Infection 1-6 Flashcards
What are the 4 steps of the Koch Henle Postulates?
- Isolate the organism from every case
- Propagate in pure culture in vitro
- Re-inoculate and produce disease
- Re-isolate
What are the key differences between Koch’s postulates and diagnosis?
Koch’s - Isolates SAME organism from MANY patients and isolates able to reproduce disease in model
Diagnosis - ONE isolate from ONE patient. Identify if the organism is a recognised pathogen.
How can microbes be classified biologically?
Prokaryote
Eukaryote
Viruses
How can microbes be classified medically?
Pathogen
Non-pathogen
Opportunistic pathogen
What are the main differences between eukaryotes and prokaryotes?
Eukaryotes have membrane bound organeles and multiple chromosomes. Prokaryotes only have one and transcription/translation is coupled (compartmentalised in eu.). Ribosomes - 30+50S=70S pro. 40+60S=80S eu.
How do viruses infect the host?
Obligate intracellular parasites that multiply using the host cell’s biosynthetic machinery.
What is a bacteriophage?
Virus which infects bacteria
What are the principle characteristics of innate immunity?
Rapid response
Invariant
Limited number of specificities
Constant during response
What are the principle characteristics of adaptive immunity?
Slow response
Variable
Numerous highly selective specificities
Improve during response
How do neutrophils act?
Phagocytosis and killing of microorganisms. Granules contain numerous bactericidal substances.
Phagocytosis particles opsonised by IgG or compliment and functions as effector cell of humoral immunity
How do eosinophils act?
Killing of antibody-coated parasites through release of granule contents - highly basic or ‘cationic’ proteins
Bind avidly to IgE-coated particles
Describe the nucleus of a neutrophil (polymorph)
multilobed
What type of white blood cells are common at the site of an allergic reaction?
Basophils and eosinophils
What is a basophil and how does it work?
A leucocyte with large basophilic granules which contain heparin, histamine and other vasoactive amines. Granules released at the site of inflammation and in immediate hypersensitivity (allergic) reactions
Express high affinity receptors for IgE - interaction causes the release of basophil granules
What is a mast cell?
A tissue cell which is not bone marrow derived but otherwise similar to its circulating counterpart, the basophil
What is the largest nucleated cell of the blood?
Monocyte - 16-20 micrometers.
What is a macrophage?
Antigen presenting cell
Mature monocytes
Strongly phagocytic
Receptors for Ig and complement
What are natural killer cells?
Type of lymphocyte able to kill virus infected cells and certain types of cancer cells
Large cytoplasmic granules distinguish them microscopically
How do NK cells and cytotoxic T cells act differently?
NK act independently of antigen presentation and recognition, which is necessary for the action of T cells
What are dendritic cells?
Antigen presenting cells. Possess long processes which interdigitate between lymphoid cells and interdigitate between lymphoid cells and present antigens to them.
What is a B lymphocyte and where is it derived?
Precursor of antibody-forming cells. Bone marrow derived
What is a plasma cell?
The B lymphocite in its high-rate antibody secreting state. Rarely seen in the blood, but found in spleen, lymph nodes etc whenever antibody is being made.
From where are T lymphocytes derived?
Thymus
What are the primary lymphoid organs?
Bone marrow where T and B lymphocytes are made. Thymus where T lymphocytes mature/are selected
What are the secondary lymphoid organs?
Eg. Spleen, lymph nodes nad peyers patches. Contain T cells, B cells, antigen presenting cells
What cells constitute the bone marrow stroma?
Fibroblasts (reticular connective tissue) Macrophages Adipocytes Osteoblasts Osteoclasts Endothelial cells forming the sinusoids
What are the 3 types of stem cells present in bone marrow?
Haematopoietic - wbc, rbc and platelets
Mesenchymal - gatekeeper cells of marrow
Endothelial stem cells
What is aplastic anaemia?
Bone marrow does not produce sufficient new cells to replenish blood cells. Deficient in all blood cell types.
Idiopathic or autoimmune - wbc attack bone marrow
Describe the development of T cells.
Precursors arrive at thymus from bone marrow. Cortex and medulla educate thymocytes into mature competent T cells. Mature T cells are released into the peripheral.
