UPPER AND LOW INFECTION AND COVID

IMED

• common cold viruses,

• influenze

• chlamydia

• local spread, local defences

• adaptive immune response sometimes too late to be important in recovery

• short incubation

Respiratory infections on surface

• measles, mumps, rubella

• shed

• little or no lesion at entry site

• microbe spreads through body returns to surface for final mutiplication and shedding

• need adaptive immune response

• longer incubation

Respiratory infections that spread

• common cold

• infection of nasopharynx are viral

• viral surface molecules bind to host cells, cilia, microvilli, resist removal by mucus flow

• spread locally on mucosal surface

• symptoms due to damage to epithelial surface and release of inflammatory molecules

• transmission by sneezing and contaminated hands

Rhinitis

• Free virus particles land on the cilia of the nasal epithelium. They stick (adsorb) to the surface receptors of the epithelial cells.

• virus penetrates the host cells and hijacks their internal machinery, multiplying rapidly until the cells are completely packed with new viral particles

• infected host cells rupture, killing the cells and releasing thousands of new viruses (virus shedding) to infect neighboring tissues.

• Clear fluid pours out which causes the classic watery, runny nose of a fresh cold.

• phagocytes rush to the site to clean up cellular debris and gobble up viral particles.

• protective epithelial layer and cilia are destroyed, the local bacterial commensals take advantage of the damage - creating green-yellow fluid

pathogenesis of rhinitis

• causes sore throat

• enters through pharynx

• activation of naive b cells which moves to the lymphoid tissue and produces plasma cells thus antibodies and memory cells

• spread by saliva

• causes Burkitt’s lymphoma, nasopharyngeal cancer, infectious mononucleosis

Epstein bar virus

• infects everyone

• causes different diseases in different populations - due to genetic predispostion or environmental cofactors

• can be oncogenic - cancer causing

• Equatorial africa - causes Burkitt’s lymphoma due to genetic rearrangement in B cells

• South Chain, Alaska, Tunisia and east Africa - nasopharngeal cancer

• everywhere else - neurological and haematological diseases - blood or bone marrow issues

clinical features and epidemiology of EBV

• can cause glandular fever - viral infection

• most are asymptomatic

• well adapted parasite

• infectious mononucleosis - contagious viral infection

• photophobia, fatigue, cough, swelling, fever,

• can stay in body for like and can re activate

infectious mononucleosis - EBV

• gram positive cocci

• group a beta-haemolytic

• common bacterial of sore throat

• bacteria attach to mucosal epithelium and cause damage by toxin production and local invasion

• readily treated with penicillin

Steptococcus pyogenes

• scarlet fever - some strains produce a toxin that spreads in the body producing a characterisitic rash on the tongue and skin - indicate septicaemia

• rheumatic fever - reactivity between antibodies produced against bacteria with self antigens as they look alike - heart damage - mimicry

Steptococcus pyogenes complications

• it is the destruction of red blood cells

• gamma - no destruction of red blood cells around bacterial growth

• alpha - incomplete destruction of RBcs, - green halo around bacterial growth

• beta - complete destruction of RBCs - clear around bacterial growth

types of hameolysis

• corynebacteria diphtheriae

• exotoxin - damage to mucus membranes of respiratory tract

• pharyngeal diphtheria - acute respiratory obstruction

• very uncommon - due to vaccination, before this - major infectious cause of death

• treated with antitoxin and antibiotics

• toxiod vaccine with tetanus and pertussis as DTPa

Diphtheria

• gram positive, rod shaped

• non sporing, no capsule or flagella

• club-shaped cells

• characteristic cytoplasmic granules

• part of normal flora in humans

• for diptheriae - only toxin causing strains are harmful, grey colonies on blood agar

Corynebacterium

• toxin is carried by a bacteriophage

• only strains of C.diptheriae infected by bacteriophage carrying the toxin producing gene

• specialised transduction occurs giving the toxin gene to bacterial cells

• lysogenic conversion of C,diptheriae following bacteriophage infection results in formation of a prophage including the toxin gene

