Elevated levels of inflammatory cytokines and D-dimer

• Bilateral lung infiltrates on CT

• D dimer is done after the presence of infection

Covid vaccines that use the mRNA spike protein sequence

• Moderna, Pfizer/BioNTech

mRNA carrying spike protein sequence (Covid vaccine: function)

• vaccines use host cells’ own translation machinery to make harmless pieces of viral spike proteins that elicit immune response to virus

Covid Vaccines that use conventional viral vector technologies (Covid vaccine: function)

AstraZeneca, Janssen (Johnson & Johnson)

Conventional viral vector technologies function (Covid vaccines)

Vaccines use modified version of one virus as a vector to deliver genetic material coding into hosts’ cells to elicit immune response to virus

Immunization against COVID-19

• Several vaccines developed globally to prevent SARS-CoV-2 infection

• Two use mRNA carrying spike protein sequence

  • Moderna, Pfizer/BioNTech

• Other vaccines use conventional viral vector technologies

  • AstraZeneca, Janssen (Johnson & Johnson)

• Unknown whether prolonged immunity to virus can be achieved

  • Booster immunizations recommended

How often is the effectiveness of vaccines retested

• every time a new variant/s occur

Drug treatment for COVID-19 levels

• Prophylaxis

• Treat mild to moderate Covid 19 (no hospitalization)

• Treat severe acute Covid-19

• drugs used depend on severity

Drug types with % makeup Covid-19 treatment

• -xi= chimeric (75% human) e.g bailiximab - more adverse reacton potential

• Zu= Humanized (90% human)e.g trastuzumab

• Mumab = Fully human (100%) e.g golimunab

What are Monoclonal Antibodies

•  a technique was developed to harvest antibodies produced by a single B cell

  • Because a single B cell produces a single antibody, it is called a monoclonal antibody (mab)

  • So, the MABs have similar names that end in -mab 

• Scientists have created approximately 30 different MABs to attack a diverse number of targets

Monoclonal antibodies function

• very specific, targeting a single type of target cell or receptor

  • This allows greater effects on the target cell or receptor at lower doses and with fewer adverse effects than using polyclonal antibodies (mixture of different antibodies)

• generally used for cancer drugs

Tocilizumab Other classification (Monoclonal Antibodies)

• DMARDs (Disease modifying anti-rheumatoid drugs)/tumor necrosis factor (TNF) modifier

What can dampening IL-6 do

• Dampening it can help reduce systemic inflammation

Tocilizumab Indications (Monoclonal Antibodies)

• Severe and/or critical COVID 19, in addition to dexamethasone (anti-inflammatory)

Tocilizumab Mechanism of action (Monoclonal Antibodies)

• inhibiting IL-6 (apart of immune system and causes inflammation)

Tocilizumab Desired effects (Monoclonal Antibodies)

• to reduce severe inflammation, improve respiratory function, prevent organ damage, and decrease ICU stays and mortality in severe COVID-19 patients.

Tocilizumab Adverse effects (Monoclonal Antibodies)

• headache

• dizziness

• hypertension

• Rash

• Infusion reactions

• Upper resp infections

• Nasopharyngitis

• bronchitis

• gastrointestinal perforation, abdominal pain, gastritis, mouth ulcerations

• neutropenia, thrombocytopenia

• serious infections, anaphylaxis, infusion-related reactions, anti-tocilizumab antibody formation, and secondary malignancy

Function of TMPRSS2 protease in SARS- COV-2 and receptors

• enhances viral entry, making viral entry efficient 

  • to fix get something else to bind to it

Antivirals: Nirmatrelvir/Ritonavir recommended dosage

• Recommended dosage is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) with all three tablets taken together orally twice daily for 5 days 

Antivirals: Nirmatrelvir/Ritonavir Prescribing window

• Within 5 days of symptom onset

Antivirals: Nirmatrelvir/Ritonavir Indications for use

• reat mild to moderate COVID-19 in clients who have

  • A positive result from a viral test and

  • A high risk of getting severe COVID-19, including hospitalization or death

Nirmatrelvir Mechanism of action (Antivirals: Nirmatrelvir/Ritonavir)

• Inhibits protease

•  inhibits SARS-CoV-2’s main protease/enzyme

• Block the binding which blocks replication

• When this protease/enzyme is inhibited, it cannot process polyprotein precursors

  • Blocks part of virus’ life cycle and prevents viral replication

Ritonavir Mechanism of action (Antivirals: Nirmatrelvir/Ritonavir)

• acts as a pharmacokinetic enhancer

• Enhances capacity of nirmatervir to work

• Inhibits cytochrome P450-mediated metabolism of nirmatrelvir

  • Increases plasma concentrations of nirmatrelvir

Antivirals: Nirmatrelvir/Ritonavir Desired effects

• Stops virus from multiplying

• Reduces severe outcomes

Antivirals: Nirmatrelvir/Ritonavir Adverse effects

• Common: hypertension, severe allergic reaction

•  Rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, liver problems

Systemic glucocorticoids

• Wide therapeutic application

• Short-term use due to potentially serious adverse effects

Systemic glucocorticoids Mechanism of action

• Suppress histamine release and inhibit the synthesis of prostaglandins by COX-2; inhibit the immune system by suppressing certain functions of phagocytes and lymphocytes 🡪 reduce inflammation

Systemic glucocorticoids adverse effects

• Suppression of normal functions of adrenal gland (adrenal insufficiency), hyperglycemia, peptic ulcers, electrolyte imbalances; mask infections

Why shouldn’t systemic glucocorticoids be stopped abruptly?

•  because could automatically stop adrenal cortex

Dexamethasone: systemic glucocorticoid Indications for use

• For clients needing supplemental O₂ for severe acute COVID-19

  • Other indications: inflammation, allergies, cerebral edema, septic shock

Dexamethasone: systemic glucocorticoid Mechanism of action

• Suppresses migration of polymorphonuclear leukocytes, fibroblasts, and normal immune response

Dexamethasone: systemic glucocorticoid Desired effects

• Decreases inflammation, reverses increased capillary permeability, causes lysosomal stabilization

Dexamethasone: systemic glucocorticoid Adverse effects

• Hypertension, seizures, hyperglycemia

Heparin: Anticoagulants Indications for use

• Prevention dose anticoagulation for severe acute COVID-19

Heparin: Anticoagulants Mechanism of action

• Binding of heparin to antithrombin III inactivates several clotting factors and inhibits thrombin activity