What are thymocytes?
Precursor lymphocytes from the bone marrow which enter the thymus via blood vessels. Proliferate and mature in the thymus. 1-3% survive the selection process that allows mature T cells to enter the peripheral circulation.
Name 2 diseases associated with Thymus disease.
Severe combined Immunodeficiency - SCID
DiGeorge Syndrome - genetic disorder causesd by deletion of a small setion of chromosome 22
What type of cells are CD3,4,8,16 and 19?
CD3 T cells CD4 Helper T cells CD8 Cytoxic T cells CD16 Macrophages CD 19 B cells
Describe the path of B cells through lymph nodes.
Travel from the blood stream entering the cortex via high endothelial venules. Leave via efferent lymph.
What happens when a B cell encounters an antigen?
Forms primary foci from which proliferating cells migrate to the primary follicle forming a secondary follicle with a germinal centre. A few weeks after it forms, the germinal centre reaction dies down.
What may cause lymph nodes to enlarge?
Infection Virus Inflammation Cancer Caner of the blood
What is GALT?
Gut Associated Lymphoid Tissue
What is MALT?
Mucosa Associated Lymphoid Tissue
What is SALT?
Skin Associated Lymphoid Tissue
What are tonsils?
Mass of lymphoid tissue in submucosa of oropharynx. Many lymphoid follicles, mostly with germinal centres
What are Peyers patches?
Organised patches of lymphoid follicles int he submucosa of the gut, mainly the ileum
What is an infection?
Invasion of a host's tissues by microorganisms Disease caused by: - microbial multiplication - toxins - host response
What is microbiota?
“commensals”
Microorganisms carried on skin and mucosal surfaces
Normally harmless or even beneficial
transfer to other sites can be harmful
How may infections be spread?
Physical contact Airborne Vector may be necessary Ingestion Inhalation Mother to child - vertical transmission
What determines the disease caused by an infection?
Pathogen: - virulence factors - inoculum size - antimicrobial resistance Patient: - site of infection - co-morbidities
How do you determine if a patient has an infection?
History - symptoms/exposure
Examination
Investigations - specific/supportive
How do microorganisms cause disease?
Exposure -> adherence -> Invasion -> Multiplication -> Dissemination
What are virulence factors?
Factors of viruses that cause disease - exotoxins e.g.. cytolytic, AB toxins, Superantigens, enzymes and endotoxins
What are some supportive investigations?
Full blood count C reactive protein Blood chemistry Imaging Histopathology
Name some tests you might use to determine specific infection bacteriology.
Specimen type
M, C & S - microscopy, culture and sensitivity (antibiotic susceptibility)
Antigen detection
Nucleic acid detection
Name some tests you might use to determine specific infection virology
Antigen detection
Antibody detection
Detecting viral nucleic acid
What are the 2 semi-independent parts of the lymphatic system?
Lymphatic capillaries and vessels
Lymphoid tissues and organs
What is the function of the lymphatic system?
Fluid balance
Fat absorption
Defence
What is the lymphatic system?
A network of vessels that assist in circulating fluids - excess fluid away from interstitial spaces to the blood stream
What is the structure of lymphatic capillaries?
Tiny closed end vessels consisting of simple squamous epithelium. More permeable than blood vessels because they lack a basement membrane.
Resemble small veins, one way valves
How are lymphatic vessels compressed?
Contraction of surrounding smooth muscle
Periodic contraction of smooth muscle in lymphatic vessel wall
Pressure changes in the chest during breathing
Where does the right lymphatic duct converge and empty into?
Upper right limb and right half of head, neck and chest and empties into right subclavian vein
Where does the thoracic duct converge and empty into?
Rest of body (compared to right lymphatic duct) and empties into the left subclavian vein
What are the lymphoid organs?
Lymph nodes
Tonsils
Spleen
Thymus gland
Describe the structure of lymph nodes.
Rounded structures distributed along the lymphatic vessels
Outer part - cortex. Follicles with germinal centre (contains dividing lymphocytes)
Inner part - medulla. Contains phagocytic macrophages.
What are lacteals?
Special lymphatic vessels located in the lining of the small intestine -. fat enters lymphatic vessels and then venous circulation
What is chyle?