Diphtheria toxin gene transfer

• toxin inhibits protein synthesis and thus cell death

• sub unit B of toxin binds to receptors on host cell surface

• subunit A is toxic segement and inhibits protein synthesis - by inactivating elongation factor EF2 by ribosome - done by adding a ADP-ribose molecule on to the EF2 protein

• single subunit A is lethal to a cell within hours

Dipheria toxin mechanism

• toxin affects mucous membranes of respiratory tract

• destroys epithelium causing inflammation

• inflammatory exudate forms a greyish or green membrane in upper respiratory tract - pseudomembrane - making it hard to breathe - acute severe respiratory obstruction

• removal of pseudomembrane can damage underlying tissue

• can affect skin wounds - localised lesions

• swollen neck - enlarged lymph nodes and odema

• toxin may be absorbed into circulation including myocarditis and neuritis (perpherial nerve inflammation)

Diphteria clinical features

• human herpes virus 5

• double stranded dna, icosahedral enveloped

• transmitted in bodily fluids - saliva, blood, urine, breast milk

• name - from formation of large multi nucleus cells

• tissue tropism effects epithelial mucosa cells, monocytes

• common infection

Cytomegalovirus

• asymptomatic in children and mild in adults

• glandular fever

• becomes latent(hidden) after primary infection

• rarely reactivates in healthy individuals mainly immunocompromised

• congential CMV - vertical transmission - in utero, birth, breast milk

• cause development abnormallities, low birth weight, microcephaly (small head), seizures,

• low chance but possible of mental retardation, hearing loss

• serious for immuncompromised

Cytomegalovirus - clinical features

• Mumps rubulavirus

• single stranded rna, enveloped

• transmission - respiratory droplets, contact

Mumps

• replication in nasopharynx and regional lymph nodes

• virus in the blood (viraemia) 12-25 days after exposure with spread to tissues

• prevented by vaccination

Mumps pathogenesis

• incubation for 14-18 days

• muscle pain (myalgia), malaise - faint, headache, low grade fever

• parotid gland swelling

• up to 20% of infectious asymptomatic

• can lead to meningitis

• Permanent neurologic sequelae - long term damage to cns - rare

• mumps encephalitis - inflammation of brain tissue

• permanent deafness

• orchitis - testicular inflammation

Mumps - clinical features

• infections of middle ear (otitis media) and sinuses usually same microbes as other upper respiratory tract infections

• acute otitis media is common in infants and young children - can have a viral causation

• Bacterial causes are usually from resident organisms - H. influenzae & Strep. pneumoniae

• localised swelling and pain but can include general symptoms like fever and vomiting

• may persist for weeks/months with hearing impairment

Otitis and sinusitis

• Gram-negative coccobacillus

• normal upper respiratory tract flora

• Capsular (typeable) - infection causing and non-capsular strains (non-typeable) - not infectious

• Six encapsulated serotypes based on distinct capsular polysaccharides - a–f

• most common serious disease causing strain

• Other strains can cause opportunistic infections especially in the respiratory tract

Haemophilus influenzae

• The type b polysaccharide capsule is the major virulence factor

• Encapsulated organisms can penetrate the epithelium of the nasopharynx and invade the blood

• Capsule gives resistance to phagocytosis and complement-mediated lysis

• does not produce exotoxins

• cause local respiratory infections and also systemic disease

• Meningitis is most common Hib disease

• Epiglotittis - inflammation of the windpipe – obstructive life-threatening condition

Haemophilus influenzae - pathogenesis

• Bordetella pertussis

• Small Gram-negative, aerobic bacillus

• obligate aerobe

• pleomorphic

• Highly infectious respiratory infection

• Spread by airborne droplets

• Characterised by violent coughing fits, due to narrow airways

• three stages: catarrhal, paroxysmal, and convalescent

Whopping cough - pertussis

1. Catarrhal – symptoms usually develop within 5–10 days - symptoms similar to minor upper respiratory tract infections - cold

2. Paroxysmal • numerous, rapid coughs due to difficulty expelling thick mucus • characteristic "whoop" at the end of the paroxysms cyanosis (bluish colour of the skin and the mucous membranes due to an insufficient level of oxygen in the blood), vomiting and exhaustion, dehydration

