Infection Flashcards
What is an infection?
Invasion of a hosts tissues by microorganisms AND Disease caused by: Microbial multiplication Toxins Host response
Neisseria meningitis is very easy to kill using a single dose of penicillin. Despite this, patients with meningococcal meningitis experience severe symptoms and may die from the disease. Why?
The patient continues to have an infection caused by the inflammatory response triggered by neisseria meningitis which persists even after they have been killed.
How do people get infections?
HAEMATOGENOSUS
• Microbiota - commensals
HORIZONTAL TRANSMISSION
• Contact
◦ Common source - environment, food/water
◦ Direct contact
◦ Vectors
• Inhalation
◦ Droplets - droplets of moisture expelled from one individual to another through sneezing or coughing
◦ Aerosols - suspension of tiny particles or droplets in the air (can stay there for a long time before being inhaled)
• Ingestion
◦ Faecal-oral transmission
VERTICAL TRANSMISSION
• Mother to child, before (intra-uterine) or at birth
ANIMALS
• Zoonosis
How do microorganisms cause disease?
- Exposure
- Adherence - bacteria enters the skin through gaps and adheres to a surface/viruses bind to cell surface receptors on cells to enter and multiply
- Invasion
- Multiplication
- Dissemination- spread
Alongside:
VIRULENCE FACTORS - molecules produced by pathogenic organisms that add to their effectiveness.
• Exotoxins- released by bacteria
◦ Cytolytic
◦ AB toxins
◦ Superantigens
◦ Enzymes
• Endotoxins- structures of bacterial cell wall that stimulate an immune response as bacteria breakdown
HOST CELLULAR DAMAGE
• Direct
• Consequent to host immune response
What are the determinants for disease?
PATHOGEN DETERMINING FACTORS
• Virulence factors - some strains of bacteria/viruses are more likely to cause disease than others
• Inoculum size- in some diseases you need large concentrations of some microorganisms to cause disease/others only a small concentration is required
• Antimicrobial resistance- determines how easy it is to treat infections
PATIENT
• Whether patient is immune or not
• Site of infection
• Co-morbidities- factors in patient that increase vulnerability to infection
Describe how to identify whether a patient has an infection.
• History ◦ Symptoms ‣ Local, systemic ‣ Severity ‣ Duration ◦ Potential exposures ‣ Where have you been? What have you been doing? With who? • Examination ◦ Organ dysfunctions ◦ Lymph node enlargement • Investigations ◦ Specific ◦ Supportive
List some supportive investigations.
- Full blood count - neutrophils (bacterial infection), lymphocytes (viral infection)
- C-reactive protein (CRP)
- Blood chemistry-liver and kidney function tests
- Imaging - x-ray, ultrasound, MRI
- Histopathology- gram stains
List some specific investigations.
These investigations aim to identify the cause of infection.
Bacteriology • Specimen types ◦ swabs, fluids, tissues • MC&S ◦ Microscopy- bacterial cells (gram stain), patient cells (cerebralspinal fluid) ◦ Culture- 18 hours incubation ◦ Antibiotic susceptibility • Antigen detection- faster, use a tray with antigen put blood in it and see if any is bound using immunoassay • Nucleic acid detection
Virology
• Antigen detection (the virus)- same as above
• Antibody detection (the patient’s response)
• Detecting viral nucleic acid (DNA or RNA)
Why might white blood cell count be increased?
- infection
- inflammation
- leukaemia
- cancer
Why might white blood cell count be decreased?
- medication
- some autoimmune conditions
- viral or severe infections
- bone marrow failure
- enlarged spleen
- liver disease
- alcohol excess
- congenital marrow aplasia
Why might neutrophil count be increased?
They one of the first lines of defence against bacterial infection.
They can be increased in some bacterial infections and would support a diagnosis.
Does white blood cell count and neutrophil count increase with all infections?
No - can be suppressed in some infections
Do all viral infections increase lymphocyte count?
No - can be increased or decreased by viral infections
Why might lymphocyte count be increased?
Viral infection
Chronic lymphocytic leukaemia
What are prions?
Proteins that generate copies of themselves and can spread from person to person to cause disease
Withstand very high temperatures and pressures
What are the significance of prions in a clinical environment?
Infection control
If instruments are sterilised and used again, prions that cause disease can remain
What is the difference between mycoplasma, chlamydiae, rickettsiae and other bacteria?
Although we classify these as bacteria, they rely on host biochemistry for reproduction like viruses and are transferred from cell to cell.
Yeast, protozoa and human cells are all eukaryotic cells.
True or false?
True
Describe the structure of genetic material in a virus.
RNA or DNA
Single stranded or double stranded
What is the capsid of a virus?
Do all viruses have it?
A protein shell that protects the genetic material.
Comes in different shapes: helical, icosahedral
All viruses have a caspid
What is the lipid envelope on a virus?
Do all viruses have it?
Derived from host
Contains virus specific antigens
Not all viruses have a lipid envelope
What is the function of spikes on viruses?
Spikes on viruses are important for binding to cell surface receptors on host cells.
Binding to receptors is essential for adhesion and hence invasion and multiplication.
Are viruses with single stranded or double stranded DNA more susceptible to mutations? Why?
Single stranded DNA as there is no way for the DNA replicating mechanism to identify a defect.
Are +ve or -ve RNA strands read to make proteins in viruses?
-ve strands
+ve strands have to be converted to -ve strands
How can viruses be classified?
- Baltimore classification - DNA structure
DNA or RNA
Single stranded or double stranded - Enveloped or non-enveloped
Parvovirus is a single stranded, non-enveloped virus. It mainly affects children. It causes a temporary suppression of bone marrow which affects the production of red blood cells.
Some people do not notice the effects of this whereas others are significantly affected.
Who would be significantly affected and what determine whether someone is affected or not?
Some people are not affected by suppression of bone marrow because red blood cells have a fairly long life - 120 days, so the time period is sufficient for them to be asymptomatic.
People with red blood cell abnormalities who may not usually have any problems experience significant anaemia as their red blood cells have a shorter life so the drop in production of red blood cells affects them. Eg. Sickle cell trait
In general, is a virus more easy to kill if it is enveloped or non-enveloped?
Enveloped
Easily disrupted and deactivated with alcohol.
What determines which cell line a virus replicates in?
Many viruses have tissue trophisms - prefer specific cell lines in which to replicate in.
What are bacteriophages?
Viruses can invade bacteria forming bacteriophages and this can be a form of transmission of DNA from bacteria to bacteria.
What are plasmids?
Double stranded DNA molecules in bacteria.
They an replicate and can be transferred between different species of bacteria.
They can transfer genes for antibiotic resistance.
All strains of the same bacteria have the same capsule. True or false?
False
How does the capsule of bacteria act as a virulence factor?
Allows organism to enter blood stream
Protects against immunological responses in host
Describe how a gram stain is carried out.
- Heat-fix specimen to slide. Flood slide with crystal violet solution. Allow to act for 1 minute.
- Rinse the slide, then flood with iodine solution. Allow iodine to act for 1 minute. Before acetone decolorisation, all organisms appear purple.
- Rinse off excess the excess iodine. Decolourise with acetone for approximately 5 seconds.
- Wash slide immediately with water. Those that remain purple are gram positive. Those that are no longer visible are gram negative.
- Apply safranin counterstein for 30 seconds. Wash in water, blot and dry in air. Gram negative organisms are visualised as red.
After a gram stain, gram positive bacteria appear…
Purple
After a gram stain, gram negative bacteria appear…
Red
How can bacteria be classified by their shape?
Cocci
Bacilli - rods
Spirillus
How can cocci be arranged?
Clusters
Chains
What is the difference between staphylococcus and streptococcus?
Staphylococcus = catalase positive
Streptococcus = catalase negative
What is the difference between gram positive and gram negative bacteria?
Gram positive bacteria have a peptidoglycan cell wall.
Gram negative bacteria have a lipopolysaccharide cell wall. Gram negative bacteria can also have some peptidoglycan in their cell wall.
What are obligate aerobic bacteria and obligate anaerobic bacteria
Obligate aerobes - require oxygen for survival
Obligate anaerobes - require oxygen-free environment for survival (unless able to form spores)
What is the function of pilli and fimbriae?
Adherence to host cells
What are virulence factors?
Properties that enable an organism to establish themselves within a host and cause disease.
How do enzymes such as collagenase act as a virulence factor?
Breaks down collagen - allows bacteria to spread between cells so it can invade cells
What are siderophores?
Siderophores are small high affinity iron chelating compounds that some bacteria produce enabling them to sequester iron.
What is an endotoxin?
Part of the bacterial structure
The term endotoxin and outer lipopolysaccharide membrane of gram negative bacteria are often used interchangeably.
What type of bacteria is often associated with sepsis?
Gram negative bacteria
Lipopolysaccharide is highly toxic and can trigger a major inflammatory response.
What is an exotoxin?
Proteins secreted by the bacteria that go out into the surrounding blood and tissue. They can damage tissues by a number of different mechanisms
Enterotoxin - exotoxin that acts on the bowel
Neurotoxin - exotoxin that acts on nerves
List some differences between prokaryotic and eukaryotic cells.
- Prokaryotes usually have a single circular chromosome although extra-chromosomal DNA may also be present (plasmids). Eukaryotes have multiple chromosomes
- Prokaryotes have no nuclear envelope or nucleoli. Eukaryotic DNA is membrane bound and nucleoli are present.
- Prokaryotes have no membrane bound organelles. Eukaryotes have membrane bound organelles.
- Prokaryotes have a cell wall, which may contain peptidoglycan. Eukaryotes do not (plants do but not made of peptidoglycan)
- Prokaryotes have a plasma membrane with no carbohydrates and few sterols. Eukaryotes have a plasma membrane with carbohydrates and sterols present.
- Prokaryotes have 70s ribosomes whereas eukaryotes have 80s ribosomes.
Why is it difficult to kill fungi without damaging our own cells?
Fungi are eukaryotic and have a very similar structure to human cells
What is the difference between yeasts and molds?
Give some examples of each.
Both are types of fungi
Yeasts are single-celled whereas molds are multicellular.
Yeast - Candida albicans, Cryptococcus neoformans, Pneumocystis jiroveci
Molds - Aspergillus species, Dermatophytes (ringworm, athlete’s foot)
What is a parasite?
A parasite is an organism that lives on or in a host and gets its food from or at the expense of its host
What are single celled parasites called?
Give some examples.
Protozoa
Plasmodium malariae
Plasmodium falciparum
Giardia lamblia
What are multi-cellular parasites called?
Give some examples.
Helminths or worms
Roundworms
Tapeworms
Flukes
Are males or females more susceptible to urinary tract infections and why?
Females because the distance between anus and urethra is shorter
What does calendar time mean in the context of infection?
Infections that occur at certain times of the year
What does incubation period mean?
Time between exposure to infection and appearance of first symptoms.
What is debridement?
Removal of damaged tissue or foreign objects from a wound
Why is PCR the best way to make a specific diagnosis of a viral infection?
It is possible to culture a virus but this must be done with live cells as this is the only way a virus can survive and replicate. Looking at a virus then requires an electron microscope. This is time consuming so PCR is much easier.
What is the human microbiome?
Total number and diversity of microbes found in and on the human body
What are the beneficial functions of normal flora?
- large number of harmless bacteria in the large intestine and mouth makes it unlikely that an invading pathogen could compete for nutrients and receptor sites
- some bacteria produce antimicrobial substances to which the producers are not susceptible
- bacterial colonisation of a newborn infant acts as a powerful stimulus for the development of the immune system
- bacteria of the gut provide important nutrients such as vitamin K (required for clotting), B vitamins and aid in the digestion/absorption of nutrients
How can our normal flora become harmful?
- Organisms are displaced from their normal site to an abnormal site
- Potential pathogens gain a competitive advantage due to diminished populations of harmless competitions
- Commonly ingested food substances converted into carcinogenic derivatives by bacteria in the colon.
- When individuals are immunocompromised, normal flora can overgrow and become pathogenic
Describe the structure of adenovirus.
Double stranded DNA
Non-enveloped
What is adenovirus the main causative organism for?
Respiratory tract disease
Can also cause:
- ocular infections
- GI infections
- UTIs
The site of the disease caused by an adenovirus infection is related to the mode of virus infection
What could injection of drugs below the skin rather than directly into a vein cause?
Infections caused by introduction of normal skin flora into subcutaneous tissue.
This includes:
Gram positive cocci:
Staphylocccus aureus
Staphylococcus epidermis
Streptococcus species
Gram positive bacilli:
Corynebacterium species
Propionibacterium acnes
Patient is unwell with increased cough and shortness of breath. He has developed conjunctivitis.
What investigation would be best to make a specific diagnosis?
Throat swab for viral PCR
How does adenovirus replicate?
- attaches to host cell receptor
- entry into cell by receptor mediated endocytosis
- viral genome transported to nucleus where transcription of viral genes, genome replication and assembly occurs
- reproductive cycle kills the host cell
In what tissue do adenoviruses replicate well in?
Epithelial cells - observed disease symptoms are related primarily to the killing of these cells
What is sepsis?
Sepsis is a life-threatening organ dysfunction due to an unregulated host response to infection.
What is septic shock?
Septic shock is persisting hypotension requiring treatment to maintain blood pressure despite fluid resuscitation
What is bactaraemia?
Presence of bacteria in the blood which persists as organisms are being constantly shed from an infected site
How do we recognise sepsis?
-Raised Early Warning Score (EWS). If 3 or higher, patient should be reviewed
If sepsis is suspected: Look for clinical features suggesting source: -pneumonia -UTI -meningitis
Check for red flags - if present then red flag sepsis
- high respiratory rate
- low blood pressure
- unresponsive
What happens if the patient has red flag sepsis?
Immediate action required
Inform senior doctor for review
Complete sepsis six bundle: (give 3, take 3)
- oxygen
- blood cultures
- IV antibiotics
- fluid challenge
- lactate
- measure urine output
What urgent investigations should be taken from a patient with red flag sepsis?
Each case is different, no set list but consider:
- FBC
- urea and electrolytes
- EDTA bottle for PCR
- blood sugar
- liver function tests
- C-reactive protein
- coagulation
- blood gases
- other microbiology samples (CSF, urine), glass test for meningitis
- imaging
What is the supportive treatment for sepsis?
What is the specific treatment for sepsis?
Supportive
- consider early referral to ITU
- sepsis 6
- regular monitoring and reassessment
Specific
-antibiotic treatment
What are the life threatening complications of sepsis?
- irreversible hypotension
- respiratory failure
- acute kidney injury
- raised intracranial pressure (in the case of meningitis)
- ischaemic necrosis of digits/hands/feet
How does sepsis result in cytokines (IL-1 and TNF) and nitric oxide being released locally into tissue fluid and systemically into the bloodstream?
- Gram negative bacteria has a lipopolysaccharide endotoxins. The bacteria dies and when it does this, the endotoxin is released.
- These endotoxins bind to endothelial cells of the circulatory system and activate macrophages.
- Macrophages secrete cytokines( IL-1, TNF) and endothelial cells release nitric oxide.
What are the local effects of the cytokines IL-1 and TNF that are released into tissue fluid in septic patients?
- Coagulation —> Prothrombin to be converted to thrombin —> brief vasoconstriction
- Inhibits fibrinolysis
- Promotes inflammatory response
- Recruits RE (reticulo-endothelial system)
What are the systemic effects of IL-1 and TNF released into the bloodstream in septic patients?
Fever as production of prostaglandins is stimulated
Acute respiratory disease syndrome —>lungs don’t work properly, destruction of respiratory epithelium —> Endothelial cells in blood vessels in the lungs are activated so neutrophils and macrophages are stuck here
What is the effect of nitric oxide being released into the bloodstream in septic patients?
Stimulates vasodilation —> low blood pressure
How does sepsis cause disseminated intravascular coagulation?
Cytokines IL-1 and TNF cause tissue factor to be released.
Tissue factor triggers the clotting cascade by the extrinsic pathway.
This causes:
Coagulation and inhibition of fibrinolysis
This results in:
• Widespread unregulated coagulation in all blood vessels resulting in microvascular thrombosis
• Compromised blood flow to tissues leading to ischaemia
• Leads to multiple organ damage
• Anti-coagulant system stimulated to a severe extent
• Platelet and clotting factors consumed- severe bleeding of various sites
What is the major cause of shock and multiorgan failure in sepsis?
Microvascular injury
Why can sepsis result in ischaemic necrosis of the hands, feet and digits?
Microvascular thrombosis blocks blood vessels
Low blood pressure
Body desperately diverts blood supply to heart, lungs, brain and kidneys so supply to distal limbs is compromised.
How is meningococcal meningitis diagnosed?
- glass test, non-blanching purpuric rash
- blood culture
- PCR of blood
- lumbar puncture if same - sample of CSF for microscopy, gram stain and PCR
Describe the structure of Neisseria meningitidis.