Lymph that is milky in appearance due to fat.
How does the lymphatic system act in the bodies defensive mechanisms?
Removes organisms and foreign substances from the lymph
Associated with activation of the immune system.
What is the collective term for lymph node enlargement?
Lymphadenopathy - may be due to lymphadenitis (painful and responding to foreign antigen) or metastatic cancer (usually painless and firm)
What is the function of tonsils?
Trap and remove bacteria and other foreign materials
How is tonsillitis caused?
Congestion of bacteria.
What is the spleen?
The largest lymphatic organ containing sinuses filled with blood. 2 tissue types - red and white pulp.
What is red pulp?
Receives arterial blood which passes into venous sinuses. Lined by macrophages - removes old red cells and recycles iron
What is white pulp?
T and B cell compartments with macrophages and other immune cells.
What is the function of white pulp?
Recognise pathogens, remove pathogens and activate T cells and B cells
How does age affect the thymus?
Largest at infancy and during puberty, small in an adult and replaced by fat and connective tissue in the elderly.
What is the function of the thymus?
Site of T lymphocyte production
Secretes protein hormones called thymosins
What are the main types of fungi?
Yeast
Mould
What are the 2 most common types of pathogenic parasites in humans?
Protozoa Helminth (worm)
How does age affect immunity?
Different antibodies at different ages - inter-uterine from mother etc
How does gender affect immunity?
Hormones
Anatomy - UTI
How do social factors affect immunity?
What you are exposed to.
How does time affect disease?
Calendar time - weather, temperature etc
Relative time - time since being somewhere (?)
How does where a patient has been affect their chances of disease?
Some diseases are more common in different countries/places and people who have visited are less likely to have immunity than those that live there. Therefore, where they currently live and have recently visited can affect their health
Name some mechanisms of infection
Contiguous spread Inoculation Haematogenous Ingestion Inhalation Vector Vertical transmission
What 3 things is a diagnosis based on?
History
Examination
Investigation
What specific treatments might be given for an infection?
Antimicrobials
Surgery - drainage, debridement, dead space removal
What supportive treatment might be given for an infection?
Symptom relief
Physiological restoration
What is a purpuric rash?
The appearance of red or purple discolouration on the skin that does not blanch on applying pressure. Looks like bleeding under the skin. 3-10 mm diameter of spots
What are the clinical features of sepsis?
Systemic inflammatory response syndrome A response to a non-specific insult Two or more of: - Temperature 38 - Heart rate >90 - Resp. rate >20/min WBC 12x10^9/L
What is bacteraemia?
Presence of bacteria in the blood
What is septicaemia?
Clinical term meaning generalised sepsis
What is sepsis?
The systemic response to infection - SIRS + documented/presumed infection
Define severe sepsis.
SIRS + organ dysfunction/hypoperfusion (hypotension, decreased urine output)
Define septic shock.
Severe sepsis + persistently low blood pressure despite administration of intravenous fluids
What is the common bacterial pathogen to cause meningococcal meningitis in a teenager and how is it spread?
Neisseria meningitidis.
Spread by direct contact with respiratory secretions. Most people are harmlessly colonised but in the unlucky few, rapidly progressive.
How is low blood pressure caused in a septic patient despite the high pulse rate?
Endotoxins that the bacteria release cause vasodilation, decreasing total peripheral resistance. Mean arterial blood pressure = Total peripheral resistance + Cardiac output
What is the role of a pilus on a bacterial cell?
Enhances attachment to other cells
What does the polysaccharide capsule on a bacterial cell do?
Promotes adherence
Prevents phagocytosis
In the inflammatory cascade, what are the local effects of cytokines?
Stimulate inflammatory response to promote wound repair and recruit RE system
In the inflammatory cascade, what are the systemic effects of cytokines?
Stimulating growth factor, macrophages and platelets. Goal is homeostasis. Lead to activation of humoral cascade and RE system
How can the release of cytokines cause organ ischaemia, dysfunction and failure?
Cytokines initiate the production of thrombin and also inhibit fibrinolysis
Coagulation cascade leads to microvascular thrombosis…
Microvascular injury is the major cause of shock and multiorgan failure
What urgent investigations would you order on someone with sepsis?