3. Less severe in older children, adults or immunised

4. Convalescent - Less persistent, paroxysmal coughs that disappear in 2-3 weeks

Whooping cough stages

• Pertussis toxin – main pathogenic mechanism

• Filamentous hemagglutinin (FHA) - adhesion

• Adenylate cyclase toxin – inhibits phagocytic cells

• Pertactin (PRN) – outer membrane protein, adhesion

• Tracheal cytotoxin – localised damage (atypical toxin)

• Endotoxin – LPS

Whooping cough virulence factors

• toxin mediated

• antibodies against toxin are protective

• bacteria attach to cilia of respiratory epithelial cells - trachea, bronchi

• toxins - paralyse cilia

• inflammation - interferes with clearance of pulmonary secretions

• allow for evasion of host defences

pathogenic mechanisms of whooping cough

• prevalent despite vaccine

• epidemic every 3-4 years

• maternal antibodies dont give protection

• waning immunity - loss of antibodies and memory cells - in adults and adolescents

• vaccine schedule - modified to improve protection, additional boosters and new vaccines

• minimise infant exposure

• booster for pregnant and adult

whooping cough epidemology

• early antibiotic therapy

• prophylaxis - exposed individuals

• vaccine contains purified antigens from B.pertussis

• combined with diptheria and tetanus vaccines

• improves immunity to tetanus and diphtheria toxoids

• contains antigen - toxoid, haemgglutinin, pertactin

• 4 doses

• may not prevent mild illness

Whooping cough vaccine

• most infectious due to viral

• secondary bacterial infections may occur with Step, pneumoniae

• primary bacterial bronchitis - due to mycoplasma pneumonia

• toxins cause damage to epithelium - antibiotic therapy

Bacterial bronchitis

• effect alveoli

• difficult to identify causative microbe as some are part of normal flora of upper resp

• less common than viral

• chest pain, cough, shortness of breath, fever

Bacterial pneumonia

• mycobacterium tuberculosis

• aerobic, slender straight or curved bacilli

• obligate pathogen

• myobacterium can cause other infections - MOTTS

• transmission - inhalation of respiratory droplets bacteria is found in nuclei of droplets - very small

• requires prolonged exposure and close proximity

Tuberculosis

• very resistant to drying, most disinfectants, acids and alkalines

• sensitive to heat and uv

• culture - complex and highly enriched, slow growing, colonies after several weeks, floats due to hydrophobic nature

Tuberculosis bacterium

• distinctive cell wall structure

• high lipid content

• impermeable to stains and dyes

• resistance to antibiotics

• resistance to killing by acidic and alkaline compounds

• resistant to osmotic lysis - causing accumulation of complement proteins

• sensitive to heat and uv

• resistance to lethal oxidation and can survive inside macrophages

• mycolic acid - survive in phagocytes

• cord factor - mutiple functions - inhibits immune cells, stops lyosoyme fusing with phagosome

• doesnt stain with gram stain but does with acid fast stain

mycobacterial cell wall

• bacteria inhaled as airbone droplets into the lungs and enters alvelous

• it is taken up and mutiply within alveolar macrophages - cannot be killed by macrophages

• immun system activates specialised macrophages and t lymphocytes to area

• multinucleated giant cells develop as the cell join together

• wall of cells, calcium salts, fibrous material form a giant cell - granuloma

pathogenesis of tb

• asymptomatic non infectious

• latent

• infected in the early decades of life and remain healthy and free of disease for decades

• some bacilli remain viable

• may be activated by cancer, immune supression, old age or chronic illness

• population has life long risk of developing - higher for HIV and AIDS

Tb clinical features

• chronic pneumonia with gradual onset

• bad cough 3 weeks or longer

• chest pain, coughing up blood or sputum, weakness, fatigue, weight loss, no appetite, chills

• overproduction of TNF by immune cells - can cause symptoms

• progressive - number of early lesions eroding into bronchioles - producing cavities and spread to other parts of the lungs - can access the lymphatics and bloodstream - lead to systemic tb effecting other organs

Primary Tuberculosis

• balance between infection and immunity is tipped

• triggered by alcoholism, diabetes, old age,

• effects oxgyenated portions of lungs - can lead to chronic pulmonary disease with one or two productive lesions