Gram negative Diplococcus - shaped like a kidney bean Encapsulated Pilli Oxidase positive
How is Neisseria meningitidis transmitted?
Inhalation of respiratory droplets from a carrier or patient in early stages of disease
Describe the virulence of Neisseria meningitidis.
Pilus - enhances attachment of the organism to nasopharyngeal mucosa
Capsule - prevents phagocytosis and promotes adherence
Lipopolysaccharide endotoxin - triggers inflammation
Where is the usual attachment site for Neisseria meningitidis?
Nasopharyngeal mucosa
Describe the pathogenesis of Neisseria meningitidis.
- Asymptomatic meningococcal pharyngitis
A. Colonises nasopharynx but nasopharyngeal mucosa normally serves as a barrier to bacteria - Bacteraemia
A. Susceptible individuals - penetrates nasopharyngeal mucosa and enters blood stream
B. Rapidly multiplies in bloodstream - Meningitis
A. Crosses blood-brain barrier and infects meninges
B. Acute inflammatory response - Sepsis:
A. Lipopolysaccharide endotoxins triggers release of cytokines which results an uncontrolled inflammatory response to infection
B. Hypotension that cannot be treated with fluid resuscitation alone
C. Multiple organ failure
What specific investigations are used to confirm diagnosis of Neisseria meningitis?
- blood culture
- lumbar puncture for isolation of CSF
- swab of nasopharyngeal region
INVESTIGATION OF THESE CULTURES BY….
—>MC&S
◦ Microscopy- diplococci often in associated with polymorphonuclear leucocytes, gram negative
◦ Glucose and protein estimation - In CSF, increased pressure, elevated protein and decreased glucose (consumption by bacteria), many neutrophils
—>antigen detection
What are the symptoms of meningitis?
Initially, • Joint symptoms • Purpuric rash that doesn't blanch (glass test) • Fever • Severe headache
Within several hours, • Rigid neck • Vomiting • Sensitivity to bright lights • Coma
Initially, • Joint symptoms • Purpuric rash that doesn't blanch (glass test) • Fever • Severe headache
Within several hours, • Rigid neck • Vomiting • Sensitivity to bright lights • Coma
How is bacterial meningitis treated?
Bacterial meningitis is a medical emergency so antibiotic treatment cannot await a definitive bacteriologic diagnosis.
Specific:
• Blood culture drawn
• Antibiotic therapy given (before lumbar puncture)
◦ effectively treated with high doses of penicillin or ampicillin (can pass blood-brain barrier) in large intravenous doses
◦ when etiology of infection is unclear- ceftriaxone recommended
Supportive:
• Corticosteroid given with first dose of antibiotic - to treat intense inflammatory reaction
Sepsis 6 bundle
Are there vaccines available for Neisseria meningitidis?
Yes
Meningococcal C conjugate vaccine
ACWY vaccines - originally for immunocompromised patients and travel protection
Serogroup B vaccine - B capsules poorly immunogenic and similar to neural tissue so was difficult to make. Current vaccine has 4 antigens. Given to babies at 2 3 and 12 months, and adults at increased risk.
How can bacterial meningitis be prevented?
- serogroup B vaccine
- antibiotic prophylaxis for close contacts
Which antibiotic is recommended to be used in the treatment of infection by Neisseria meningitidis?
Ceftriaxone - cephalosporin (inhibits cell wall synthesis)
Penetrates into CSF so is active against Neisseria meningitidis
What is infectious disease?
A pathogen succeeds in evading and/or overwhelming the host’s immune defences
What is the immune system?
Cells and organs that contribute to immune defences against infectious and non-infectious conditions (self vs non-self)
Innate immunity is not required for adaptive immunity to work.
True or false.
FALSE
State 4 differences between innate and adaptive immunity.
Innate immunity - immediate protection Fast (within seconds) Lack of specificity Lack of memory No change in intensity
Adaptive immunity - long lasting protection Slow (days) Specificity Immunologic memory Changes in intensity
What are the different types of innate barriers to infection?
What is their function?
- physical barriers
- physiological barriers
- chemical barriers
- biological barriers
- prevent entry and limit growth of pathogens
- prevent local infection from becoming systemic by entering the bloodstream
What are the different physical barriers to infection?
Skin
Mucous membranes - can sense microbes at surface of mucous membrane and initiate a local immune response via MALT
(Found in mouth, respiratory tract, GI tract, GU tract)
Bronchial cilia
What are the physiological barriers to infection?
These symptoms are also present in non-infectious conditions
• Diarrhoea ◦ Food poisoning • Vomiting ◦ Food poisoning ◦ Hepatitis ◦ Meningitis • Coughing ◦ Pneumonia • Sneezing ◦ Sinusitis
What is the pH of the skin, stomach and vagina?
Skin = 5.5 Stomach = 1-3 Vagina = 4.4
Low pH so kills microorganisms
What are the biological barriers of infection?
Normal flora in strategic locations:
- nasopharynx
- mouth/throat
- skin
- GI tract
- vagina
- under NO circumstances should they be found in blood/organs/tissues
Patient is taking anti-acids for a stomach ulcer. Which infection is he prone to develop?
Skin infection, UTI, food poisoning?
Food poisoning because acidic environment prevents bacterial growth in the stomach and colonisation of the intestines
Patient is being treated for cellulitis in left leg. Which conditions are a probable cause for his medical problem?
eczema, dermatitis, insect bites
Cellulitis is infection of soft tissue under the skin. All of the above breach the integrity of the skin.
A patient is being treated for a UTI. She developed severe vaginal thrush. Which class of medicine is likely to be the cause?
Antibiotics can reduce normal flora allowing the colonisation by pathogenic microbes
Taking antibiotics can reduce normal flora in the gut. What condition does the predispose to?
Clostridium difficile associated disease
Why are people with cystic fibrosis more susceptible to infection?
Cystic fibrosis is caused by a defect in the CFTR gene which codes for a chloride ion channel.
Absence of this channel leads to less chloride and hence water exiting the cell and mucus becoming thick. This damaged cilia in the bronchi.
The cilia lose their ability to trap microorganisms in the mucus and sweep them to be excreted.
What does IgA do?
Where is it found?
Binds to microbe and prevents microbe from adhering to epithelia affecting its infectivity
Tears, salvia, mucous membranes
What does lysozyme do?
Where is it found?
Breaks the cell wall of the bacteria reducing its survival
Sebum, perspiration, urine
What do beta-defensins do?
Where are they found?
Highly toxic for gram positive and gram negative bacteria
Epithelium of mucous membranes
What normal flora is found in the nasopharynx?
Streptococcus pneumoniae
Neisseria meningitidis
Haemophilus species
What is the normal flora of the skin?
Staphylococcus aureus Staphylococcus epidermis Streptococcus pyogenes Candida albicans Clostridium perfringens
How can normal flora cause disease?
- normal flora is displaced from its normal location to a sterile location
- normal flora overgrows and becomes pathogenic when host becomes immuno-compromised
- normal flora is depleted by antibiotics
Poor dental hygiene can cause serious infections in high-risk patients. Who is at risk?
- asplenic patients
- damaged or prosthetic valves
- previous infective endocarditis
(Antibiotic prophylaxis given to these patients)
How can flora be displaced from its normal location to a sterile location?
- breaching of skin integrity
- faecal-oral route
- faecal-perineal-urethral route
- poor dental hygiene
Taking antibiotics can reduce normal flora in the gut. What condition does he predispose to?
Clostridium difficile associated disease
What is vaginal thrush caused by?
Depletion of normal flora of the vagina allowing colonisation by pathogenic microbes
When is the second line of defence in the innate response activated?
Integrity of one of the barriers that prevent entry and limit growth of pathogens is compromised eg. Break in skin
What are the second lines of defence in the innate immune response?
What is their overall function?
- phagocytes
- chemicals eg. Complement system, cytokines
- inflammation
These contain and clear the infection
What are the main cells of the innate immune cystem?
- monocytes which differentiate into macrophages
- neutrophils
- basophils
- mast cells
- eosinophils
- natural killer cells
- dendritic cells
What is the function of macrophages?
- phagocytosis
- antigen presentation
- produce cytokines/chemokines
What is the function of neutrophils?
How are they recruited to the site of infection?
-phagocytosis of pyogenic bacteria
Recruited by chemokines to the site of infection
Eosinophils are important in defence against…
Multi-cellular parasites (helminths/worms)
What do natural killer cells do?
Kill all abnormal host cells (virus infected or malignant)
What is the function of dendritic cells?
Antigen presentation to T cells
How are pathogens recognised by cells of the immune system?
-microbial structures - pathogen associated molecular patterns (PAMPs)
Can be carbohydrates, lipids, proteins, nucleic acids
Phagocytes have pathogen recognition receptors (PRRs) eg. Toll like receptors, that recognise PAMPs
-opsonisation of microbes - coating proteins called opsonins bind to microbial surfaces leading to enhanced attachment of phagocytes and clearance of microbes
What are toll like receptors?
A type of pathogen recognition receptor
Phagocytes that have most the toll like receptors are able to recognise gram positive and gram negative bacteria
Where are pathogen recognition receptors found?
- cell surface of phagocytes to identify bacteria
- inside the cell to identify viruses
What is the difference between pathogen recognition using PAMP-PRR and opsonisation?
When a PRR on a phagocyte binds to a PAMP on a pathogen, the phagocyte is activated to release cytokines and chemokines that are necessary to initiate an inflammatory response
When opsonin receptors bind to an opsonin on a pathogen, the phagocyte is simply activated to phagocytise the pathogen- no inflammatory response is activated
List some examples of opsonins.
Complement proteins = C3b , C4b
Antibodies = IgG , IgM
Acute phase proteins = C-reactive protein, mannose-binding lectin
What type of pathogen opsonins essential in the clearance of?
Encapsulated bacteria eg.
Neisseria meningitidis
Streptococcus pneumoniae
Haemophilus influenzae b
How does phagocytosis occur?
- Chemotaxis and adherence of microbe to phagocyte
- Ingestion of microbe by phagocyte
- Formation of a phagosome
- Fusion of the phagosome with a lysosome to form a phagolysosome
- Killing of ingested microbe by enzymes/oxidative burst
- Formation of residual body containing indigestible material
- Discharge of waste materials
What are the intracellular killing mechanisms of phagocytes?
Oxygen dependent pathway
Oxidative burst using hydrogen peroxide, hydroxyl radical, superoxide, nitric oxide
Oxygen independent pathway
Lysozyme - breaks down cell wall of bacteria
Lactoferrin/transferrin - deprives bacteria of essential nutrients
Cationic proteins
Proteolytic and hydrolytic enzymes
What is the complement system composed of?
20 serum proteins
Most important C1-C9
What are the two pathways of the complement system?
-Alternative pathway
Initiated by cell surface microbial constituents eg. Endotoxin
-MBL pathway
Initiated when MBL binds to mannose containing residues of proteins found on many microbes
What is mannose-binding lectin (MBL)?
It is an acute phase protein
Functions:
- opsonisation
- activates MBL pathway of complement system by binding to mannose containing residues of proteins found on many microbes
Why does the MBL pathway occur after the alternative pathway of the complement system?
The MBL pathway occurs later than the alternative pathway because MBL needs to be released by the liver. Chemokines released by macrophages stimulate the release of MBL from the liver.
The alternative pathway is activated by the microbial surface.
Therefore, this must occur first before the complement pathway is activated via the MBL pathway.
What do the complement pathways activate complement to do?
C3a and C5a = mediators for chemotaxis
C3b and C4b = opsonisation of pathogens
C5-C9 = killing of pathogens via membrane attack complex
Which chemokines are released by macrophages?
TNFa
IL-1
IL-6
What is the function of the chemokines TNFa, IL-1 and IL-6?
Liver - opsonins
CRP
MBL - complement activation
Bone marrow
Neutrophil mobilisation
Inflammatory actions
Vasodilation
Vascular permeability
Adhesion molecules —> attraction of neutrophils
Hypothalamus
Increased body temperature
Summarise the innate immune response.
- Innate barrier is breached: entrance and colonisation of the pathogens
- Complement, mast cells and macrophages activation (PRR)
Phagocytosis (opsonins)
Cytokine/chemokine production - Vascular changes - vasodilation + increased permeability
Chemoattraction - neutrophils, monocytes - Hypothalamus —> fever
Liver —> acute phase response - Local inflammation (redness, heat, swelling, pain)
Name a disease in which there is impaired neutrophil function.
Chronic granulomatous disease
NADP oxidase deficiency
You have been called to care for a 60-year-old patient in the intensive care unit who was admitted following a car accident.
He is currently unconscious and has signs of cerebral oedema. The patient has a tube into his trachea, a central venous line and urinary catheter inserted. He was given high-dose of corticosteroids to reduce his cerebral oedema and the anti- convulsant phenytoin.
Why does he have an increased risk of developing a serious infection?
Urinary catheter provides entry route
What is an antimicrobial agent?
An agent that is active against a microbe. Includes • Antibacterial • Antifungal • Antiviral • Antiprotazoal
What is an antibiotic?
An agent derived from a creature and is active against a microbe
What is the difference between bactericidal and bacteriostatic antibiotics?
Bactericidal - kills bacteria directly
Bacteriostatic - prevents bacteria from reproducing while not necessarily killing them
What are the ideal features of antimicrobial drugs?
- selectively toxic- few adverse effects
- reach site of infection
- oral/IV formulation
- long half life - infrequent dosing
- no interference with other drugs
What are the different mechanisms of action of antibacterials?
- prevent cell wall synthesis
- prevent protein synthesis
- disrupt cell membrane function
- prevent nucleic acid synthesis
Which classes of antibacterials prevent cell wall synthesis?
Beta-lactams
Glycopeptides
Which classes of antibacterials prevent protein synthesis?
Tetracyclines
Aminoglycosides
Macrolides
Which class of antibacterials disrupts cell membrane function?
Polymixins
Which class of antibacterials inhibits nucleic acid synthesis?
Quinolones
Give some examples of beta-lactams
Penicillins
Cephalosporins
Carbapenems
Monobactams
How does penicillin work?
Beta-lactam - prevents cell wall synthesis
Penicillin binding protein is required to form cross-linkages between peptidoglycan side chains. These linkages prevent movement.
Penicillin binds to penicillin binding protein so that cross linkages cannot form between peptidoglycan molecules via the side chains.
How do co-amoxiclav and tazocin counteract resistance?
• Co-amoxiclav = Amoxicillin + clavulanate
Clavunalate is a beta lactamase inhibitor so this antibiotic is active in bacteria with a beta-lactamase enzyme.
• Tazocin = piperacillin + tazobactam
same as above
What type of bacteria is penicillin mainly active against?
Streptococci
What type of bacteria is amoxicillin mainly active against?
Streptococci and some gram-negatives
What kind of bacteria is flucloxacillin active against?
Staphylococci and streptococci
What are the main types of penicillins?
Penicillin
Amoxicillin
Flucloxacillin
Which cephalosporin has good activity in the CSF?
Ceftriaxone - used in the treatment of Neisseria meningitidis and sepsis
Which carbapenem is generally safe in a penicillin allergy?
Meropenem
How does vancomycin work?
Glycopeptide - prevents cell wall synthesis
Vancomycin binds to side chains on peptidoglycan molecules and prevents penicillin binding protein from binding.
Cross linkages cannot form between peptidoglycan molecules via the side chains.
Vancomycin is toxic so why is used?
- penicillin allergy/intolerance
- resistance to penicillin
What type of bacteria is vancomycin active against?
Most gram positive
Why can’t tetracyclines be used in children?
Stain bone and teeth yellow
What class of antibacterial is gentamicin?
Aminoglycoside - prevents protein synthesis
When is gentamicin used?
Aminoglycoside - inhibits protein synthesis
Profound activity against gram negatives. Good activity in blood and urine.
Generally preserved for severe gram negative sepsis
Which macrolide can be used as an alternative to penicillin for mild gram positive infections?
Erythromycin
Macrolide - prevent protein synthesis
What is the commonest type of quinolone?
Ciprofloxacin
How do quinolones work and are they broad spectrum?
Inhibits two enzymes in DNA replication, one of these is involved in supercoiling
Quinolones are broad spectrum
Use of quinolones is associated with a risk of…
C.difficile
How do trimethoprim and sulphonamides work?
Inhibit DNA synthesis by inhibiting folic acid synthesis
Which antibiotic is used in treatment of UTI’s?
Trimethoprim - inhibits folic acid synthesis and hence DNA synthesis
What is used to treat pneumocystic pneumonia?
Co-trimoxazole
Trimethoprim + suphamethoxazole
Inhibits folic acid synthesis and hence DNA synthesis
What are the different types of antibiotic resistance?
Intrinsic
Acquired
Adaptive
What is intrinsic antibiotic resistance?
Intrinsic - certain antibiotics do not work against certain bacteria
No target or access for the drug
Usually permanent
What is acquired antibiotic resistance?