Full blood count, urea and electrolytes EDTA bottle for PCR Blood sugar Liver function test C-reactive protein Clotting studies Blood gases
What are the sepsis 6 and when must they be delivered?
Within 1 hr:
Deliver high flow oxygen
Take blood cultures and other cultures and consider source
Administer empirical IV antibiotics
Measure serum lactate
Start IV fluid resuscitation
Commence accurate urine output measurement
What are the requirements for an antibiotic for meningitis?
Active against the pathogen that penetrates the CSF
Empiric choice is ceftriaxone
What are some life threatening complications of sepsis?
Irreversible hypotension Respiratory failure Acute kidney injury Raised intracranial pressure Ischaemic necrosis of digits/hands/feet
How is a diagnosis of sepsis confirmed?
Blood culture
PCR of blood
Lumbar puncture (if safe) - culture of CSF and PCR
What is the cerebrospinal fluid examined for in sepsis?
Appearance - turbidity and colour
Microscopy - WBCs and RBCs
Gram stain
Referral for PCR
Describe Neisseria meningitidis.
Gram-negative diplococcus
Numerous serogroups based on polysaccharide capsular antigen - evades immune response by preventing phagocytosis
Outer membrane acts as an endotoxin
What % of adults may be carriers of meningococcal disease?
25%
How is meningococcal disease spread?
aerosols and nasopharyngeal secretions. Acquired by clearance, carriage or invasion
What is the most common group of meningococcal disease?
In England, 1000 cases/yr mainly group B, fatality rate approx 10% but elsewhere, group A predominates. ‘Meningitis belt’ across Africa.
Describe some preventions of meningitis.
Meningococcal C conjugate vaccine
ACWY vaccines available for immunocompromised patients and travel protection
People in close contact to patients can be given antibiotic prophylaxis and considered for vaccinations
Why is there no vaccine in routine use for meningococcal group B?
B capsule poorly immunogenic and similar to neural tissue.
Vaccine developed after screening candidate proteins from genome
Define the immune system.
Cells and organs that contribute to immune defences against infectious and non-infectious substances
Define infectious disease.
When the pathogen succeeds in evading and/or overwhelming the host’s immune defences.
What are the roles of the immune system?
Pathogen recognition
Containing/eliminating the infection
Regulating itself
Remembering pathogens
What type of barriers can the innate immune system form?
Physical barriers Physiological barriers Chemical barriers Biological barriers (limit entry and growth of pathogens)
What physical barriers does the innate immune system provide?
Skin
Mucous membranes
Bronchial cilia
What physiological barriers does the innate immune system provide?
Diarrhoea
Vomiting
Coughing
Sneezing
What are the chemical barriers of the innate immune system?
Low pH - skin, stoomac, vagina
Antimicrobial molecules - IgA, lysozyme, mucous, beta-defensins, gastric acid and pepsin
What are some biological barriers of the innate immune system?
Normal flora - non pathogenic microbesin strategic locations eg nasopharynx, mouth, skin, GI tract, vagina etc. Absent from internal organs
What are the benefits of normal flora?
Compete with pathogens for attachment site and resources
Produce antimicrobial chemicals
Synthesize vitamins
What are some examples of normal flora that inhabit the skin?
Staphylococcus aureus Staphylococcus epidermidis Streptococcus pyogenes Candida albicans Clostridium perfingens
What are some examples of normal flora that inhabit the nasopharynx?
Streptococcus pneumoniae
Neisseria meningitidis
Haemophius species
How might normal flora be displaced from its normal location to a sterile location?
Breaching the skin integrity - skin loss, surgery, injection drug users, IV line
Fecal-oral route - food borne infection
Fecal-perineal-urethral route - urinary tract infection (women)
Poor dental hygiene/dental work (most common) - dental extraction, gingivitis, flossing
Who are considered to be high risk patients for infection?
Asplenic (and hyposplenic)
Patients with damaged or prosthetic valves
Patients with previous infective endocarditis
Would be given antibiotic prophylaxis
When might normal flora overgrow and become pathogenic?
When host is immune-compromised - diabetic, AIDS, malignant disease, chemotherapy
When might normal flora be depleted by antibiotics?