• tubercles - lesion in lung which may contain a reservoir for bacteria

Secondary TB

• chest x ray

• positive skin reactivity to antigen

• Tuberculin test - takes up to 3 days or microscopy acid fast stain takes 1 hour

• culture for definitive confiramtion may take up to 6 weeks

• molecular diagnosis - bacteria DNA or RNA in specimen

• antibody test - for IFN-gamma levels in T cells

Clinical diagnosis

• long term therapy - supervised to ensure compliance

• slow replication and dormant state - 6 month treatment to ensure sterilisation of lesion

• muti-drug resistant - combination of 3 anti-tuberculous drugs are used

• vaccine - live attenuated - using M bovis strain

• BCG vaccine effective in some population but not in africa - protects against systemic infection

• useful for high risk groups

• newer vaccine may be subunit

Therapy and vaccine

• responsible for adult deaths in developing world

• re-emerging disease

• emerging multi-drug resistant strains of TB

• infections have continued in developing world and increase in spread

• HIV people are susceptible

• Low in australia

• National myobacterial surveilance system

Epidemiology

• restricted to children

• bronchioles, narrow, inflammation and swelling blocks them, restricting air passage - epithelial death

• mainly due to RSV - respiratory syncytial virus

Viral bronchiolitis

• paramyxoviruses

• single stranded RNA, enveloped

• group A and B strains

• 2 envelope spikes - G and F proteins

• G - attachment cell

• F - fusion of host cells - syncytia for entry

• transmitted through droplets, contaminated hands - winter outbreak

• upper and low resp infection

• 4-5 day incubation

• severe in infants - mortality 3 months - rapid respiratory rate, cyanosis -bronchiolits and pneumonia - damaged/infection of alveoli

• child and adults - cold-like symptoms

Respiratory syncytial virus

• rehydration, bronchodilators, oxgyen provided, possible hospitalisation

• vaccine - none

• prophylaxis with monoclonal antibody in children below 2 - such as pre-term babies, congenital malformations of the heart and airways

Respiratory syncytial virus treatment and vaccine

• healthy individuals at risk

• virus has surface molecules that attach specifically to epithelium

• virus may cause epithelium damage instead of secondary bacterial pneumonia

Viral pneumonia

• single stranded RNA, enveloped

• 2 enveloped spikes - haemagglutinin - neuraminidase - allows for host cell binding

• fusion protein

• spread by respiratory droplets and infect respiratory epithelium

• Parainfluenza 1-3 - pneumonia, pharyngitis, bronchiolitis, croup - acute-laryngo-tracheo-bronchiolitis - harsh barking

• Parainfluenza 4 - less common, cold-like symptoms, no vaccine

Parainfluenza virus

• highly infectious respiratory viral illness

• many pandemics and effects several regions

• acute respiratory tract infection

• fever, cough, running nose

• common cold - less severe, no fever, runny nose

Influenza

• orthomyxoviruses

• single stranded RNA enveloped

• types A,B,C based on proteins on capsid

Influenza Virus

• moderate to severe illness

• all ages

• human and other animals and reservoir birds

• cause epidemics, occasional pandemics

Influenza Type A

• milder disease

• epidemic occurs every year

• children and elderly

Influenza Type B

• no epidemic

• rarely in humans

• minor resp illness

Influenza Type C

• major surface antigens - haemagglutinin and neuraminidase

• determine antigenic variation and are targets for host immunity

• type A - highly variable

• type B - show some variablity

• Type c - antigentically stable

antigenic properties of influenza

• occurs in all types A,B

• minor change in viral surface antigens

• due to selective pressure of the host immune response - point mutations in genes

• same subtype - cause epidemic

Antigenic drift

• type A only

• major change resulting in new subtype

• exchange of gene segments - due to co-infection of host by different viral strains or antigen gene recombine can cause epidemics and pandemic

Antigenic shift

• based on glycoprotein combination

• Haemagglutinin - gain entry, attach to sialic acid (sugar on cell membrane)

• Neuraminidase - cleaves sialic acid off the host cell membrane allowing new virion to exit cells