Acquired - organism that was once susceptible is no longer susceptible
Acquires new genetic material or mutates
Usually permanent
What is adaptive antibiotic resistance?
Adaptive - a few organisms in the colony develop a potential to withstand the adverse circumstance
Organism responds to a stress eg. Sub-inhibitory level or antibiotic
Usually reversible - take away adverse circumstances, susceptible organisms will reappear
What are the mechanisms of antimicrobial resistance?
• Drug inactivating enzymes
◦ Eg. B-lactamases, aminoglycoside enzymes
• Altered target- Target enzyme has lowered affinity for antimicrobial
◦ Eg. Resistance to meticillin (MRSA), macrolides, trimethoprim
• Altered uptake- decreased permeability/ increased efflux
◦ Eg. Decreased permeability- B-lactams
◦ Eg. Increased efficacy - tetracyclines
What is the mechanism of antibiotic resistance to meticillin (MRSA)?
Altered target -
Target enzyme in bacteria has lowered affinity for the antimicrobial
What type of genetic material is found in bacteria?
- Chromosome - double stranded circular DNA
- Plasmids- non-chromosomal DNA
- Transposon- strands of non-chromosomal DNA
Transposons can be integrated into plasmids which can be integrated into chromosomes
What are transponons?
Strands of non-chromosomal DNA in bacteria
Describe how vertical gene transfer in bacteria can lead to antibiotic resistance.
◦ A spontaneous mutation occurred which enables the organism to be resistant. This may be in plasmid or in the chromosome.
◦ All susceptible organisms die and those with resistant genes survive.
◦ Organisms with resistant genes multiply and dominate the environment
◦ Genes for resistance passed on to all offspring.
Describe how horizontal gene transfer in bacteria can lead to antibiotic resistance.
◦ Conjugation
‣ Genetic material transferred from one organism to another
◦ Transduction
‣ Injected into bacterium by a virus forming a bacteriophage
◦ Transformation
‣ Free DNA can enter cell wall via pores
Why is minimum inhibitory concentration better than disc testing for measuring antibiotic activity?
• Disc testing
Grow bacteria on an agar plate.
Measure the circumference of space where the antibiotic has killed the bacteria.
• Minimum inhibitory concentration
Make solutions of different concentrations of antibiotic
See which solutions enable growth of the bacteria
Find minimum concentration that inhibits bacterial growth
MIC- gives quantitative value for antibiotic against bacteria to compare against different organisms and antibiotics. Gives a way of defining sensitive and resistant strains.
Which antifungal can be used to treat vaginal thrush?
Fluconazole - inhibits cell membrane synthesis
What are the two classes of antifungals?
Azoles - inhibit cell membrane synthesis
Polyenes - inhibit cell membrane function
Which antiviral drug can be used against Herpes simplex in the treatment of genital herpes and encephalitis?
Aciclovir- when phosphorylated inhibits viral DNA polymerase
Which antiviral drug can be used in the treatment of Varicella zoster in the treatment of chicken pox and shingles?
Aciclovir
What is antimicrobial stewardship?
- Appropriate use of antimicrobials
- Optimal clinical outcomes
- Minimise toxicity and other adverse events
- Reduce the costs of healthcare for infections
- Limit the selection for antimicrobial resistant strains
To prevent resistance, should patients complete every dose of antibiotics even after they feel better?
No because there is a greater chance of selecting for resistant bacteria with longer doses.
Do short courses of antibiotics cause resistance? If not, why are they disadvantageous over longer courses under some circumstances?
No - they are less likely to cause resistance
May not be long enough to kill all bacteria- need to find optimum dose.
Where are antigen presenting cells found?
Lymphatic tissue where antigen presenting cells can interact with B cells and T cells
• Skin (SALT)
• Mucous membranes MALT (GALT, NALT, BALT, GUALT)
• Lymphoid organs (lymph nodes, spleen)
• Blood circulation (plasmacytoid and myeloid DCs)
How do antigen presenting cells present antigens?
- Pathogen capture
A. Phagocytosis (whole microbe)
B. Macropinocytosis (soluble particles) - Process
A. Detect intracellular pathogens (virus) or extracellular pathogens (bacteria) using diverse pathogen sensors (PRRs- located inside and outside of the APC)
B. Process antigens using MHC molecules - Presentation
Which cells are antigen presenting cells and where are they found?
Dendritic cells
Location: lymph nodes, mucous membranes, blood
Langerhans cells
Location: Skin
Macrophages
Location: Various tissues
B cells
Location: Lymphoid tissues
Which antibiotic is used in the treatment of gram positive bacteria?
Vancomycin - glycopeptide
What do antigen presenting cells do?
For an antigen to be recognised by a T cell (the main cell of adaptive immunity), antigen presentation by antigen presenting cells is essential.
Why can’t asplenic patients mount a full response to blood-borne pathogens?
- site of phagocytosis of opsonised pathogens
- encapsulated bacteria are phagocytised here
Which type of T cells do dendritic cells and Langerhans’ cells present antigens to?
Naive T cells - T cells that have not yet encountered an antigen
Which cells do macrophages present antigens to?
Effector T cells - T cells that have encountered an antigen before
Which cells do B cells present antigens to?
Effector T cells - T cells that have encountered an antigen before
Naive T cells - T cells that have not yet encountered an antigen
What are naive T cells?
T cells that have not yet encountered an antigen
What are effector T cells?
T cells that have encountered an antigen before
Which MHC molecule is present on the surface of antigen presenting cells (dendritic cells, Langerhans’ cells, macrophages, B cells)?
MHC class II
What is the difference between Class I and Class II MHC molecules?
Class I molecules • found on all nucleated cells • present peptides from INTRACELLULAR microbes • Recognised by CD8+ T cells • Genes they are coded for by are found on p and q arm of chromosome 6 ◦ HLA A ◦ HLA B ◦ HLA C
Class II molecules
• found on APC’s (dendritic cells, macrophages, B cells)
• present peptides from EXTRACELLULAR microbes
• Recognised by CD4+ T cells
• Genes they are coded for are found on the q arm of chromosome 6
◦ HLA DR
◦ HLA DQ
◦ HLA DP
Which class of MHC molecule is found in all nucleated cells?
Class I
Which class of MHC molecule is found in antigen presenting cells?
Class I
Class II
What does MHC Class I do?
Presents peptides from intracellular microbes
Recognised by CD8+ T cells
What does MHC Class II do?
Present peptides from extracellular microbes
Recognised by CD4+ T cells
Where are the genes that code for MHC Class I molecules found and what are they?
P and q arm of chromosome 6
HLA A
HLA B
HLA C
Where are the genes that code for MHC Class II found and what are they?
Q arm of chromosome 6
HLA DR
HLA DQ
HLA DP
Why is it advantageous to have a diverse class of MHC molecules?
More microorganisms can be processed and presented by antigen presenting cells with a greater variety of MHC molecules.
What determines the diversity of MHC molecules that an individual has?
• Co-dominant expression - Both parental genes are expressed
◦ Increased number of different MHC molecules
• Polymorphic genes - Different alleles among different individuals
◦ Each individual can present different antigens/microbes
Describe the structure of MHC Class I and explain how this relates to its function.
There are 2 subunits- a large subunit (spans the membrane) and a small subunit.
• Peptide binding cleft = variable region with highly polymorphic residues so many different types of peptides can bind and be presented by the same MHC molecule (broad specificity)
◦ Binds to peptides between 9 and 10 amino acids in length
Describe the structure of MHC Class II and explain how this relates to its function.
There are 2 subunits equal in length and both transmembrane
• Peptide binding cleft = variable region with highly polymorphic residues so various different types of peptides can bind and be presented by the same MHC molecule (broad specificity)
◦ Binds to larger peptides
◦ Peptide binding cleft is between the 2 subunits
A patient has contracted a flu virus. He has a terrible headache, fever and is coughing a lot.
The viral proteins on the airway epithelial cells are presented by the MHC molecules called HLA-DP, HLA-DQ, HLA-DR.
True OR False?
False- viruses are only presented by MHC class I, these are HLA-A, HLA-B, HLA-C
A patient has contracted a flu virus. He has a terrible headache, fever and is coughing a lot.
The viral proteins on the airway epithelial cells are presented by the MHC molecules called HLA-A, HLA-B, HLA-C.
His dendritic cells will also express the viral peptides
True OR False?
True- dendritic cells have MHC I and MHC II because they are nucleated and APC’s
It is the nature of the pathogen that determines the way it is processed.
True or false?
False
It is not the nature of the pathogen that determines the way it is processed. Instead, it is the route of trafficking into the cell.
Describe antigen presentation of all nucleated cells via the endogenous pathway.
- The virus/tumour or self antigen (intracellular antigen) enters the cell.
- This is targeted for degradation by the cell. Ubiquitin is added to the antigen and signals for their degradation via proteasomes. Proteasomes are protein complexes that degrade unneeded or damaged proteins by proteolysis.
- Antigenic peptides are produced by the the proteasomes which is transported into the ER via a specific transporter.
- There is a dynamic system inside the ER where MHC class I is constantly produced. When there is a match between MHC class I and the viral antigenic peptide/self antigen, the MHC class I binds and moves to the cell surface.
- The viral antigenic peptide/self antigen is presented alongside MHC class I at the cell surface.
- This activates CD8+ T cells.
Both self and non-self peptides are presented to T cells.
True or false.
True
What are proteasomes?
Protein complexes that degrade unneeded or damaged proteins by proteolysis
What is ubiquitin?
It is added to antigens and signals for their degradation via proteasomes
Where is MHC class I produced?
There is a dynamic system in the ER where MHC class I is constantly produced
Where do MHC Class I molecules bind to antigens?
In the ER -
The MHC Class I and antigen complex then moves to the cell surface
Describe how antigens are presented by antigen presenting cells via the exogenous pathway.
- The exogenous antigen is engulfed by the cell by endocytosis.
- The vesicle fuses with lysosomes and the proteins are digested forming a phagosome
- The phagosome fuses with a vesicle containing the MHC class II molecule. when there is a match between MHC class II and the exogenous antigen, the MHC class II binds to it and moves to the cell surface.
- The exogenous antigen is presented alongside MHC class II at the cell surface.
- This activates CD4+ T cells.
Are all peptides from the same microbe presented by the same MHC molecule?
No- peptides from the same microbe may be presented by different MHC molecules
What does susceptibility to infections depend upon in relation to MHC molecules?
The more diverse MHC molecules an individual has, the less susceptible they are to an infection
In a healthy individual, antigen presenting cells present both self and non-self peptides. Why do their normal tissues not get damaged?
T cells do not react with self antigens on antigen presenting cells. They only react with foreign antigens.
Why do people who are infected with HIV have different responses to the virus?
Slow progressors have MHC molecules that present key peptides that are essential for the survival of the virus eg. P24 (unmutated). Therefore, there is an effective T cell response.
• High CD4+ count
• High CD8+ cytotoxic T lymphocyte count
• Viral load is controlled
Rapid progressors have MHC molecules that present peptides that are not essential for the survival of the virus and can be mutated. Therefore, there is poor recognition of virally infected cells and a poor T cell response.
• Low CD4+ count
• Low CD8+ cytotoxic T lymphocyte count
• Viral load is not controlled
A 27 year old male
• History of injection drug use
• Pneumonia (Pneumocystis jirovecii) and CNS toxoplasmosis
• His viral load was 200,000 copies/ml
• CD4+ T cell count <200 cell/μl (mm3).
Treatment: Highly Active Anti-Retroviral Therapy (HAART)
What disease is this patient likely to have and what is he at risk of?
IV drug use—> blood borne infection, HIV?
CD4+ T cell count is low—> HIV destroys CD4+ T cells. CD4+ T cells very important in adaptive immune response.
Pneumocystis jirovecii and high viral load—> He won’t die from the virus but because his CD4+ T cell count is low, he is immunosuppressed and can die from an opportunistic infection
What is the importance of MHC molecules in transplant rejection?
GRAFT-VERSUS HOST REACTION (GVH)
MHC molecules are one of the major causes for transplant rejection.
HLA molecules mismatch between donor and recipient (allograft)
Why does it matter if HIV attacks CD4+ T cells when CD8+ T cells can be activated by the endogenous pathway by all nucleated cells?
CD8+ T cells require activation by CD4+ T helper cells to replicate. Therefore, APC’s can process intracellular microbes by endogenous and exogenous pathways using MHC class II and MHC class I
Where do T cells mature?
Thymus
What is the antigen receptor on T cells called?
TCR
What determines which TCR a lymphocyte has?
Random process which depends on gene rearrangement
What determines the function of T effector cells?
The nature of cytokines they produce
Describe the structure of TCR.
Has a variable region and a constant region.
Does not work in isolation- works as part of a complex with other receptors
CD4+ on T cells that recognise MHC Class II
CD8+ on T cells that recognise MHC Class I
How are naive T cells activated?
A complementary peptide binding to the complementary TCR forming a complex.
They are only fully activated when costimulatory signals (due too the release of cytokines) are produced by the binding of CD80/86 presented by mature APC’s with CD28 on the T cell.
What happens to antigen presenting cells when they present a peptide?
They mature and present a different class of proteins (CD80/86) that enhances the attachment between APC’s and T cells as it is recognised by CD28 on T cells.
Describe the T cell response against intracellular microbes.
Antigen-presenting cells express antigenic peptides via MHC Class I and MHC Class II.
MHC Class I antigen TCR complex and costimulation activates naive T cells to become CD8+ T cells.
MHC Class II antigen TCR complex and costimulation activates naive T cells to become T helper 1 CD4+ T cells.
CD8+ T cells are stimulated by T Helper 1 CD4+ T cells to divide and develop into cytotoxic T lymphocytes.
Cytotoxic T lymphocytes bind to MHC Class I antigen complexes on infected cells and kill them by secretion of
• Perforins - creates holes on the virally infected cell membrane
• Granzymes - initiates an apoptotic process in the virally infected cell
B cells are activated by cytokines released by T Helper 1 CD4+ T cells to create antibody IgG for opsonisation of microbes.
Macrophages are activated by cytokines released by T helper CD4+ T cells to phagocytise opsonised microbes.
Describe the T cell response against extracellular microbes.
Antigen presenting cells express antigenic peptides via MHC Class II
MHC Class II antigen TCR complex and constimulatory signals activates naive T cells to become CD4+ T helper 2 cells and CD4+ T helper 17 cells.
Eosinophils are activated by cytokines released by CD4+ T helper 2 cells.
Eosinophils kill parasites.
B cells are activated by cytokines released by CD4+ T helper 2 cells.
B cells produce antibodies for opsonisation and phagocytosis.
Mast cells are activated by cytokines released by CD4+ T helper 2 cells.
Mast cells cause local inflammation in response to allergies when activated by IgE
Neutrophils are activated by CD4+ T helper 17 cells.
Neutrophils phagocytise the pathogen.
Describe how the ratio of IgG and IgM changes with primary and secondary response to an antigen.
• Primary response - first encounter High concentration of IgM Low concentration of IgG, lower than IgM concentration Ratio of IgM: IgG is high Total antibody count lower
• Secondary response
Same concentration of IgM as primary response
Higher concentration of IgG than in primary response, exceed IgM concentration
Ratio of IgM: IgG is low
Total antibody count higher
What is the difference to the primary and secondary antibody response to an antigen?
It is faster
It is stronger as there is more antibodies produced
It lasts for a longer duration
The antibodies have a higher affinity for the antigen
There is an isotype switch from IgM to IgG as these are better for opsonisation
What are the functions of IgG?
Opsonisation
Complement activation - (classical pathway is activated when it binds to an antigen-antibody complex)
Neonatal immunity
Toxin/virus neutralisation
What are the functions of IgE
Immunity against helminths
Mast cell degranulation (allergies)
What is the function of IgA
In breast milk
Mucosal immunity
What is the function of IgM?
Complement activation
Which factors from adaptive immunity are used against a virus?
CD8+ —> cytotoxic T cells
CD4+ T1H —> macrophages / IgG
Cell - dependent immunity
One of the nurses in charge of a ward is 2 months pregnant. How would you check whether she has had chicken pox before?
VzF IgM: IgG ratio
It would be high in a primary response
It would be low in a secondary response
Which factors from adaptive immunity are used against helminths?
CD4+ TH2 —> eosinophils/ B cells/ mast cells
CD4+ TH17 —> neutrophils
Humoral immunity
What are healthcare infections?
Infections arising as a consequence of providing healthcare. They are a major cause of harm in patients receiving healthcare and limit the potential benefits of healthcare innovations.
What are hospital acquired infections?
Infections arising as a consequence of a patient being admitted to hospital. In hospital patients, it is neither present nor incubating at time of admission. This means onset is at least 48 hours after admission. This includes infections in hospital visitors and healthcare visitors.
List some viruses that cause healthcare infections.
Blood borne viruses (Hep B, Hep C, HIV)
Norovirus
Influenza
Chicken pox
List some bacteria that cause healthcare infections.