Intestine -> severe colitis (Clostridium difficile)
Vagina -> thrush (Candida albicans)
What is the second line of defence in innate immunity?
Phagocytes and chemicals -> inflammation (factors that will contain and clear the infection)
How are pathogens recognised?
Microbial structures: Pathogen-associated molecular patterns (PAMPs): carbohydrates, lipids, proteins, nucleic acids recognised by:
Phagocytes: Pathogen Recognition Receptors (PRRs): Toll like receptors
Opsonins might bind to the microbial surfaces leading to an enhanced attachment of phagocytes and clearance of microbes
What are some examples of PAMPs and PRRs for gram negative bacteria?
Lipopolysaccharide (LPS) -> TLR4
Lipoprotein and lipopeptides -> TLR2
Porins
What are some examples of PAMPs and PRRs for gram positive bacteria?
Peptidoglycan -> TLR2
Lipoteichoic acids -> TLR4
What are some examples of PAMPs and PRRs for all mycobacteria?
Lipoarabinomannan -> TLR2
Mannose-rich glycans
What is an example of a PAMP and PRR for Bacterial flagella?
Flagellin -> TLR5
Give some examples of opsonins.
Complement proteins eg C3b and C4b
Antibodies - IgG, IgM
Acute phase proteins - C-reactive protein (CRP), manose-binding lectin (MBL)
Theses are essential in clearing encapsulated bacteria
How do phagocytes act?
Recognise PAMPs/opsonins, engulf and degrade infectious microbes
What are the 2 pathways by which phagocytes might kill pathogens?
Oxygen-dependent pathway (respiratory burst)
Oxygen-independent pathways
How does the oxygen dependent pathway by which phagocytes may kill pathogens work?
Produces toxic O2 products for teh pathogens: Hydrogen peroxide, hydroxyl radical, nitric oxide, singlet oxygen, hypohalite
What are the oxygen independent pathways by which a phagocyte might destroy a pathogen?
Lysozyme
Lactoferrin or transferrin
Cationic proteins
Proteolytic and hydrolytic enzymes
What are the 2 activating pathways of the complement system?
Alternative pathway - initiated by cell surface microbial constituents
MBL pathway - Initiated when MBL binds to mannose containing residues of proteins found on Salmonella app. Candida albicans
What do serum proteins C3a and C5a do?
Recruit phagocytes
What do serum proteins C3b -C4b do?
Opsonisation of pathogens
What do serum pathogens C5-C9 do?
Kill pathogen’s membrane and attack complex
What do cytokines/chemokines do?
chemoattraction
phagocyte activation
inflammation
What are the anti-microbial actions of macrophage-derived TNF/IL-1/IL-6?
Liver (opsins) - CRP and MBL (-> complement activation)
Bone marrow - Neutrophil mobilisation
Inflammatory actions - Vasodilation
Vascular permeability
Adhesion molecules -> attraction of neutrophils
Hypthalamus - increased body temperature
How does an infection cause sepsis and multi-organ failure?
Infection activates microbial toxins (LPS) which can cause overreaction of TLR4 receptor and complements. This can cause an excessive inflammatory response which leads to sepsis and multi-organ failure.
How does an excessive inflammatory response lead to decreased tissue/organ perfusion?
cytokine shower
coagulopathy
vasodilation
capillary leak
Why might phagocytosis be reduced?
Decrease spleen function (asplenic/hyposplenic)
Decrease neutrophil number (cancer chemo, certain drugs, leukaemia and lymphoma)
Decrease neutrophil function (chronic granulomatous disease (no reps burst), Chediak-Higashi syndrome (no phagolysosome formation))
What are the 5 stages of innate immunity?
- Innate barriers
- Compliment, mast cells and macrophages activation (PRR)
- Vascular changes and chemoattraction
- Hypothalamus and liver are involved
- Redness, heat, swelling and pain - local inflammation
What is the mechanism of action of the first line of defence in innate immunity?
Limit entry and growth of pathogens at portals of entry
What is the mechanism of action of the second line of defence in innate immunity?
Contain and eliminate the infection
What are healthcare infections?
Infections arising as a consequence of providing healthcare. In hospital patients neither present nor incubating at time of admission. For practical purposes, this means onset is at least 48 hrs. Also includes infections in hospital visitors and healthcare workers
Why are healthcare infections important?