• H has 18 subtypes

• N has 9 subtypes

• H5N1 - very virulent high infection rate

naming of influenza A

• respiratory transmission of virus droplets

• replication in respiratory epithelium with subsequent destruction of cells

• viraemia may occur

• virus shed in respiratory secretions 5-10 days

Influenza pathogenesis

• incubation of 2 days

• fever, myalgia, sore throat, non-productive cough, headache

• fever up to 3 days

• respiratory symptoms - last another 3-4 days

• cough and weakness 1-3 weeks

• children - higher fever and Gi issues

• complications - pneumonia, secondary bacterial, primary influenza

• myocarditis, mortality, severe in pandemic

Influenza clinical features

• antigenic changes - drift and shift

• peak in winter with periodic outbreaks

• High susceptibility to a particular antigenic change can result in an epidemic

• antigenic shift in influenza type A - due to related influenza a viruses circulate in animals and birds

• outbreak occurs in waves influenza A 2-3 years

• every 10-40 years a new subtype of influenza A appears - Spanish flu, asian, hong kong

Epidemiology of influenza

• prevents morbidity (getting sick) and mortality - preventing infection and attenuating disease

• changing antigenic nature of virus creates a problem in vaccine production

• gives protection only against strains in vaccine and also against related strains

• monitor viral antigenic changes

• effective only for 1 year

• inactivated vaccines

• prepared from purified influenza virus in embryonated hen eggs - egg allergy contraindicated

• recommended in the population

• mainly for elderly, indigenous people, health workers

Influenza vaccination

• single stranded rna

• enveloped

• highly infectious

• infected prior to vaccine - asymptomatic or subclinical infection

• complete life-long resistance

• killed many

Measles

• transmitted via respiratory droplets

• Virus enters in the upper/lower respiratory tract or conjunctiva and spreads to sub-epithelial and local lymphatic tissues

• after few days - primary viraemia: virus spreads and multiplies in lymphoid tissues spleen, respiratory tract

• Secondary viraemia, ~5 days after the infection, virus disseminates (systemic) to a variety of epithelial sites including the skin, kidney, and bladder

• replicates systemically and sheds from resp epithelium

pathogenesis of measles

• 9-10 days post infection - runny nose, fever, cough, conjunctivitis

• highly infectious

• shed in respiratory secretions

• Koplik spots appear inside the cheek, maculopapular rash - discoloured red bumps on face then spreads down body

• treated with antiviral - Ribvirin or MMR vaccine

• more severe in malnourished

measles clinical features

• fungal infection of the respiratory track

• immuncompromised

• immune supressive treatment

• concomitant disease

• Aspergillosis fumigatus and Aspergillosis flavus

• not in normal flora

• spores inhaled and cause range of diseases

Aspergillosis

• Allergic reaction to antigens in lungs, in asthma patients

• can cause systemic infections

• high mortality due to limited number and toxicity of antifungals

Allergic bronchopulmonary aspergillosis

• A fungal ball growth in lung cavities, from pre-existing condition, no invasion of tissue but can cause respiratory problems

• fungus doesnt doesnt create a cavity - cavity formed by another infection

• can cause systemic infections

• high mortality due to limited number and toxicity of antifungals

Aspergilloma (Fig. B)

• Severe acute respiratory syndrome coronavrius 2

• found in 2019, China

SARS - COV -2

• family - Coronaviridae

• genus Betacoronavirus.

• Alpha and beta - infect humans by crossing animal to human barriers and becoming human pathogens known as zoonotic disease

• Beta - bat coronavirus but pandemic outbreaks appear to need an intermediate host e.g - mammal

Family and genus of coronavirus

• in china, taiwan canada - 2002-4 - virus jumped from civets or raccoon dogs

  sold at crowded markets to humans

• middle east, africa - Middle Eastern respiratory syndrome coronavirus (MERS-CoV - from camels to humans

Previous corona outbreaks

• largest RNA viruses, enveloped nucleocapsid, non-segmented

• positive-single-stranded RNA virus.