Staphylococcus aureus including MRSA
Gram negative and tend to be resistant to many antibiotics: Clostridium difficile Escheria coli Klebsiella pneumoniae Myobacterium tuberculosis
What patient factors can increase the risk of them developing a hospital acquired infection?
Obesity/malnourished
Particularly before elective surgery
Diabetes
Blood sugars to be kept stable particularly before elective surgey. High blood sugar levels can weaken the patient’s immune system defences and can cause peripheral vascular damage
Cancer
Immunosuppressed
Smoker
More prone to lung infections eg. Pneumonia
Increased risk of surgical wound infection as less oxygen is transported to tissues
Surgical patient
Emergency admission
Already unwell and immunosuppressed
What are the 4 Ps of infection prevention and control?
Patient
- general and specific patient risk factors for infections
- interactions with patients/HCW/visitors
Pathogen
- virulence factors
- ecological interactions (antibiotics/other bacteria)
Practice
- general + specific activities of healthcare workers
- policies and implementation
Place
-healthcare environment
What is the most common mode of transmission for healthcare infections?
Most healthcare infections are caused by the patients own flora moving somewhere on themselves where it is now pathogenic.
Eg.
E.coli moving from the large bowel where it is normal flora, moving to the urinary tract where it can cause kidney infection or cystitis (UTI)
Staphylococcus aureus moving from the mouth/nose where it is normal flora, moving into a wound where it can cause infections of skin and soft tissue and septicaemia
How can we reduce patients from getting hospital acquired infections due to their own flora moving to a site where it is now pathogenic?
General
- optimise patient’s condition (smoking, nutrition, diabetes)
- antimicrobial prophylaxis
- skin preparation
- hand hygiene
Specific
- MRSA screens
- disinfectant body wash
How can we reduce the risk of infections being transmitted from patient to patient?
Physical barriers
- isolation of infected patients in sideroom/ positive pressure room
- protection of susceptible patients in sideroom/ positive pressure room
How can we reduce the risk of healthcare workers transmitting infections to patients?
Healthy (disease free + vaccinated)
Good practice
- good clinical techniques
- hand hygiene
- personal protective equipment (things to protect healthcare worker from being contaminated by the patient e.g. Plastic aprons, rubber gloves, face masks, respiratory protection)
How can we reduce the risk of the environment being a mode of transmission of infection in hospitals?
- appropriate kitchen and ward food facilities
- good food hygiene practice
- theatres
- positive/negative pressure rooms for immunosuppressed/infected patients
How can healthcare workers identify patients who are at high risk of infection transmission?
Identify
- abroad
- blood borne infections
- colonised
- diarrhoea/vomiting
- funny looking rash
Isolate
Investigate
Inform
Initiate
What promotes antimicrobial resistance?
All exposure of bacteria to antimicrobials - whether appropriate or not
What are the consequences of antimicrobial resistance?
- Treatment failure
- Prophylaxis failure - cannot perform surgery without a high risk of infection
- Economic costs
What does MDR (multi-drug resistant) mean?
Non-susceptibility to at least one agent in three or more antimicrobial categories.
What does XDR (extensively-drug resistant) mean?
Non-susceptibility to at least one agent in all but two or fewer antimicrobial categories
What does PDR (pan-drug resistant) mean?
Non-susceptibility to all agents in all antimicrobial categories.
What are the three types of antimicrobial stewardship interventions?
- persuasive
- restrictive
- structural
Describe the structure and virulence of Clostridium difficile.
Structure:
Bacilli
Gram positive
Virulence: Anaerobic Forms endospores Toxin A - excessive fluid secretion Toxin B - disruption of cell cytoskeleton
How is Clostridium difficile transmitted?
C.difficile is a minor component of the flora of the large intestine
After its introduction to a site, the environment becomes permanently contaminated with spores and new residents are easily colonised
Faecal-oral route
Describe the pathogenesis of Clostridium difficile.
• C.difficile is a minor component of the normal flora of the large intestine
• When antimicrobial treatment suppresses more predominant species in this community, C.difficile proliferates. Virtually all antimicrobial drugs have been reported as predisposing to diseases caused by C.difficile.
◦ Most commonly, clindamycin, ampicillin and cephalosporins
• Pathogenic strains produce two toxins
◦ Toxin A = enterotoxin that causes excessive fluid secretion and stimulates an inflammatory response
◦ Toxin B = disrupts protein synthesis and causes disorganisation of the cytoskeleton
• Forms endospores
What are endospores?
An endospore is a dormant, tough, non-reproductive structure produced by a small number of bacteria.
These are formed when favoured nutrients are exhausted.
Endospores can survive environmental assaults that would normally kill the bacterium.
What diseases are caused by C.diff?
- antibiotic associated diarrhoea
- pseudomembranous colitis (PMC)
Which specific investigation would you request if you suspected an individual of having a C.diff infection?
Stool sample
MC&S
Antigen detection
How is C.diff treated?
Discontinuance of predisposing drug
Fluid replacement
Antibiotic:
fidaxomicin (UHL)
metranidazole (anti-bacterial and anti-protozoal agent, used to treat anaerobic bacteria)
Reconstitution of normal colonic flora
Describe the structure and physiology of Staphylococcus aureus.
Cocci Gram positive Catalase positive Coagulase positive Facultative anaerobe
How is Staphylococcus aureus transmitted?
Staphylococcus aureus is frequently carried by healthy individuals on the skin and mucous membranes. Carriers serve as a source of infection to themselves and others.
• Direct contact
• Contamination of surfaces
• Contamination of food
What are the risk factors for Staphylococcus aureus transmission?
A significant host compromise is required for S. aureus infection
• Break in the skin
• Insertion of a foreign body eg. Wounds, surgical infections, central venous catheters
• Obstructed hair follicle
• Compromised immune system
Describe the virulence of Staphylococcus aureus.
Capsule - prevents phagocytosis by preventing attachment of antibodies/complement
Protein A - binds to IgG exerting an anti-opsonin and anti-phagocytic effect
Cytolytic exotoxins - attack cell membranes (including erythrocytes-haemolysin) resulting in osmotic lysis
Leukocidin - pore-forming toxin loses polymorophonuclear leukocytes
Coagulase - converts fibrinogen to fibrin causing clot formation
Superantigen exotoxins - stimulate enhanced T cell response which can cause toxic shock syndrome by increased release of cytokines
Which skin and soft tissue infections can be caused by Staphylococcus aureus?
Furuncles, carbuncles - boils/ infected hair follicles infected with bacteria
Wound infection
Cellulitis - bacterial skin infection involving the dermis and subcutaneous fat
Impetigo - bacterial skin infection involving the superficial skin
What are the signs and symptoms of toxic shock syndrome caused by Staphylococcus aureus?
Fever
Hypotension
Multisystem organ dysfunction
Erythematous rash with desquamation occurring
How do Staphylococcus aureus infections cause the formation of abscesses?
The development of an abcess is a complex process that involves both bacterial and host factors. S. aureus infections cause a rapid and extensive influx of white blood cells eg. Neutrophils. S. aureus lyses neutrophils (leukocidin) and red blood cells (cytolytic exotoxins and haemolysin) that have entered the infection area. The lysed neutrophils pour out large numbers of lysozymal enzymes, which damage surrounding tissue.
What is pus?
Dead or dying white blood cells and cellular debris and serous fluid and fibrin and bacteria
What diseases are caused by toxins released by Staphylococcus aureus?
- toxic shock syndrome
- scalded skin syndrome
- food poisoning (gastroenteritis)
What is the recommended antibiotic for skin and soft tissue infections caused by Staphylococcus aureus?
IV vancomycin
What infection control measures are important for MRSA?
• Active screening of high risk patients and exposed healthcare workers for carriage
• Strict implementation of transmission based precautions
◦ Hand washing- remains the cornerstone for effective control in hospitals. MRSA spreads from patient to patient via hands of healthcare providers so this is possibly the most important measure to reduce the spread of MRSA in a healthcare setting
◦ Isolation
• Treatment of carriage using topical applications of mupirocin nasal cream (a topical antibiotic) and washing with disinfectant agent, such as stellisept or chlorhexidine
How is norovirus spread?
• Mainly faecal-oral • Respiratory Can be spread by: • Direct person-person contact • Contact with contaminated surfaces • Ingestion of contaminated food
Describe the structure of norovirus.
Small
Non-enveloped
Single positive stranded RNA
What organism is commonly known as the winter vomiting bug?
Norovirus - more common in winter although you can catch it any time of the year
How can the risk of norovirus transmission be reduced?
- Stay off work or school until at least 48 hours after symptoms have passed
- Wash hands frequently with soap and water
- Disinfect any surfaces or objects that could be contaminated
- Wash any items of clothing or bedding contaminated
- Do not share towels and flannels
How is norovirus treated?
None
Supportive measures - fluid
What is a surface?
Interphase between a solid and either liquid or gas
What surfaces are present in a patient?
Skin • Epithelium • Hair • Nails Mucosal surfaces • Conjunctival - eye • Gastrointestinal • Respiratory • Genitourinary
What is commonly used for the culture of bacteria?
Agar plates
This is agar commonly with additional ingredients to facilitate bacterial growth, including proteins and sodium chloride.
What is agar?
Polysaccharide derived from seaweed
Why is agar used to culture bacteria?
- allows creation of a medium that can be inoculated at 40degrees in its cooled molten state and incubated at 60degrees without melting
- clearer than gelatin
- resists digestion by bacterial enzymes
Why is the standard agar plate red?
Addition of blood
This is an enriched medium as the plate with protein and blood provides nutrients for a number of common bacteria - however, some bacteria are inhibited by the presence of blood
Give an example of bacteria that will only grow in chocolate agar and what is this?
Haemophilus influenza
Chocolate agar - lysed red blood cells release intracellular nutrients (lysed blood is a darker colour)
Which viruses are found on the skin?
Papilloma
Herpes simplex
Which gram positive bacteria are found on the skin?
Staphylococcus aureus
Coagulase negative staphylococci
Corynebacterium
Which gram negative bacteria are found on the skin?
Enterobacteriaceae
Which fungi were found on the skin?
Yeasts eg. Candida
Dermatophytes
Which parasites are found on the skin?
Mites
What is the microbiota of the nasopharynx?
Neisseria meningitidis
Streptococcus pneumoniae
Haemophilus influenzae
Why do people with more sugar in their diet have an increased risk of dental caries and endocarditis?
Number of bacteria in the mouth is directly proportional to amount of sugar in diet.
The more bacteria there are in the mouth, the greater the chance of bacteria entering the blood stream from the mouth
When might the microbiota of the eye get to the wrong place?
Surgery eg. Cataract surgery
When is the microbiota of the large intestine disturbed and what can this cause?
Antibiotics (strong association with cephalosporins)
Reduced competition creates a monoculture of C.diff
How do the microbiota of the vagina protect it from pathogens?
Lactobacillus produce lactic acid which lowers the pH
Dermatophytes cause…
Athletes foot
Superficial skin infections
How can microbiota get to the wrong place? (4)
Invasion eg. Strep pyogenes (skin to pharynx)- pharyngitis
Migration eg. Escherichia coli (large intestine to urinary tract) - UTI
Innoculation eg. Coagulase negative staphylococcus (skin to joint capsule) - prosthetic joint infection
Haematogenous eg. Viridans Streptococci (mouth to blood)- endocarditis
Give some examples of external natural surface infections.
Skin:
Epithelium - cellulitis
Mucosal surfaces: Conjunctival - conjunctivitis Gastrointestinal - gastroenteritis Respiratory - pneumonia Genitourinary - UTI's
Give some examples of internal natural surface infections.
Vascular - endocarditis, vasculitis
Septic arthritis - infection of synovial fluid at a synovial joint
Osteomyelitis - infection of bone via blood
Empyema - infection of synovial fluid in pleural space
Give some examples of medical interventions that increase the risk of prosthetic surface infections.
Catheters
Prosthetic joints
Cardiac valves
Endovascular grafts
Which bacteria commonly causes prosthetic surface infections?
Coagulase negative Staphylococci
(Staphylococci epidermis is a good example of a commensalism on the skin that has low virulence. The exception is if it gets into the blood then onto an artificial surface. It produces ‘slime’ which contributes to the development of a biofilm that is difficult to get rid off. The extracellular matrix protects the bacteria from exposure to innate immune defences (opsonisation and phagocytosis) and from antibiotic treatment.)
What is hydrocephalus and what prosthetic device is used to treat it?
Hydrocephalus
Caused by obstruction of outflow of fluid in the ventricles of the brain. Fluid pressure in ventricles builds up and because the skull is still growing in a child, it accommodate the increased pressure by the skull getting bigger.
Treatment:
Ventricular peritoneal shunt- fluid from the brain drains into peritoneal cavity and a valve is present to prevent any bacteria in the peritoneum from entering the brain.
What is a Hickman line used for?
Hickman line
Used to deliver chemotherapy
It is buried under skin for several inches before entering the bloodstream to minimise the chance of bacteria from the surface of the skin entering the bloodstream
What is endocarditis?
Endocarditis = endocarditis is a rare and potentially fatal infection of the inner lining of the heart (the endocardium). It’s most commonly caused by bacteria entering the blood and travelling to the heart
What is cardiac pacing wire endocarditis and which organisms is it caused by?
Pacemaker software is implanted in a socket around the pectoral muscle. A wire from this goes through the subclavian vein into the right atrium. The end of the wire is buried in heart muscle.
Pacemaker endocarditis
Endocarditis = endocarditis is a rare and potentially fatal infection of the inner lining of the heart (the endocardium). It’s most commonly caused by bacteria entering the blood and travelling to the heart
Bacteria grows on the pacemaker wire-
particularly coagulase negative Staphylococcus (Staphylococcus epidermis)
Staphylococcus aureus
What are the causative organisms for prosthetic valve endocarditis?
Native valve endocarditis and prosthetic valve endocarditis > 1 year post-operation: Viridans Streptococci Enterococcus faecalis Staphylococcus aureus HACEK group Candida
Prosthetic valve endocarditis < 1 year post-operation:
Coagulase negative Staphylococci
What are the causative organisms of prosthetic joint infection?
Coagulase negative staphylococci
Staphylococcus aureus
Why is Staphyloccocus epidermis harmful if it gets into the bloodstream?
Settles on a surface eg. Prosthetic joint surface, prosthetic heart valve, pacemaker wire, endocardium of the heart
Produces a ‘slime’ which contributes to the development of a biofilm that is difficult to get rid of.
The extracellular matrix acts as a barrier from exposure to innate immune defences (phagocytosis or opsonisation) and from antibiotic treatment
What are the risk factors for endocarditis?
- Endocardium is non-sticky and normally resists bacterial seedling. Most cases of infective endocarditis relate to structural defects. Bicuspid aortic valve is the most common congenital cardiac defect- the structural abnormality and abnormal tissue provides a place for bacteria to stick and form a colony.
- prosthetic heart valves or pacemakers
- injectable drug use
What is the hallmark of endocarditis?
Formation of a vegetation (clot composed largely of fibrin, platelets and sometimes microorganisms, adherent to a diseased heart orifice or valve often initiated by infection of the structures involved) that binds to valves or mural endocardium.
Describe the pathogenesis of endocarditis.
Hallmark of endocarditis = formation of a vegetation that binds to valves or mural endocardium
- turbulent flow predisposes to a collection of fibrin, platelet and inflammatory cells. This forms the basis for the vegetation..
- micorrganisms enter the blood stream from skin, mucosa or other sites of local infection. They bind to the vegetation and cause local infection.
- further fibrin deposition, platelet aggregration and bacterial invasions leads to an infection cascade causing infective endocarditis.
Why does infective endocarditis often require surgery rather than antibiotics to treat the condition?
Hallmark of endocarditis is a vegetation that binds to valves or mural endocardium.
A collection of platelets, fibrin, inflammatory cells and bacteria form a mass. The vegetation has features of a biofilm. Bacterial micro-colonies deep within the vegetation are dormant and therefore, difficult to eradicate. It is difficult for antibiotics to penetrate the vegetation so often requires surgery to remove the valve and replace it with an artificial valve.
How do microorganisms cause an infection at surface by forming a biofilm?
- Adherence to host cells or prosthetic surfaces (surfaces are often negatively charged so attract the bacteria. This is often via pilli/fimbrae.
- Biofilm formation
Bacteria settle on a surface and produce chemicals called quorum sensing chemicals. The more bacteria there are, the more quorum sensing molecules released. This is sensed by other bacteria and when there are a certain number of bacteria detected, the bacteria changes the phenotypic expression from being in a plantanoic form to a sessile form that produces this mucopolysaccharide. - Invasion and multiplication.
This biofilm protects the bacteria against host defences and antimicrobials. Therefore, prosthetic devices with biofilms must be removed. - Host response
- pyogenic (neutrophils—> pus)
- granulomatous (fibroblasts, lymphocytes, macrophages —> nodular inflammatory regions)
What structures are involved in quorum sensing?