Frequent - prevalence = 8% of in-patients
Impact on health
Impact on healthcare organisations
Preventable
Av of 1 day extra in hospital (not everyone gets them but can stay in hospital for 10 days…)
What type of HCAI is most common(roughly)?
GI - 21%
UTI - 20%
Varies across hospitals and departments
How might you prevent infection?
Prevent pathogen entering
Prevent the mechanism of infection
Prevent infection occurring
What are some common healthcare infection viral pathogens?
Blood borne (Hep. B/C, HIV)
Nonovirus
Influenza
Chicken pox
What are some common healthcare infection bacterial pathogens?
Staph aureus inc. MRSA (MSSA more common than MRSA)
Clostridium difficile
Escherichia coli, Klebsiella pneumoniae
Pseudomonas aeruginosa
Mycobacterium tuberculosis - histopathologists
What are some common healthcare infection fungi pathogens?
Candida albicans
Aspergillus species
What are some common healthcare infection parasites?
Malaria
What risk factors are common in patients that make them more susceptible to infection?
Extremes of age Obesity/malnourished diabetes cancer immunosuppression smoker surgical patient emergency admission
What are the 4 Ps of infection, prevention and control?
Patient - risks/interactions with other people
Pathogen - virulence/ecological factors
Practice (of the hospital and staff)
Place - fixed and variable features (beds in a bay, patients:toilets
How can we prevent patients becoming infected?
General: optimise patient's condition Antimicrobial prophylaxis Skin prep Hand hygiene
Specific:
MRSA screens
Mupirocin nasal ointment
Disinfectant body wash
How might we halt patient to patient transmission of HCAI?
Physical barriers:
Isolation of infected patients
Protection of susceptible patients
How can HCAI be prevented from transferring from healthcare professionals to patients?
Healthcare workers should be disease free and vaccinated
Good practice:
Good clinical techniques (eg. sterile non-touch)
Hand hygiene
PPE - personal protective equipment
Antimicrobial prescribing
What are some environmental features that may contribute to HCAI?
-Built environment: space/layout Toilets Wash hand basins - Furniture and furnishings - Cleaning: - Medical devices - Appropriate kitchen and ward food facilities -must have good food hygiene practice - Theatres/patient rooms - positive/negative pressure rooms.
How must the hospital be cleaned?
Disinfectants
Steam cleaning
Hydrogen peroxide vapour - v toxic to vapour and humans - whole, empty room.
How must medical devices be cleaned to prevent HCAI?
Single use equipment
Sterilisation
Decontamination
Why is travel history important?
Imported disease
Different strains of pathogen - antigenically different, impacts on protection and detection, antibiotic resistance
Infection prevention - on the ward and in the lab
What are the key aspects of the travel history?
Where When How (direct or via) Accommodation How long Specific risks (including sexual contacts) Preventive measures
What are the 4 main species of malaria?
Plasmodium falciparum, vivax, ovals and malariae
How many deaths does malaria cause each year?
1 million (250 million cases)
How is malaria spread?
Vector - female Anopheles mosquito (contained in salivary gland)
No case-to-case spread but cryptic and iatrogenic cases rarely reported
What is the incubation period of malaria?
1-3 weeks after bite
What will the presenting history of a patient with malaria be?
Starts non-specific - headache, cough, fatigue, malaise, athralgia, myalgia
Fever chills and sweats which eventually cycled every 3rd or 4th day
What would you expect to see on examination of a patient with malaria?
Other than fever often few signs (+/- splenomegaly)
Cerebral features - coma
Respiratory distress - metabolic acidosis, pulmonary oedema
What investigations would be done to confirm malaria?
Blood smear to detect parasite
FBC, U&Es , LFT, glucose
Head CT if CNS symptoms
What treatment would be given to a patient with malaria?
Dependent on species:
P. falciparum (‘maignant’) - quinine or artemisinin
P. ovale, vivax malariae (‘benign’) - chloroquine +/- primaquine ( for exo-erythrocytic phase)
Hw can malaria be prevented?
Assess risk
Bite prevention
Chemoprophylaxis
What is the mechanism of infection of typhoid?