• Club-shaped projections from the envelope resemble a crown - made of the glycoproteins - thus corona name

Structure of SARS-COV - 2

• binding of the spike glycoprotein (S) to the angiotensin-converting enzyme 2

(ACE2) receptor on the host cells

• S1 subunit - attachment to ACE2 via receptor binding

• S2 subunit - has a fusion peptide and transmembrane domains allowing it to activates fusion of virus into the host cell membranes.

• host enzymes cut of the S1 subunit allowing for the fusion of the S2 subunit

Entry of SARS-COV2

• Virus spreads between people who are close to each other

• When people talk, sneeze, sing, breath

• Short range transmission = intaking from virus being airborne - sneezing

• Long range transmission = droplet transmitting

Transmission of SARS-COV2

• Performed by a diagnostic lab.

• Very sensitive

• Nasal or buccal swab and sent to a diagnostic lab

• Detects genetic material of virus

• Enzymatically amplified - multiple copes of genetic material is made

• Results are ready in several hours

PCR test for SARS- COV2

• Self-administered and usually performed at home.

• the monoclonal antibodies attached to coloured particles in the test re act with the antigens collected from the person the reaction is immbolised on a specific region of the test

• Results are available within 10-15 minutes

• Not as accurate as PCR test

RAT test for SARS - COV2

• cold-flu like symptoms

• requires diagnostic testing not just symptoms

• asymptomatic to severe

Clinical symptoms

• Bronchitis – coughing and chest congestion, difficulty breathing, excessive amounts of sputum in airways

• Pneumonia – difficulty breathing, alveoli inflamed and full of fluid - secondary bacterial infection can occur

• Acute respiratory distress syndrome (ARDS) - lung failure, cannot breath hospitalisation, may require ventilator

Impact of SARS- cov 2 to lungs

• after 4 weeks when virus is not detected

• Fatigue, shortness of breath (dyspneal), chest pain, cognitive disturbances (brain fog) arthralgia (joint pain) chronic kidney disease

Post acute symptoms of SARS-COV2

• first case in china and spread to all continents within months

• mortality rate of covid-19 is higher in the elderly population across all continents

• high mortality and confirmed cases globally

Epidemiology

• new variants

• waning antibody protection - decrease in antibody concentration due to age

• relaxing public measures and lack of adhering to them - social distancing, masks seasons - winter - people are indoors

Factors that impact surge in cases

• Increase in cases - due to emergence of new variants

• omicron variant - more transmissible and reduced sensitivity to immune mechanisms, more efficiently infect upper airway - more severe and infectious

• new variants - risk to vaccine effectiveness and long term population immunity

Variants

• mutations changing substituting nucleotides on the viral genome during replication – more frequent for RNA genome viruses, error-prone

• Genetic recombination between different variants simultaneously infecting the same cell

• Mutations in viral proteins that interact with host mediated RNA editing mechanisms.

• variants of concern - increase transmissible, resistant to vaccines or immunity from previous infection, harder to detect by diagnostic test

How new variants are created

• encode for proteins that inhibit interferon production in infected cells

• uncontrolled system inflammation, associated with lymphopenia (reduced lymphocytes) leads to organ damage and failure and death; starting in the lungs

• targets tissue with ACE2 receptors - Lung (alveolar epithelial cells, pneumocytes, bronchial transient secretorycells), Small intestines – Enterocytes, Heart - pericytes, Kidney

impact of covid in innate immune system

• Cell injury and death through direct viral infection and subsequent maladapted immune response

• Breakdown of alveoli epithelial layer

• Inflammation and oedema flooding alveoli

• Damaging the alveoli surface and reducing exchange ability

• macrophage activation

• excessive cytokines - chemokines, interleukins 1 and 6, TNFa, interferon

• immune cell infiltration - macrophages, neutrophils

• hyper activation of immune system

SARS damage to lungs

• monoclonal antibodies given to stop virus from entering cells nucleotide analogues that act on viral RNA polymerase to limit its replication;

• immunosuppressive therapy to dampen hyperactive immune response e- steroids, IFN

• passive immunity with convalescent serum - serum with antibodies

Treatment of SARS COVID

• population protection through herd immunity to stop infection– vaccine programs

• issues are waning immune resistance over time, new variants, vaccine hesitancy, remote areas

• many approaches and provide benefits for different groups

Vaccine for SARS COVID