Quorum sensing signalling molecules (autoinducers)
Cell surface/cytoplasmic receptors
Gene expression —> cooperative behaviours and more autoinducers produced
What does quorum sensing control?
Sporulation - formation of dormant forms of bacteria
Biofilm formation
Virulence factor secretion
What substance is biofilm made of?
Mucopolysaccharide
Why is it difficult to identity organisms and their antimicrobial susceptibilities at infected surfaces?
Adherent organisms - stick to prosthetic device/internal surfaces so difficult to isolate these organisms
Small colony variants/low metabolic state
How are are bacteria obtained from infected surfaces to identity the infecting organism and its antimicrobial susceptible?
Blood cultures
Tissue/prosthetic material sonication and culture
What is the aim of treatment of infection at surfaces?
- sterilise tissue
- reduce bioburden
Why is it difficult to treat infections at surfaces?
- poor antibacterial penetration into biofilm due to mucopolysaccharides
- low metabolic activity of biofilm micro-organisms so less susceptible to antibiotics as they tend to work when the organism is replicating and active - this is why you have a very long course of antibiotics (organisms replicate slowly)
Often requires surgery
How can infections at natural surfaces be prevented?
Maintain surface integrity
Prevent bacterial surface colonisation
Remove colonising bacteria
How can infection at prosthetic surfaced be prevented?
Prevent contamination
Inhibit surfaced colonisation
Remove colonising bacteria
Why do patients go to the dentist before valve surgery?
To ensure there is not any way of bacteria entering and colonising in the bloodstream from the mouth
This reduces the risk of infective endocarditis
What is the difference between Staphylococci and Streptococci?
Streptococci - catalase negative, chains of cocci
Staphylococci - catalase positive, bunches of cocci
How are Staphylococcus classified?
Coagulase positive or negative
Coagulase positive:
Staphylococcus aureus
Coagulase negative:
Staphylococcus epidermis
Staphylococcus saprophyticus
How are streptococci classified?
Haemolysis
Alpha haemolysis (viridans Streptococci) - partially lysed erythrocytes
Beta haemolysis - fully lysed erythrocytes
Gamma non-haemolytic - no lysis of erythrocytes
How does alpha haemolytic streptococci appear on blood agar plates?
Give some examples of these.
Green colouration around colonies on blood agar plates
Viridans streptococci
Streptococci pneumoniae
How do streptococci pyogenes appear on blood agar plates?
Give an example.
Lightened yellow and transparent around colonies on blood agar
Streptococcus pyogenes
How do gamma non-haemolytic streptococci appear on blood agar?
Give an example.
Normal colonies form on blood agar
Enterococcus faecalis
How are streptococci classified based on Lancefield antigens?
Classifies streptococci based on their antigens depending on which antibodies bind to them
Describe the virulence of Streptococcus pyogenes.
Hyaluronic acid capsule - inhibits phagocytosis, poor immunogen (similarity to human connective tissue hyaluronate)
M protein - resistance to phagocytosis by inhibiting activation of alternative complement pathway on bacterial cell surface
Adhesins - includes M protein, fibronectin binding proteins, adherence is the first step in colonisation
Streptolysins O and S - lysis of erythrocytes, neutrophils and platelets
DNAases A B C D - degradation of DNA
Streptokinase - dissolution of clots through conversion of plasminogen to plasmin
Streptococcal pyrogenic exotoxins (superantigen) - cleaves IgG bound to Group A strep, produces fever
M protein is a virulence factor of Streptococcus pyogenes. What does it do?
- resistance to phagocytosis by inhibiting activation of alternative complement pathway on bacterial cell surface
- enhances adherence (first step in colonisation/infection)
What virulence factors of Streptococcus pyogenes cause it to be beta-haemolytic?
Streptolysins O and S - lysis of erythrocytes, neutrophils and platelets
Bacteria or viruses can cause a sore throat. Bacterial sore throats are primarily caused by…
Streptococcus pyogenes
Beta haemolytic streptococci
Gram positive
At what age do people tend to get Streptococcal pharyngitis?
5-15 years - the more exposure over your life, the more antibodies you have for different M proteins
How is Streptococcus pyogenes transmitted?
Droplet infection
Skin contact
Resides on skin and mucous membranes of normal human carriers and infected patients.
Name a risk factor for a Streptoccocus pyogenes infection?
Association with overcrowding
The main causative organism for Streptococcal pharyngitis is…
Streptococcus pyogenes
What are the clinical features of Streptococcal pharyngitis?
- abrupt onset of sore throat
- malaise, fever, headache
- lymphoid hyperplasia
- tonsillopharyngeal exudates - pus on tonsils indicates bacterial sore throats rather than viral
What specific investigations would you request to confirm an infection with Streptococcus pyogenes?
Throat swab
MC&S
Antigen detection
How is Streptococcal pharyngitis treated?
Penicillin - (beta-lactam - inhibits cell wall synthesis)
What are the complications of streptococcal pharyngitis?
Scarlet fever
Suppurative complications (pus-forming)
Acute rheumatic fever
Acute post-streptococcal glomerulonephritis
Skin infections: impetigo, erysipelas, cellulitis, necrotising fasciitis
Toxic shock syndrome
What are the clinical features of scarlet fever?
Rash extending from neck down the trunk Pyrexia Sepsis Arthritis Jaundice
How do suppurative complications of streptococcal pharyngitis arise?
Pus spreads from tonsil to lateral pharyngeal space disrupting local structures:
- peritonsillar abscess
- retropharyngel abscess
- mastoiditis, sinusitis, otitis media
- meningitis, brain abscess
What is acute rheumatic fever?
Inflammation of heart, joints, CNS
ONLY follows on from Streptococcal pharyngitis
Caused by Streptococcus pyogenes with rheumatogenic M types
Pathogenesis is unclear
What is acute post-streptococcal glomerulonephritis?
Acute inflammation of renal glomerulus
Follows on from streptococcal pharyngitis but has other causes
Caused by Streptococcus pyogenes with a specific M type but not the same as the acute rheumatic fever M type
A skin complication of a Streptococcus pyogenes infection is impetigo. What is impetigo?
Childhood infection: 2-5 years
Initial skin colonisation followed by intradermal inoculation
The symptoms of non-bullous impetigo begin with the appearance of red sores – usually around the nose and mouth but other areas of the face and the limbs can also be affected.
The sores quickly burst leaving behind thick, golden crusts typically around 2cm across. The appearance of these crusts is sometimes likened to cornflakes stuck to the skin.
After the crusts dry, they leave a red mark that usually fades without scarring. The time it takes for the redness to disappear can vary between a few days and a few weeks.
A skin infection of a Streptococcus pyogenes infection is erysipelas. What is erysipelas?
Dermis infection with lymphatic involvement
Affects face and lower limbs
Facial lesions frequently preceded by pharyngitis
Lower limb infection usually secondary to invasion of skin via trauma, skin disease or local fungal infection by dermatophytes
Name some risk factors for cellulitis.
Impaired lymphatic drainage
Illicit injecting drug use
What is necrotising fasciculation?
- infection of deep subcutaneous tissues and fascia
- rapid, extensive necrosis
- usually secondary to skin break
- severe pain, high fever and high mortality
What is Streptococcal toxic shock syndrome?
Deep tissue infection with Step pyogenes
Bactaraemia
Vascular collapse
Organ failure
(From health to death in hours)
Describe the pathogenesis of streptococcal toxic shock syndrome.
Deep tissue infection with group A Streptococcus pyogenes
Streptococcal pyrogenic exotoxins stimulate T cells by binding to MHC class antigen presenting cells. This induces cytokine release.
M-protein fibrinogen complexes activates leucocytes damaging endothelial cells and causing vascular damage. Leads to hypercoaguability and hypotension.
Describe the structure of Streptococcus pyogenes.
Cocci in chains
Gram positive
Beta-haemolytic
Encapsulated
How is Streptococcus pneumoniae transmitted?
Found in nasopharynx of many healthy individuals - extremely sensitive to environmental agents
Infection can be endogenous or exogenous
Endogenous- resides in nasopharynx and when individual is compromised, they develop impaired resistance. Patients with sickle cell disease or those who are asplenic are particularly at risk.
Exogenous- droplets from the nose of a carrier transferred to another
Describe the structure and appearance of Streptococcus pneumoniae.
Cocci in chains
Gram positive
Alpha haemolytic
‘Wet-looking capsule’
Is Streptococcus pneumoniae encapsulated?
Yes
This acts as a virulence factor-
- antiphagocytic
- poor immunogen
What diseases are caused by Streptococcus pneumoniae?
Pneumonia
Otitis media
Sepsis
Adult meningitis
Which antibiotic is used to treat Streptococcus pneumoniae infections?
Amoxicillin (penicillin- beta-lactam - inhibits cell wall synthesis)
How does viridans streptococci cause infection?
Part of oral flora
Relatively avirulent but patients at risk with valvular disease should receive prophylactic treatment before dental procedures
What diseases are caused by Viridans streptococci?
Endogenous infections -
Endocarditis (although main causative organism for this is coagulase negative Staphylococcus)
Dental caries
What determines transmissibility of a disease?
Infectious dose - number of microorganisms required to cause infection.
This varies depending on:
- microorganism
- presentation of microorganism
- immunity of potential host
Some infectious diseases are transmissible from a non-human source. Give an example of a microorganism transmissible from food/water.
Food poisoning organisms eg. C.diff
Some microorganisms are transmissible from a non-human source. Give an example of one that is transmissible from the environment
Legionella pneumophila
Some microorganism are transmissible from a non-human source. Give an example of one that is transmissible from animals.
Rabies virus
Some microorganisms are transmissible from direct person-to-person contact. Give examples of some.
Influenza virus
Norovirus
Neisseria gonorrhoea
Some microorganisms are transmitted indirectly from person-to-person via a vector. Give an example of one.
Malaria - mosquitos
Give an example of an infection that requires physical contact?
Sexually transmitted infections
Give an example of an infection that is spread via inhalation of aerosols.
Chicken pox
How can people get infections from the environment?
Water/food - faecal-oral transmission of food poisoning microorganisms eg. C.diff (onward transmission possible as it forms endospores)
Inhalation of contaminated air - eg. Varicella zoster (chicken pox) Myobacterium tuberculosis (TB), Legionella pneumophila
Contact with contaminated surfaces including medical devices
What are AB toxins?
AB toxins consist of 2 parts:
A - active component that enzymatically inactivates some host cell protein or signalling pathway to interfere with a host cell function
B - binding component that binds the exotoxin to a receptor molecule on the surface of the host cell membrane and determines the type of host cell to which the toxin is able to effect
What are types of exotoxins that can be released by bacteria?
Cytolytic exotoxins
AB toxins
Superantigens
Enzymes
What is Red Flag sepsis?
Atleast one of the following:
High respiratory rate > 25 per minute
Low blood pressure, systolic < 99 mmHg
Unresponsive
Non-blanching rash
What are the signs and symptoms of sepsis?
- mottled/discoloured skin
- severe breathlessness
- feel like I’m going to die
- extreme shivering/muscle pain
- slurred speech/confusion
- not passing urine (for approx a day)
What is endemic disease?
The usual background rate of infection.
What is an outbreak?
Two or more cases linked in time and place.
What is an epidemic?
A rate of infection greater than the usual background rate.
What is a pandemic?
A very high rate of infection spreading across many regions, countries, continents.
What is the basic reproduction number?
R0
The average number of cases that one case generates over the course of its infectious period, in an otherwise uninfected, non-immune population.
R0 > 1
What does this show?
There is an increase in cases
(R0 = the average number of cases one case generates over the course of its infectious period, in an otherwise uninflected, non-immune population)
R0 = 1
What does this show?
Stable number of cases
( R0 = average number of cases one case generates over the course of its infectious period, in an otherwise uninfected, non-immune population)
R0 < 1
What does this show?
Decrease in cases
(R0 = average number of cases that one case generates over the course of its infectious period, in an otherwise uninfected and non-immune population)
What are the 4 P’s of infection prevention?
Patient
Pathogen
Practice
Place
What factors about the pathogen should be considered in infection prevention?
- virulence factors
- ecological interactions (other bacteria, antibiotics/disinfectants)
What factors about the patient should be considered in infection prevention?
-general and specific patient risk factors for infections
-interactions with:
Other patients
Healthcare workers
Visitors
What factors about practice should be considered in the context of infection prevention?
- general and specific activities of healthcare workers eg. Immediate disposal of sharps
- policies and their implementation eg. Goal to decrease MRSA cases
- organisational structure and engagement
- regional and national political initiatives
- leadership at all levels from government to the ward
What factors about the place should be considered in the context of infection prevention?
Healthcare environment:
Fixed features
Eg. Number of isolated rooms
Variable features
Eg. Clean toilets, how close beds are placed to one another
What interventions can be taken for infection prevention?
Pathogen (+ vector) -
Reduction or eradication
Patient -
Improved health
Immunity
Practice -
Behavioural change
Protective equipment
Place -
Environmental
Engineering
How can pathogens be eradicated/reduced for infection prevention?
- Antibacterials including disinfectants
- Decontamination
- Sterilisation
How can vectors be eradicated/reduced for infection prevention?
Eliminate vector breeding sites
How can health of patients be improved for infection prevention?
Nutrition
Medical treatment
How can immunity of patients be improved for infection prevention?
- passive eg. Maternal antibodies, IV immunoglobulin
- active eg. Vaccination
What is herd immunity and why is it important?
Vaccination of a significant proportion of the population provides a measure of protection for individuals who have not yet developed immunity.
Most members of the community are protected against the disease so those who are not immunised are less likely to get the disease and there is little opportunity for an outbreak.
How can practice be improved for infection prevention?
• Avoidance of pathogen or its vector ◦ Geographic - don't go there ◦ Protective clothing or equipment ‣ Eg. Long sleeves + long trousers for protection against mosquito bites ◦ Personal protective equipment in hospitals ‣ Eg. Gowns, gloves, masks • Behavioural ◦ Safe sex ◦ Safe disposal of sharps ◦ Food and drink preparation
How can a place be changed for infection prevention?
- safe water
- safe air
- good quality housing
- well designed healthcare facilities
What are the benefits of effective infection control.
Decreased incidence or elimination of disease/organism
Give examples of diseases that now have a decreased incidence/have been eliminated due to effective infection control.
Small pox
Polio
Dracunculiasis
Why might infection control be counter-productive?
- decreased exposure to pathogen —> decreased immune stimulus —> decreased antibody —> increased susceptibles —> outbreak
- later average age of exposure —> increased severity
Give an example of conditions where interventions to prevent infection have resulted in later average age of exposure and hence, increased severity?
Polio
Hep A
Chicken pox
Congenital rubella syndrome
Give an example of a microorganism with a high infectious dose.
Salmonella (food poisoning)
Cholera
Give an example of a microorganism with a low infectious dose?
E.coli
What are the common causes of pharyngitis?
Viral (40 to 80%) Adenovirus Influenza virus Epstein-Barr virus Common cold viruses - rhinovirus, coranavirus, RSV
Bacteria
Group A streptococci
Other beta-haemolytic streptococci
Fungal
Candida
Does enlargement of cervical lymph nodes indicate whether the cause of pharyngitis is bacterial or viral?
Enlarged cervical lymph nodes are common in children.
They often enlarge with either a viral or bacterial infection. The nodes settle over a few weeks. A lymph node enlargement on its own does not imply that the cause of pharyngitis is bacterial or requires an antibiotic.
What is the feverPAIN score and why is it used?
It is a scoring system which is recommended to be used by GPs and primary care staff to manage patients with pharyngitis.
Why? An important objective is to reduce antibiotic prescriptions.
What does the Fever-PAIN score measure?
- fever in the last 24 hours
- rapid attendance
- moderately bad or worse muscle aches
- moderately bad or worse sore throat
- absence of a bad cough
- severely inflammed tonsils (eg. Pus on tonsils)
- anterior cervical glands
How would a patient with a fever-PAIN score of 0-1 be managed?
Only 13-18% have streptococcus
No antibiotic strategy is appropriate with discussion
How would a patient with a fever-PAIN score of 2-3 be managed?
34-40% have streptococcus
A back-up/delayed antibiotic is appropriate with discussion.
How would a patient with a fever-PAIN score of >4 be managed?
62-65% have streptococcus
Consider immediate antibiotic if symptoms are severe or a short 48 hour delayed antibiotic prescribing strategy may also be appropriate after agreement with the patient and safety netting advice.
Outline management strategies for pharyngitis.
Most cases are viral and most cases of Streptococcal pharyngitis will get better without antibiotics.
However, many complications arise from Streptococcal pharyngitis so the greater the risk that it is a Streptococcal infection, the more reason there is to prescribe an antibiotic.
Most of the time, tonsillitis with pus is treated with an antibiotic.
What are the signs and symptoms of viral disease a result of?
Culmination of a series of interactions between the virus and host.
What must a virus be able to do after encountering a host cell?