Faecal-oral from contaminated food/water source is cases or carrier. Widely distributed in some countries due to poor sanitation
Who is typhoid most common in?
Children
What organisms might cause Typhoid?
Salmonella enterica serovar Typhi/paratyphi A, B or C
Entericobacteriaceae, aerobic gram - rod
Non-lactose fermenter
What is the virulence of salmonella?
Gram - endotoxin, VI antigen
Invasion which allows intracellular growth
Fimbriae adhere to epithelium over ileal lymphoid tissue (Peyers patches) -> RE system
What are the 2 phases of malaria?
Exo-erythrocytic (liver - asymptomatic) and erythrocytic (RBCs - fever etc)
What are the signs and symptoms of enteric fever (typhoid)?
Systemic disease with fever and headache Incubation period 7 - 24days Abdominal discomfort Constipation Dry cough Hepatosplenomegaly Occasionally rash Relative bradycardia Complications include intestinal haemorrhage and perforation Paratyphoid is generally milder
What would be seen on investigation of an enteric fever?
Moderate anaemia
Relative lympopenia
Raised LFTs (transaminase and bilirubin)
Culture of blood and faeces taken
Serology (antibody detection) no longer used
What treatment would be given to someone with enteric fever?
Antibiotics - usually ceftriaxone or azithromycin for 7 - 14 days
How might enteric fever be prevented?
Food and water hygiene precautions
Typhoid vaccine to high risk travellers and lab personnel - Vi capsular polysaccharide antigen or live attenuated vaccine
Protective effect - 50 - 75%
Other than typhoid, what else might a salmonella infection cause?
‘Food-poisoning’ eg. Salmonella typhimurium or Enteritidis
Widespread distribution
Diarrhoea, fever, vomiting, abdominal pain
Generally self limiting but bacteraemia and deep-seated infections may occur
What type of organism is Brucellosis?
A zoonosis - primary animal pathogen eg B. abortus (cattle), B. melitensis (goats and sheep)
Gram negative coccobacillus
How is Brucellosis transmitted?
Through skin breaks/GI tract
What are the signs and symptoms, how is a diagnosis made and what is the treatment of Brucellosis?
Non-specific febrile illness - undulant fever
Bone/joint involvement, epidydimitis
Diagnosis from blood culture
Treat with doxycycline and rifampicin
What is the virion of a virus?
Genome (nucleic acid) + capsid (protein surrounding genome)
What are the stages of replication of a virus?
Adsorption Entry Uncoating Transcription Virion synthesis Assembly Release
How might you detect an infection (what do you look for)?
Antibodies
Antigen
By PCR
How are blood borne viruses transmitted?
Blood
Sex
Therefore if they have one, may have another so must check for all
How does silent transmission of BBVs occur?
Asymptomatic period so may transfer then
Describe the pathogen of HIV.
Retrovirus
Single stranded RNA
HIV-1 from chimpanzee
HIV-2 from sooty mangabey
How do HIV affect the host cell?
Attach to CD4 cell Reverse transcriptase makes DNA from teh RNA Integration into host nucleus Reproduction of viral components Assembly of new HIV viruses Released
What are the symptoms of primary HIV illness?
Fever Rash Flu-like Weight loss Pharyngitis Generalised lymphadenopathy Immune system deteriorates so other disease present
What is classified as AIDs?
CD4 count less than 200
What tests would you do for HIV?
Standard - CVS, resp, abdomen, neurology... MOuth Eye Skin Genitals Lymphs
How is HIV diagnosed?
HIV 1&2 comined ab/ag test (window period) 2 week Immunoblot HIV viral load Resistance profile CD4
What investigations are ordered for a patient with known HIV?
General organ systems
Status of HIV/immune system
Infections - other BBV, opportunistic infections, past history
Underlying co-morbidities
What can you do for a person with HIV? How can you iproce their life?
Prevent related disease - undetected viral load, increase CD4 Reduce co-morbidity and mortality Improve quality of life Prevent resistance Prevent transmission
How do you treat HIV?
3 drugs acting in defferent parts of the lifecycle
HAART
patient must be compliant
How can you prevent HIV?