- enter it
- undergo primary replication
- spread to a final target tissue - infect and successfully replicate in a susceptible population of host cells
What are the possible outcomes of infection of a host organism by a virus?
- Acute infection
- Latent infection
- Chronic infection
What is an acute infection (virus)?
The virus undergoes multiple rounds of replication.
Replication results in the death of the host cell, which is used as a factory for virus production.
Give some examples of viruses that result in acute infection.
Poliovirus
Influenza virus
What is a latent infection (virus)?
Does not result in the production of progeny virus.
Caused by DNA viruses or retroviruses
Reflect the persistence of viral DNA either as:
• extrachromosomal element (herpes viruses)
• integrated sequence within the host genome (retroviruses). Retrovirus= ssRNA —> DNA —> ssRNA
During cell growth, the genome of the virus is replicated along with the chromosomes of the host cell.
Latent infection by some retroviruses may result in transformation of the cell, which leads to cancer.
Give an example of a latent infection.
Infection caused by herpes simplex virus type 1 (HSV-1)
Result of reactivation = fever, blisters, cold sores
What is a retrovirus?
RNA virus that uses reverse transcriptase to form DNA
What is a chronic infection?
Virus particles continue to be shed after the period of acute illness, sometimes without death of the host cell or significant cellular injury
Generally caused by RNA viruses
Amount of virus produced is usually less than in acute infections
Virus is often mutated from the original ones
Chronic infections are associated with defective host immune responses that are insufficient to clear the infection
Give an example of a virus that causes chronic infection.
Hepatitis C virus can cause a chronic infection in the liver.
This eventually leads to chronic hepatitis and even liver cancer.
Describe how latent infection with retroviruses can cause cancer?
Retroviruses have RNA DNA that is converted to DNA by reverse transcriptase.
The DNA is integrated into the host cell genome.
During cell growth, the genome of the virus is replicated along with chromosomes of the host cell.
This results in transformation of the cell which leads to cancer.
Describe how an infection with Herpes-simplex virus Type 1 (HSV-1) can cause re-occurring blisters and cold sores.
Viral DNA persists as an extrachromosomal element.
During cell growth, the genome of the virus is replicated along with the chromosomes of the host cell.
The result of reactivation is fever, blisters and cold sores.
Which group of viruses foes Epstein-Barr virus belong to?
Herpes
Which cell is first infected by EBV?
Epithelial cells in the oropharynx
After infecting epithelial cells in the oropharynx, which cells does EBV subsequently infect?
What happens do these cells?
B cells
B cells proliferate.
Which MHC molecules are expressing the early EBV peptides? Which cells?
All infected cells
MHC Class I (CD8+)
Antigen presenting cells
MHC Class I —> (CD8+)
MHC Class II —> (CD4+ TH1)
Of the 3 types of viral infection, which type does EBV belong to?
Acute infection-
Infectious mononucleosis
Latent infection -
Throughout life, healthy EBV carriers continue to have episodes of asymptomatic virus shedding in infected oropharyngeal cells.
Re-activation can cause nasopharyngeal carcinoma/Burkitt’s lymphoma
I DONT KNOWWWWWWW TBH
What is the common name for EBV infection?
‘Kissing’s disease’
Or
Infectious mononucleosis
Describe the structure of EBV.
DNA virus
Enveloped
How is EBV transmitted?
Exposure to oropharyngeal secretions
Describe the microbe-host interaction for EBV.
- EBV in saliva
- Infection of epithelial cells of oropharynx
- Infection of B cells
- B cell proliferation
- Expression of EBV early proteins
All infected cells (MHC class I ) —> CD8+
APCs (MHC class I and class II) —> CD8+and CD4+
Cell-mediated response:
- CD8+ kill infected cells
- IgM and anti-EBV antibodies produced
- cytokines produced —> dramatic activation of immune system. Excess TNF and IL-6 cause fatigue and fever
- As the number of EBV-infected B cells falls, the immune response dies down. Only a few CD4+ T cells and CD8+ T cells and B memory cells remain.
What makes a person who is infected with EBV infectious?
Occasional bursts of lytic infection in oropharyngeal B cells make the host infectious via oropharyngeal secretions
Describe the main clinical features of EBV infection.
Primary infection in infancy or childhood - usually asymptomatic
Primary infection later in life - monoinfectious mononucleosis
(Pharyngitis, lymphadenopathy, fever, splenomegaly, headache, malaise)
Can also cause…
Burkitt lymphoma
Epstein-barr associated nasopharyngeal carcinoma
What is the classic clinical triad seen in infectious mononucleosis?
Fever
Pharyngitis
Lymphadenopathy (usually enlargement of anterior and posterior cervical lymph nodes)
How does Staphylococcus epidermis cause infection normally?
Present in large numbers as part of the normal flora of the skin.
Infection usually caused by contamination of blood from skin by:
-infections of implants such as heart valves or catheters
Describe the structure and physiology of Staphylococcus epidermis.
Cocci - catalase positive
Gram positive
Coagulase negative
How would you differentiate between Staphylococcus aureus and Staphylococcus epidermis?
Staph aureus - coagulase positive
Staph epidermis - coagulase negative
Which bacteria causes infection often related to medical devices (eg. Catheters, prosthetic devices, heart valves)?
Staphylococcus epidermis
What are opportunistic pathogens?
Pathogens that cause disease only when the immune system is depressed.
Describe the virulence of Staphylococcus epidermis.
Biofilm production - resists phagocytosis and vancomycin in some cases
Which investigations would you request for specific diagnosis of Staphylococcus epidermis.
MC&S Coagulase test (negative)
What is used to treat Staphylococcus epidermis?
Flucloxacillin (penicillin- beta lactam, inhibits cell wall synthesis)
If resistant,
Vancomycin (glycopeptide- beta lactam, inhibits cell wall synthesis)
Where is Staphylococcus aureus found as part of our normal flora?
Skin
Where is viridans streptococci found as part of the normal flora?
Mouth
Describe the virulence of Streptococcus pneumoniae.
Capsule - anti-phagocytic, anti-antigenic
Pilli - enhances attachment to epithelial cells of upper respiratory tract
Autolysins - hydrolyses components of biological cells in which it is produced
Pneumolysin - attacks mammalian cell membrane
How do bacteria reproduce?
How does the number of cells increase?
Binary fission
Number of cells increases exponentially with time
Give an example of a rapidly growing species of bacteria.
Escherichia coli
What are the different phases of bacterial growth?
Lag phase
Exponential phase - bacteria reproduces by binary fission
Stationary phase - growth ceases entirely as nutrients are depleted and toxic waste products cumulate
Death phase
What does a colony on an agar plate represent?
Multiplication of a single bacterial cell that has been placed on the agar.
Explain how sepsis results in a reduction in blood pressure?
Mean arterial blood pressure = TPR x CO
Lipopolysaccharide binds to endothelial cells in the circulatory system. This results in the release of nitric oxide. Nitric oxide is a powerful vasodilator resulting in reduced TPR. This decreases mean arterial blood pressure.
What is the NEWS?
The NEWS provides the basis for a unified and systemic approach to the first assessment of acutely ill patients in hospitals. It is a simple scoring system in which a score is allocated to physiological measurements.
Is there a vaccine available for Streptococcus pneumoniae infections?
Yes
Given to patients with increased susceptibility
How long should the Sepsis six bundle be completed in?
1 hour
Describe the structure of E.coli
Bacilli
Gram negative
Describe the virulence of E.coli
Pilli - enhances adherence
Lipopolysaccharide - stimulates inflammatory response
How is E.coli transmitted?
Faecal oral route
Contaminated food/water
Where is E.coli part of the normal flora?
Colon
Can be pathogenic both within and outside of the GI tract
What diseases are commonly caused by E.coli?
Commonest cause of UTI’s
Sepsis
Others:
Some strains cause diarrhoeal disease (ETEC, EIEC, EHEC, EPEC)
Gut and nerve syndrome
Cholangitis (inflammation of bile ducts)
Which investigations would you request for a specific diagnosis of E.coli?
MC&S - gram negative bacilli
Positive dipstick test for nitrites in urine - nitrites are generally found in urine due to reduction of nitrates to nitrites by the enzyme nitrate reductase
Why might nitrites be detected in the urine?
presence of gram-negative bacteria such as E.coli in urine with the enzyme nitrate reductase
What is detection of bacteria in urine by nitrite positive dipstick dependent on?
- nitrates from patient’s diet (vegetables)
- sufficient bladder incubation time
Gram positive uropathogens such as Staphylococcus saprophyticus and enterococcus produce nitrate reductase so a dipstick will be negative for nitrite.
True or false?
FALSE
Gram positive uropathogens such as
Staphylococcus saprophyticus and enterococcus do not produce nitrate reductase and therefore when infection is due to these bacteria, the dipstick will be negative for nitrite.
What is leucocyte esterase and what does its presence in the urine indicate?
Leukocyte esterase is an enzyme released by neutrophils and macrophages. A urine dipstick positive for this enzyme indicates pyuria (an increased number of leukocytes / white blood cells).
Urinary tract infections including cystitis and urethritis are common causes of pyuria.
What is pyuria?
Presence of pus (dead neutrophils) in urine, particularly due to bacterial infection.
What type of infections are common causes of pyuria?
How is pyuria detected?
UTI’s including cystitis and urethritis
Detected by urine dipstick positive for leucocyte esterase
Which antibiotic is used in the treatment of UTI’s caused by E.coli?
Trimethoprim (Quinalones - inhibits folic acid synthesis)
What is the mechanism of resistance to trimethoprim
Altered target - target enzyme has lowered affinity for trimethoprim
What is community-acquired pneumonia?
Pneumonia in a previously healthy person who acquired the infection outside of a hospital
What factors in the respiratory system are an important part of the innate immune response in preventing infections in the lung?
Physical: BALT, cilia
Ciliated Epithelium moves particles towards the pharynx and therefore down the digestive tract away from the respiratory system
Physiological: coughing, sneezing
Cough reflex designed to aid expulsion of harmful substances
Chemical: beta-defensins in epithelium, IgA in mucous membrane, mucus
Goblet cells secrete mucus which both creates a physical barrier to infections but also contains lysozymes and IgA antibodies which can attack invading pathogens.
Biological: normal flora (Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus species)
Rich vasculature of the respiratory system results means high levels of neutrophils and alveolar macrophages are available in the lungs to battle invading bacteria
Which microorganisms are the most common cause pneumonia in a community setting?
Streptococcus pneumoniae - most common
Haemophilus influenzae
Staphylococcus aureus
Viruses
Describe the structure of Haemophilus influenza.
Gram negative
Bacilli
How is Haemophilus influenza transmitted?
Inhalation of droplets
Normal flora of nasopharynx
Which antibiotic is used for the treatment of Haemophilus influenza?
Encapsulated - usually disseminated spread so ceftriaxone (cephalosporin - betalactam, inhibits cell wall synthesis)
Non-encapsulated - usually contiguous spread so amoxicillin/co-amoxiclav (penicillin-betalactam, inhibits cell wall synthesis)
Describe the typical presentation of community-acquired pneumonia.
Chest pain and dyspnea
Fever
Chills
Cough
Which bacteria that causes pneumonia can become systemic with bacteria spreading via the blood to the CNS?
Haemophilus influenzae
Which bacteria does the pneumococcal vaccine protect against?
Streptococcus pneumoniae
What is the coagulase test used for?
Coagulase is an enzyme that causes a clot to form when bacteria are incubated with plasma.
This test is used to differentiate Staphylococcus aureus from coagulase negative Staphylococci
Does Hepatitis B or C have a greater incidence in UK?
Hep C
Untreated, HIV infection will always progress to AIDS.
True or false?
True
People with HIV must use condoms to prevent HIV negative partners from getting HIV.
True or false?
True
Describe the structure of HIV.
Single stranded RNA
Enveloped
What class of virus does HIV belong to?
Retrovirus= ssRNA —> DNA —> ssRNA
How is HIV transmitted?
Contact of infected bodily fluids with mucosal tissue/blood/broken skin due to:
- sexual contact
- transfusion
- contaminated needles
- perinatal transmission
- medical procedures
When would you advice a mother not to breast feed?
If she has HIV
Which medical procedures have a risk of HIV transmission?
Blood transfusion
Skin grafts
Organ donation
What factors affect HIV transmission?
• Type of exposure
◦ Receptive anal sex > vaginal sex > oral sex
◦ Transfusion > mucous membrane > needlestick
• Viral load
◦ Transmission unlikely if there is an undetectable viral load
• Condom use
• Breaks in skin or mucosa
◦ Due to STI eg. Chlamydia, gonorrhoea (cause inflammation of genital tract)
◦ Sexual assault
What is the purpose of assessing factors that affect HIV transmission?
Helps to inform whether prophylaxis should be given
Describe the pathogenesis of HIV.
Infects cell with CD4+ receptor
-T helper lymphocytes - cause maturation of B lymphocytes/stimulate cytotoxic T lymphocytes/monocytes and macrophage activation
HIV replicates inside cells
- destroys the cell
- causes inflammation
- spreads to/infects more cells
What are the stages after being infected with HIV?
Primary infection/seroconversion
Stage I - Latent infection
Stage II - mild symptomatic infection
Stage III - advanced symptomatic infection
Stage IV - Severe infection/AIDS
Which white blood cell count is used to indicate the stage of HIV?
CD4+ count
Patient has CD4+ found <200
What stage of HIV are they in?
Stage IV or AIDS
Patient has CD4+ found >500.
What stage of HIV are they in?
Stage I - asymptomatic
Patient has CD4+ count <500 and >350
What stage of HIV are they in?
Stage II - Mild symptomatic
Patient has CD4+ count <350 and >200
What stage of HIV are they?
Stage III - advanced symptomatic
List the symptoms of HIV in the order that they occur with decreasing CD4+ count.
Lymphadenopathy/thrombocytopenia
Bacterial skin infections
(Herpes simplex, zoster)
Oral, skin fungal infections
Kaposi’s sarcoma
Hairy leukoplakia TB
Pneumocystic pneumonia
Toxoplasmosis
Cryptococcis
Cytomegalovirus
Lymphoma
What are the main acute symptoms of HIV?
Flu-like symptoms
Systemic:
- fever
- weight loss
Central:
- malaise
- headache
- neuropathy
Lymph nodes:
-lymphodenopathy
Skin:
-rash
Gastric:
- nausea
- vomiting
Liver + spleen:
-enlargement
Muscles:
-myalgia
Oesophagus:
-sores
Mouth:
- sores
- thrush
- pharyngitis
What are the peripheral signs of HIV?
Oral candidiasis
Kaposi’s sarcoma
Pneumocystic pneumonia
What is oral candidiasis?
Oral thrush
Most common causative organism: Candida albicans
Presentation:
- white patches inthe mouth that can often be wiped off leaving behind red areas that may bleed slightly
- loss of taste or an unpleasant taste in mouth
- painful burning sensation in the mouth
What is Kaposi’s sarcoma?
Rare type of cancer that affects skin and internal organs. Almost solely linked to HIV
Presentation:
Distinct shiny purple-red raised lesions
Causative organism: Human herpes virus type B
What is pneumocystis pneumonia?
Pneumonia - infection that causes inflammation and fluid build up in the lungs
Causative organism: Pneumocystis jirovecii (fungus)
What is an opportunistic infection?
An opportunistic infection is an infection caused by pathogens (bacteria, viruses, fungi or protozoa) that take advantage of an opportunity not usually available, such as a host with a weakened immune system, altered microbiota (such as disrupted gut flora), or breached integumentary barriers.
Which type of microorganisms are likely to cause an opportunistic infection in a patient with HIV/AID’s?
Tuberculosis
Causative organism: mycobacterium tuberculosis (bacteria)
Toxoplasmosis
Causative organism: Toxoplasma gondii (protozoa)
Pneumocystis pneumonia
Causative organism: Pneumocystis jirovecii
Cryptococcal disease
Causative organism: Cryptococcus neoformans
CMV
Causative organism: Cytomegalovirus
What is the outcome of infection with HIV?
Chronic infection
+/- disability
Death if diagnosed late and untreated
The average life expectancy of someone with HIV in UK is 77 years.
How can HIV patients increase their chances of survival?
- early detection - the later the detection, the worse the prognosis as they start with a lower CD4+ count to begin with so recover to a lower level
- treatment
- adherence
- healthy living
How is HIV diagnosed?
Blood tests
-serology
HIV antigen (Ag) - viral protein
HIV antibody (Ab)
Current test: detects both Ag and Ab
-PCR
Detects HIV nucleic acid
-rapid tests but has to be confirmed with serology
Is serology or PCR more likely to give you a false negative in the diagnosis of HIV?
Serology
Serology gives you a positive test after 4 weeks of infection. You may get a false negative if you do the test too early.
PCR detects very early infection (few days)
Do you get results more quickly with serology or PCR when detecting HIV?
Serology - result on same day
PCR - results slow (up to a week)
PCR is primarily used for the diagnosis of HIV.
True or false.
False
PCR is used to detect viral load in follow up/treatment response)
Serology is generally used for diagnosis
Rapid tests can be used for the detection of HIV in under an hour. How do they work?
They usually detect HIV antibody.
Finger-prick (blood test)
Saliva (oral)
Rapid tests for HIV may result in a false negative,
True or false?
False.
If negative - accurate
May get false positive (need to confirm with serology)
Who should be tested for HIV?
Everyone if rate >2/1000 in population
Why is it important for HIV to be detected early?
Treatment is recommended for everyone who is HIV positive.
The later it is diagnosed, the lower CD4+ count is and with treatment it will recover to a lower number. Therefore it should be treated as soon as it is diagnosed when CD4+ count is at its highest.
What are the aims of HIV treatment?
Decrease viral load to an undetectable level (doesn’t get rid of it completely)
Reconstitute CD4+ count
Reduce general inflammation
Reduce risk of transmission
Good quality of life
What do anti-retroviral drugs target?
- HIV spikes (virus binds to CD4+ molecule via these spikes)
- reverse transcriptase (single strands of viral RNA are converted not double stranded DNA by this enzyme)
- integrase (viral DNA is combined with the cells own DNA by this enzyme)
Why is there no vaccination for HIV?
The HIV antigens present on the envelope are polymorphic and are constantly changing.
Different people have different antigens.
When is HIV treated?
Anti-retroviral treatment is given as soon as HIV is diagnosed.
Does the presence of HIV antibody mean the patient has a confirmed infection with HIV?
The presence of HIV antibody means the patient has confirmed infection with HIV. Positive HIV serology is a bad thing. Antibodies against HIV are produced by the immune system in response to exposure to the virus, but are not effective at eliminating it. Therefore, this patient is infected with HIV. A second sample would be required to confirm the correct identity of the patient (make sure there has not been a mistake in labelling the blood test bottle).
Why are 3 anti-retroviral drugs used in the treatment of HIV?
The are millions of rounds of viral replication each day.
The virus mutates every 2-3 rounds
Resistance to drugs develops in days
1 drug - resistance develops quickly
3 drugs - more difficult to develop resistance
PATIENT MUST KEEP TAKING DRUGS
What strategies would you use to treat and reduce the prevalence of HIV?
- increase condom usage
- prevent mother-to-child transmission
- ARV treatment as prevention
- medical circumscision
- post-exposure prophylaxis (PEP)
- pre-exposure prophylaxis (PrEP)
What is AIDS?
If left untreated, HIV can lead to AIDS (acquired immunodeficiency syndrome).
CD4 count is <200 so opportunistic infections or cancers can take advantage of a very weak immune system.
What is hepatitis?
Inflammation of the liver
What is collateral liver damage and which viruses cause this?
Systemic viruses- Herpes viruses (EBV, CMV), shingles virus (VZV)
They affect many different organs as well as the liver
What is the difference between viruses that cause collateral liver damage and hepatitis viruses?
Hepatitis viruses replicate specifically in hepatocytes (hepatotrophic). They cause destruction of hepatocytes leading to cirrhosis and liver cancer.
Which viruses cause hepatitis?
Hepatitis A - E
During pregnancy, which hepatitis virus is there an increased risk of getting an infection with?
Hepatitis E
Describe the structure of Hepatitis B.
Double stranded DNA
Enveloped
Describe the structure of Hepatitis C.
Single stranded (+ve) RNA Enveloped
Describe the typical presentation of hepatitis.
Signs and symptoms:
- fatigue
- loss of appetite
- abdominal pain
- nausea
- yellow tinge to eyes
Investigations:
- raised bilirubin
- raised ALT and AST (in 1000s)
History:
-clear infection within 6 months (incubation period 6 weeks-6 months)
What is billirubin and how is it normally excreted?
Bilirubin is a product of the breakdown of red blood cells.
Bilirubin gets conjugated in the liver to make it more soluble. Some of it is secreted in urine (urobillin) but most is excreted in the faeces via bile (stercobillin)
Why does hepatitis cause jaundice?
Inflammation of the liver causes there to be pressure on the portal triads in the liver lobules.
This causes intrahepatic cholestasis as bile cannot move from the liver.
Therefore, bilirubin accumulates in the blood causing intrahepatic jaundice.
What causes prehepatic jaundice?
Haemolysis
What does raised ALT and AST indicate?
Hepatocyte damage
What does raised plasma alkaline phosphatase (ALP) indicate?
Produced in cells of the biliary tree. If raised, there is cholestasis.
Biliary tree = bile ducts in liver, common bile duct, gall bladder.
Therefore, if ALP is raised —> extrahepatic jaundice
What does plasma albumin indicate?
Tells you about liver function
Is a protein that is synthesised in the liver
If production drops —> oedema
How does damage to the liver affect clotting?
Increased risk of bleeding
Clotting factors are synthesised in the liver
How is hepatitis B transmitted?
Vertical transmission Sexual contact IV drug abuse Close household contacts Healthcare workers via needlestick injuries
What are the signs and symptoms of Hepatitis B.
- Jaundice
- Fatigue
- Abdominal pain
- Anorexia/nausea/vomiting
- Arthralgia- pain in a joint
What is the incubation period for Hepatitis B?
6 weeks - 6 months
What happens in chronic hepatitis B infections?
- 25% of cases lead to cirrhosis
- 5% lead to hepatocellular carcinoma
What is used to diagnose Hepatitis B?
Serology - there are 3 unique antigens that can be detected and 3 antibodies that can be detected.
Viral load can be detected using PCR
Which antigens and antibodies can be detected in Hepatitis B serology.
1) surface antigen first
2) e-antigen
3) core antibody (IgM)
4) e-antibody
5) surface antibody
6) core antibody (IgG)
What does presence of surface antibody in Hepatitis serology indicate?
Clearance of virus/recovery
What does presence of core antibody IgG in hepatitis serology indicate?
Patient has had Hep B at some point in the life
Which hepatitis B antigen is not detected in the blood?
HBcAg (core antigen)
But core antibodies (IgM and IgG) are.
State whether you would expect to detect
Surface antigen
Core antibody
Surface antibody
In a patient with an acute infection with Hep B.
Surface antigen - positive
Core antibody - positive (IgM)
Surface antibody - negative
State whether you would expect to detect
Surface antigen
Core antibody
Surface antibody
In a patient with a past (cleared) infection with Hep B.
Surface antigen - negative
Core antibody - positive (IgG)
Surface antibody - positive
State whether you would expect to detect
Surface antigen
Core antibody
Surface antibody
In a patient with a chronic infection with Hep B.
Surface antigen - positive
Core antibody - positive (IgG)
Surface antibody - negative
Which is the last antibody to appear in an immune response to Hep B?
Surface antibody
Which is the first antibody to appear in an immune response to Hep B?
Core antibody (IgM)
State whether you would expect to detect
Surface antigen
Core antibody
Surface antibody
In a patient who has never been infected but is vaccinated for Hep B.
Surface antigen - negative
Core antibody - negative
Surface antibody - positive
How is Hep B treated?
• No cure
• Life-long anti-viral to suppress viral replication
• Not required for everyone - some people are inactive carriers of Hepatits B
◦ Low viral load
◦ Normal LFT
◦ No liver damage
◦ BUT this can change so may need to be treated
How can Hep B transmission be prevented?
Vaccination available • Genetically engineered surface antigen • 3 doses + boosters if required • Effective in most people • Produces surface antibody response
Who is at risk of Hep C infection?
IV drug users (>90% of those with Hep C in UK)
Sexual contact
Infants born to mothers with infection
Needlestick injuries to healthcare workers
Is everyone who is infected with Hep B or Hep C symptomatic?
No
Hep B - 50% have no/vague symptoms
Hep C- 80% have no symptoms - rest are vague
What are the symptoms of Hep C?
Fatigue
Anorexia
Nausea
Abdominal pain
What is the difference between the proportion of people that are chronically infected by Hep B and Hep C?
Hep B - 10%
Hep C - 80%
80% of people infected with Hep C become chronically infected. Of these some will develop _______
Chronic liver cirrhosis
What does chronic liver cirrhosis result in?
- decompensated liver disease
- hepatocellular carcinoma
- transplant
- death
How is Hep C diagnosed?
- serology - anti-Hep C antibody only
- viral PCR
Does presence of Hep C antibody mean that the patient is infected with Hep C?
No - remains positive life-long even after clearance
If Hep C antibody is detected, what further test must be done to confirm diagnosis.
Presence of antibody does not mean infection is present because it remains positive life-long
Therefore, if positive, viral PCR confirms on-going chronic infection.
Does presence of anti-Hep C antibody mean the patient is protected from being re-infected?
NO
How is Hep C treated?
Can be cured
Directly acting antiviral drug combo (but can be reinfected)
Is there a Hep C vaccine?
No
What is the difference in the risk of transmission from needlestick injury between HIV, Hep B and Hep C
HIV - 1/300
Much lower if patient is on ARVs
Hep C - 1/30
Hep B - 1/3
Much lower if recipient has been vaccinated
What immediate precautions should be taken after a needlestick injury?
- first aid - bleed and wash wound
- collect blood from patient and HCW
- inform occupational health
- check HCW Hep B status
- assess risk and need for immediate HIV PEP
Why is HIV PEP given?
Early initiation of anti-retroviral drugs reduces dissemination and replication of HIV in tissue and bodily fluid.
What are the symptoms of acute infection with Hep B?
Jaundice
Abdominal pain
Anorexia
What is the outcome of untreated Hep B and Hep C infection?
Hep B
- cure (majority)
- chronic infection (minority)
Hep C
-chronic infection (majority)
Lifelong anti-retroviral drugs are used to treat HIV and Hep C.
True or false
FALSE
HIV always treated with life-long ART
Hep B - sometimes not treated or can be treated with life-long ART
Hep C - 8-12 weeks of ART
What are the main types of pathogens that are associated with travel infections?
Bacterium: Rickettsia/ spirochaete
Parasites: Protozoa/ Helminths
How are Richettsia and spirochaete different to regular bacteria?
They are obligate intracellular bacterium that enter the cell and rely on cell contents for survival.
Why is the travel history important?
-recognise imported diseases
Rare/unknown in UK
-different strains of pathogen
Antigenically different
Impacts on protection/detection
Antibiotic resistance
-infection prevention
On the ward
In the lab
What questions would you ask in a travel history?
When did they travel? Duration of travel? Who did they travel with? Any unwell travel companions/contacts? Pre-travel vaccinations/preventative measures? Recreational activities? Healthcare exposure?
Which places do people commonly acquire malaria from?
Sub-saharan Africa
South east Asia
South and central America
What is the typical incubation period of malaria (falciparum)?
10-21 days or longer
What is the typical incubation period of HIV?
> 21 days
What is typhoid fever?
Typhoid fever is a type of enteric fever along with paratyphoid fever.
What is the causative organism for enteric fever?
Salmonella enterica/typhi
Describe the structure of Salmonella enterica/typhi.
Type of rickettsia/spirochaete - intracellular bacterium
Gram-negative
Describe the virulence of Salmonella enterica
Lipopolysaccharide endotoxin
Invasin - allows intracellular growth
Fimbrae - adherence to epithelial over ileal lymphoid tissues (Peyer’s patches) to enter reticulo-endothelial system and bloodstream
How is Salmonella enterica transmitted?
Faecal-oral route
Food/water contaminated with faeces of infected person
What are the signs and symptoms of enteric fever?
Symptoms: Fever Headache Abdominal discomfort Constipation Dry cough
Signs:
Relative bradycardia
Mild splenomegaly
What are the complications of enteric fever?
Intestinal haemorrhage and perforation
10% mortality
Which investigations would you request for diagnosis of Salmonella enterica?
- FBC - moderate anaemia
- LFT - raised
- MC&S - culture blood + faeces
- Serology - not reliable due to variable antigen
How is enteric fever treated?
Ceftriaxone 7-14 days
How can enteric fever be prevented?
Food and water hygiene
Typhoid vaccine
Who is the typhoid vaccine given to?
High-risk travel
Lab personnel
What are the different types of typhoid vaccine?
Vi capsular polysaccharide antigen
Live attenuated vaccine
How protective is the typhoid caccine?
Modest protective effect (50-75%)
Salmonella enterica/typhi is usually resistant to….
Ciprofloxacin (fluoroquinolone, inhibits DNA synthesis)
What is a common non-typhoidal salmonella infection?
Food -poisoning
Symptoms: Diarrhoea Fever Vomiting Abdominal pain
Name some non-typhoidal salmonella bacteria.
Salmonella typhimurium
Salmonella enteritidis
What class of virus does Dengue belong to?
Arbovirus
Describe the pathogenesis of Dengue.
• First infection asymptomatic to severe febrile illness ◦ Lasts 1-5 days ◦ Improves 3-4 days after rash ◦ Supportive treatment only • Re-infection with different serotype ◦ Antibody dependent enhancement occurs - the antibody for the first serotype helps the the second serotype to invade cells which leads to: ‣ Dengue haemorrhagic fever ‣ Dengue shock syndrome
Which investigations would you request if you suspected Dengue fever.
Ensure it is not malaria
Malaria screen negative
Blood culture negative
Stool/urine negative
Dengue PCR
Dengue serology
What are the symptoms of Dengue fever?
Severe myalgia
Headache
Rash
Fever
What are the causative organisms for malaria.
One of the 5 species of Plasmodium: • Plasmodium falciparum - most common and most lethal • Plasmodium vivax • Plasmodium ovale • Plasmodium malariae
What is the incubation period of the causative organisms of malaria?
- Minimum 6 days
- P. falciparum 6-12 days
- P. vivax/ovale: up to 1 year+
How is malaria transmitted?
Vector - female anopheles mosquito
What are the symptoms of malaria?
Fever, chills and sweats - cycle every third of fourth day
Severe falciparum malaria -Affects most of the body
P. falciparum is the most dangerous plasmodial species. It can cause a rapidly fulminating disease, characterized by persistent high fever and orthostatic hypotension. Infection can lead to capillary obstruction and death if treatment is not prompt. P. malariae, P. vivax, and P. ovale cause milder forms of the disease, probably because they invade either young or old red cells, but not both. This is in contrast to P. falciparum, which invades cells of all ages
How many blood films would you request if malaria infection is suspected?
3
3 negatives are required to rule out malaria
How is malaria treated?
Depends on species • P. falciparum (malignant) ◦ Artesunate ◦ Quinine + doxycycline • P. vivax, ovale, malariae (benign) ◦ Chloroquine + primaquine ◦ Hypnozoites (liver stage) ◦ Can reoccur months - years later
How can malaria be prevented?
• Assess risk - knowledge of at risk areas • Bite prevention ◦ Repellant ◦ Adequate clothing ◦ Nets • Chemoprophylaxis ◦ Specific to region ◦ Start before and continue after return
What diseases present similarly to malaria?
Typhoid
Dengue
Rickettsial infection
Describe the life cycle of the malaria parasite.
- Transmission to human (injects sporozoites via bite)
- Sporozoites migrate to the liver and infect hepatocytes. Here they form merozites.
- Mitotic replication of hepatocytes. Liver cells rupture and merozoites are released.
- In the erythrocyte, the merozoite becomes a trophozoite.
- In the erythrocyte, the trophozoite multiples, producing new merozoites. These are released when the erythrocyte ruptures, and can infect other erythrocytes
- Some merozoites become gametocytes
- The female anopheles mosquito picks up the gametocytes from an infected human. The sexual cycle occurs in the mosquito where the sporozoites are formed.
- The female mosquito picks up gametocytes from an infected human. The sexual cycle occurs in the mosquito, where sporozoites are formed.
What are emerging infections?
Emerging infectious diseases are infections that have recently appeared within a population or those whose incidence or geographic range is rapidly increasing or threatens to increase in the near future.
They can be caused by previously undetected or unknown infectious agents.
Where would you look up information on travel related infections?
WHO
Public Health England
Primaquine is used to treat the hypnozoite stage of P.vivax and P.ovale. Which blood test needs to be done before commencing treatment?
G6PD screen to ensure no G6PD deficiency - can cause haemolysis in the presence of primaquine
What is a hypnozoite?
Infections of P.vivax and P.ovale differ from the other two types of malaria in that some of the sporozoites may remain dormant in the liver in a hypnozoite stage for months or even years before merging to attack red blood cells and cause a relapse of the disease.
What is Katayama fever?
Acute schistosomiasis
Relevant travel history and exposure to fresh water
Marked eosinophilia
Hepatosplenomegaly
Would suggest a diagnosis of…
Acute schistosomiasis
Name 3 opportunistic infections that are linked to AIDS
Pneumocystis pneumonia
Causative organism: Pneumocystis jirovecii (fungus)
Tuberculosis
Causative organism: Myobacterium tuberculosis (bacteria)
Cryptococcal disease
Causative organism: Cryptococcus neoformans (fungus)
Which is the most dangerous plasmodial species?
P.falciparum
Is case-to-case spread of malaria possible?
No
Name a common helminth?
Schistosomiasis - flatworm
How do helminths cause disease?
Establish residence in deep tissues
How can helminths enter deep tissues?
- intestinal helminths acquired by ingestion
- penetration of skin either by direct entry of the parasites or by insect bites
What kind of diseases are caused by helminths?
Involve chronic inflammation
Caused in part by the host immune response to the parasite
Because many worms are long lived in humans, they may gradually accumulate in large numbers as the consequence of repeated encounters.
When present in sensitive target organs, helminths can produce severe disease and even death.
Helminths infections are rarely symptomatic when worm burden is low.
True or false?
True
What are the different types of helminths that cause deep tissue infections?
Roundworms
Tapeworms
Flukes
What does the life cycle of schistosomiasis involve?
Water
What type of microorganism is Legionella?
Bacteria
What infection does Legionella cause?
Pneumonia
Where is Legionella found?
Man-made water systems such as cooling systems or spa pools
How is Legionella transmitted?
Spread by droplet from the water system
Which cell does L.pneumophilia invade and replicate in?
Macrophages
The bacteria are phagocytised by macrophages but prevent the phagosome from fusing with a lysosome so evades destruction by the macrophage and instead uses the macrophage as a site to replicate ad spread.
Is Legionella pneumophila a common cause of pneumonia?
No
How is L.pneumophila treated?
Readily treated with correct antibiotic if it is identified- usually a quinolone class antibiotic
Which antiretroviral drugs are used to treat HIV?
Nucleoside reverse transcriptase inhibitor x2
AND
Non-nucleoside reverse transcriptase inhibitor
OR
Protease inhibitor
OR
Integrase inhibitor
Do primary immunodeficiency diseases only affect children?
No
>60% of patients will be 18 years or older when diagnosis is made
What is an immunocompromised host?
State in which the immune system is unable to respond appropriately and effectively to infectious microorganisms
Due to a defect in one or more components of the immune system (innate or adaptive)
Which cells of the immune system do the most severe forms of primary immunodeficiency affect?
B and T lymphocytes
Why is a host immunocompromised?
- primary immunodeficiency (congenital)
- secondary immunodeficiency (acquired)
What causes primary immunodeficiency?
Congenital - due to intrinsic gene defect
- missing protein
- missing cell
- non-functional components
Give an example of a primary immunodeficiency disease that affects an intrinsic gene resulting in non-functional components of the immune system.
Chronic granulomatous disease NADPH oxidase deficiency in neutrophils Respiratory burst (oxidative dependent killing mechanism) not possible
What causes secondary immunodeficiency?
Acquired - due to an underlying disease/treatment
- decreased production/function of immune components
- loss or catabolism of immune components
When should you suspect an immunodeficiency?
S - severe (life-threatening requiring surgery/antibiotics)
P - persistent (infection that will persist without treatment or requires a long course of antibiotics)
U - unusual (unusual site/opportunistic microorganism)
R - recurrent (keeps coming back despite treatment)
(All don’t have to present)
There are 10 warning signs for the recognition and diagnosis of primary immunodeficiencies. How many warning signs would suggest that the patient has primary immunodeficiency?
2 or more
What question would you ask all patients who you suspect may have a primary immunodeficiency?
Do you have a primary family history of PID?
What are the limitations of the ‘10 warning signs’ for the recognition and diagnosis of primary immunodeficiency diseases?
- lack of population-based evidence
- PID patients with different/defects/presentations
- PID patients with non-infectious manifestations
Which of the 10 warning signs were found to be the most useful for detecting PID?
- family history
- failure to thrive
- diagnosis of sepsis treated with IV antibiotics
(But only for certain PID’s)
Primary immunodeficiency diseases only cause an increased susceptibility to infection.
True or false.
FALSE They cause: -autoimmunity -malignancy -inflammatory responses
Why is it important that primary immunodeficiency diseases are detected early?
They can cause cancer (lymphomas, leukaemia etc…)
What are the four classes of primary immunodeficiency diseases?
- antibody deficiencies
- combined T and B cell
- phagocytic defects
- other cellular immunodeficiencies
What is SCID?
Severe combined immunodeficiency
Group of diseases that have the same clinical presentation.
Affects T cells.
When there is a T cell defect, there is also a B cell defect because CD4+ T helper cells are required for B cells to proliferate.
Which antibody is deficient in common variable immunodeficiency (CVID)?
IgG
Age of onset of a primary immunodeficiency is <6 months old
Which components of the immune system are likely to be defective?
T-cell or phagocyte
Age of onset of a primary immunodeficiency is > 6 months and < 5 years old.
Which components of the immune system are likely to be defective?
B-cell/antibody or phagocyte defect
Age of onset of immunodeficiency disease is > 5 years old and later in life.
Which components of the immune system are likely to be defective?
B cell/antibody/component
Or
Secondary immunodeficiency
Which types of infection are likely to occur in patients with primary immunodeficiency diseases that result in a complement deficiency?
Infections:
C3 - Pyogenic infections
C5-C9 - Meningitis/sepsis/arthritis (Encapsulated bacteria:
Neisseria meningitidis
Streptococci
Haemophilus influenzae)
C1 Inhibitor - Angioedema (deep tissue swelling)
Which types of infection are likely to occur in a patient with phagocytic defects due to a primary immunodeficiency disease?
- skin/mucous infections
- deep seated infections
- invasive fungal infections (aspergillosis)
Which types of infectious are likely to be found in patients with primary immunodeficiency diseases that cause antibody deficiencies?
- sinorespiratory infections (upper resp tract)
- arthropathies
- GI infections (Giardia lamblia (protozoa)) - will not respond to antibiotics
- malignancies
- autoimmunity
Which types of infections are likely to be found in patients with T cell defects due to primary immunodeficiency diseases?
Death if not treated
Failure to thrive
Deep skin and tissue abscesses
Opportunistic infections
Patient has an upper respiratory tract infection and a GI infection caused by Giardia lamblia.
A defect in what part of the immune system due to a primary immunodeficiency disease is likely to be the cause of this?
Antibody deficiency
Which viruses cause the most harmful opportunistic infections?
Herpes viruses
6 month-old boy who was born at term (40 weeks)
physically normal and apparently healthy.
In last 3 months, he has been plagued with
recurrent fungal (diaper rash, oral candidiasis),
viral (upper respiratory tract infections), and
bacterial (otitis media) infections, all of which
resolved with appropriate pharmacologic
intervention.
Below the 50% percentile for weight.
Routine childhood immunization OK
Weak IgG response to vaccines
Both sexes of the family have been affected by these infections.
Diagnosis?
Severe combined immunodeficiency disease (SCID)
12-month-old boy with 4 episodes of severe gram-positive bacterial pneumonia in the last
6 months
He has had recurrent diarrhoea (Giardia
lamblia) and his tonsils are barely
detectable.
Below the norm for height and weight
Recommended paediatric immunizations (low
IgG, undetectable IgE, IgA and IgM and no B
cells)
Patient has three healthy sisters aged 3, 5,
and 7 years. The family lost a boy at 10
months of age to bacterial pneumonia 8 years
ago.
Diagnosis?
Why did he develop diseases after 6 months?
Bruton’s disease
(X-linked agammaglobinaemia)
Only presented after 6 months due to maternal immunity (have maternal antibodies so protected against all microorganisms she has been exposed to for six months)
What is the only primary immunodeficiency disease that causes no antibodies to be produced?
XLA (x-linked agammaglobinaemia)
Also called,
Bruton’s disease
A young patient who developed since the age
of 4 weeks multiple staphylococcal abscesses
in the chest, face and buttock requiring
surgical incision and a course of systemic
antibiotics for 10 days.
• By the age of 2 he was admitted to the
hospital 5 times for staphylococcal infections
and pulmonary aspergillosis.
• Height and weight below the average
• Three elder brothers had died of infections at
an early age but sisters healthy
• Neutrophils failed to produce oxygen radicals
(respiratory burst)
Diagnosis :
Chronic granulomatous disease.
Phagocytic defects result in increased susceptibility to…
Fungal infections
Eg.
Pulmonary Aspergillosis
Skin infections
40 year-old women is referred to the Allergy &
Immunology clinic after suffering throughout her
life recurrent bacterial respiratory (sinusitis, otitis,
tonsillitis) and gastrointestinal infections
(intermittent diarrhoea).
• As a child she was hospitalized for pneumonias and
GI infections (Giardia lamblia)
• Both IgG, IgM, IgA below normal. Poor IgG response
to pneumococcal vaccines. Number of B cells and T
cells were normal.
• Mother and sister had also poor response to
polysaccharide vaccines and died from haemolytic
anaemia and non-Hodgkin’s lymphoma.
Diagnosis :
Antibody deficiency
Common variable immunodeficiency disease
What is the supportive treatment for primary immunodeficiency diseases?
- infection prevention (prophylactic antimicrobials)
- treat infections promptly and aggressively (passive immunisation)
- nutritional support (vitamins A/D)
- avoid live attenuated vaccines
What specific treatment can be given to patients with antibody deficiencies or SCID?
Regular immunoglobulin therapy
SCID: haematopoietic stem cell therapy
Which comorbidities are considered in the management of primary immunodeficiency diseases?
Autoimmunity and malignancies Organ damages (lung function assessment) Avoid non essential exposure to radiation (reduce oxidative stress)
What is the goal of immunoglobulin replacement therapy?
IgG > 8g/L
How long would you give a patient with a primary immunodeficiency disease immunoglobulin replacement therapy for?
Lifelong
Which primary immunodeficiency diseases are treated with immunoglobulin replacement therapy?
CVID - low levels of IgG
XLA (Bruton’s disease) - no antibodies
Hyper-IgM syndrome (T cells do not signal B cells to switch from IgM to IgG)
Why might someone develop a secondary immune deficiency due to decreased production of immune components?
Decreased production of immune components:
- malnutrition
- infection (HIV-CD4+)
- liver disease (acute phase proteins, complement, cytokines)
- lymphoproliferative diseases
- splenectomy
A patient is undergoing chemotherapy. which white blood cell is likely to significantly decrease in number?
Neutrophils
Neutropenia
Why might someone have a splenectomy?
- infarction (eg. Sickle cell anaemia)
- trauma
- autoimmune haemolytic disease
- infiltration (tumour)
- coeliac disease
- congenital
What are the immune functions of the spleen?
Immune functions of the spleen:
-only organ that fights bloodborne pathogens
Encapsulated bacteria
-antibody production
Acute response: IgM production
Long term: IgG production
-splenic macrophages
Removal of opsonised microbes
Removal of immune complexes
Why is an asplenic patient immunocompromised?
-Increased susceptibility to encapsulated bacteria Eg. Haemophilus influenzae Streptococcus pneumoniae Neisseria meningitidis
-OPSI (overwhelming post-splenectomy infection)
Sepsis and meningitis
How are asplenic patients managed?
- penicillin prophylaxis
- immunisation against encapsulated bacteria
- medic alert bracelet
Why are patients with haematological malignancies immunocompromised?
Increased susceptibility to infections
- chemotherapy-induced neutropenia
- chemotherapy-induced damage to mucosal barriers
- vascular catheters
How is neutropenic sepsis managed?
Acute medical emergency
Offer empiric antibiotic therapy
Assess patient’s risk of septic complications
Why might someone develop a secondary immune deficiency due to loss or catabolism of immune components?
-protein-losing conditions:
Nephropathy
Enteropathy
-burns
If there are persistent viral and fungal conditions, which components of the immune system are likely to be affected by a primary immunodeficiency disease?
T cell deficiency
If there are persistent bacterial and fungal deficiencies, which components of the immune system are likely to be affected by a primary immunodeficiency disease?
B cells/granulocytes deficiency
Which laboratory investigations would you request in a patient suspected to have an immunodeficiency?
Humoral antibody immunity:
- IgG, IgA, IgM
- IgG levels specific to previous vaccines
- antibody in response to ‘test’ immunisation
Cell mediated immunity:
- lymphocyte count
- subset analysis (CD4+, CD8+, NK, B)
Phagocytic cells:
- neutrophil count
- neutrophil function tests
Complement:
-individual components
Definitive tests - molecular testing + gene mutations
What is a Hickman line and why might it result in patients being immunocompromised?
An artificial plastic line inserted through the skin and directly into the vascular system. This is a source of direct entry for micro-organisms. In addition, it provides an artificial surface within the body for organisms to attach to.
Why might mucositis result in a patient being immunocompromised?
Allows for breaks in the mucosal barrier
Why might loose stool cause a patient to be immunocompromised?
Likely that the whole of the GI tract is affected in a similar manner to the mouth. The normal mucosal lining is eroded, altering the motility of the bowel and a site for organisms to enter
How is a patient on cancer treatment for lymphoma be immunocompromised?
Innate immune system:
Hickman line - entry for microbes + artificial surface
Mucositis - breaks in mucosal barrier
Loose stool - site for organisms to enter, altered motility
Low neutrophil count - chemotherapy acts on dividing cells in the bone marrrow so affects all cell lines. Neutrophils are part of the first line of defence
Adaptive immune system:
-some normal T cells but affected by chemotherapy designed to target T cells as lymphoma is a malignancy of lymph nodes made up of lymphocytes. The lymphoma itself can impair aspects of the adaptive immune response
How does the fungal cell wall differ from that of bacteria?
Fungal cell wall - chitin
Bacterial cell wall - peptidoglycan
Why are fungi unaffected by beta-lactams and glycopeptide anti-bacterials if they have a cell wall?
These anti-bacterials target the peptidoglycan cell wall of bacteria.
The cell wall in fungi is made of chitin so is unaffected.
How do fungi grow?
Where is the natural habitat for most fungi?
Derive nourishment form a preformed organic carbon source for growth
Produce enzymes to degrade surrounding material that is then soluble and can cross the cell membrane
The natural habitat for most fungi is therefore soil or water containing decaying organic matter.
Where is Aspergillus found?
Found in dust in buildings and the surrounding environment
Does Aspergillus usually infect people with a normal host immune response?
NO
People with reduced immunity can be at risk
What does an Acute Aspergillus infection commonly cause?
Infections of the lung but other organs can be involved
Which group of viruses does the Varicella zoster virus belong to?
Name another virus that is part of this class?
Herpes virus
Epstein-Barr virus
What pattern of infection does the varicella zoster virus have?
Latent infection pattern
Which virus causes chicken pox?
Varicella zoster
Describe how someone who previously had chicken pox can develop shingles later on in life?
Following the acute chicken pox infection, Varicella zoster virus enters ganglia where it becomes dormant or enters a latent phase. It is not cleared but is kept in check by T-cell surveillance and usually does not cause any further problem.
However, in some situations it can deactivate. Viral particles originating in the dorsal root ganglion neurone travel along the nerve to the sensory terminals in the skin. The rash beings when the virus escapes the nerve terminals and invades the skin. This is called shingles.
Shingles can occur in healthy individuals.
True or false?
True - it is usually associated with ageing (which might be linked to reduced T cell responses)
It is uncommon in young adults who have normal immunity.
How is a varicella zoster viral infection diagnosed?
Clinical presentation is usually diagnostic:
Chicken pox
Shingles - take fluid from rash. Rash usually has vesicles - fluid containing papilla on the skin
Viral PCR
Describe the pathogenesis of varicella zoster virus.
- infection of upper respiratory mucosa with virus-containing droplets
- virus spreads to regional lymph nodes where it replicates
- infection of skin leads to appearance of vesicular rash (chicken pox)
- virus enters cutaneous neurones and migrates to ganglia where it enters a latent state
How is varicella zoster virus transmitted?
Droplet infection
Why is good dental hygiene essential for asplenic patients?
Poor dental hygiene is the main way in which microorganisms enter the bloodstream.
The spleen is the only microorganism that deals with bloodborne pathogens and this is is absent in asplenic patients.
Do B lymphocytes require antigen presentation by APC’s for activation?
NO
They have BCR that can recognise the pathogen and this stimulates them to produce IgM
Why do B cells require activation by CD4+ helper cells?
So they can switch antibody production from IgM to IgG
What is an arbovirus?
Virus transmitted by arthropod vectors
Where is Candida usually found?
Candida is usually found on wet mucous membranes (mouth and vagina)
When does Candida usually cause disease?
Antibiotic use kills competition giving Candida a competitive damage
What anti-viral drug can be used to treat chicken pox and shingles?
Acyclovir
Patients with normal immunity do not require specific treatment.
Why is identification of a fungal infection usually done via a biopsy and not a blood culture?
Fungal infections are localised and hence hard to diagnose from blood (even serology)
List the normal flora that inhabit the skin.
Staph aureus
Staph epidermis
Strep pyogenes
Candida albicans
What is Helicobacter pylori associated with?
Gastric ulcers (chronic inflammation so increase risk of cancer)
What is Helicobacter pylori associated with?
Gastric ulcers (chronic inflammation so increase risk of cancer)