No sex Use condoms Know who you are having sex with No IVDU Use clean needles if you are Screened negative blood for transfusions
How can you reduce the risk of HIV transmission?
Don’t breast feed if safer - if not, only 6 months
Circumcision
Pre exposure drugs
Post exposure drugs - antiretroviral drugs
Vaccination not yet established
Describe the Hepatitis virus.
Hepadnaviridae
double stranded DNA virus
Genotype A-D
What is the difference between acute and chronic Hep B?
Acute - fever, surface antigen, antibody produced -> cured
Chronic - body doesn’t heal itself - liver cirrhosis
Both can also cause liver failure
What signs will a patient with Hep B present with?
Jaundice
Signs of chronic liver disease
What is practice-staging of Hep B?
Combination of different specific antigens/antibody tests
- acute
- chronic
- past
- vaccinated
WHat investigations will be done on a patient with suspected hep B?
General state Liver function Other BBV/STI Cancer screening Other causes of liver disease Image liver - biopsy/ultrasound endoscopy for oesophageal viruses Any complications from liver damage
What should be done for a patient with hep B?
Monitor viral load, liver function and complications
Decide when to give antivirals
Monitor antiviral side effects
Prevent other liver disease
What is given for Hep B?
Usually single drugs - supression rather than cure
Follow NICE 2013 guidelines - interferon, tenofovir
How can the transmission of hep B be prevented?
Vaccination - generalised/targeted Safe sex Mother to child interventions Screening blood/products Post exposure prophylaxis - needlestick injury
Describe the pathogen of Hep C.
Single stranded RNA
Flavivirus
6 genotyeps
How is hep C mostly transmitted?
Injecting drug use most common
Also through sexual transmission but less common (more common for B and HIV)
How can Hep C be fatal?
Cause liver cancer
What type of Hepatitis is curable?
Hep C
Where are antigen presenting cells present?
Skin (SALT) Mucu membrane (GALT, NALT, BALT) Lymphoid organs (lymph node, spleen) Blood circulation (plasmacytoid and myeloid DCs)
How are pathogens captured?
Phagocytosis (whole microbe)
Micropinocytosis (soluble particles)
How do pathogen sensors differ?
Extracellular pathogens (bacteria) -present to CD4+ T cells - humoral immunity Intracellular pathogens (viruses) - present to CD8+ T cell - cell dependent immunity
Where do interdigitating dendritic cells exist?
Lymph nodes - present to T and B cells
Where are langerhans’ cells present?
Skin - present to T cells
What class of molecules are found on all nucleated cells?
Class I
Where are class II molecules found?
Dendritic cells
Macrophages
B cells
What are the key features of MHC class I and class II molecules?
Co-dominant expression - Both parental genes are expressed -> increase number of different MHC molecules
Polymorphic genes - different alleles among different individuals -> increase presentation of different antigens/microbe
What ain the main function of MHC class I molecules?
Present viral peptides
What is the main function of MHC class II molecules?
Present bacterial peptides
What is the structure of MHC class I and class II molecules?
Peptide binding cleft - variable region with highly polymorphic residues Broad specificity - Many peptides presented by the same MHC molecule Responsive T cells - MHC class I: CD8+ T cells, class II: CD4+ T cells
What are Elite Suppressors?
Long term nonprogressors (LTNP) can control viral replication. Dependent on MHC molecule presen - HLA-B27, B51, B57 present key peptides for teh survival of the virus causing an effecting T cell response
Rapid progressors have HLA-B35 and are homozygotes in HLA-1 alleles. This icauses a mutation in the less critical peptides presented by MHC I causing weak T cell response
What molecule is mismatched in a rejected transplant organ?
HLA molecule. Graft-versus-host reaction
How is HLA associated with autoimmune disease?
Ankylosing spondylitis - HLA-B27 in 90% of patients
Insulin-Dependent Diabetes Mellitus - HLADQ2 -> 50-75% of patients
What is a common problem with MHC molecules? Give examples.
Cross reactivity between microbial and host antigens
Rheumatic heart disease - Streptocoocus progenies and antigen in cardiac muscle
Guillain-Barre syndrome - Campylobacter jejuni and Myelin-associated gangliosides
Type 1 diabetes - Coxsakieviruses (A2, A5 and A9) and pancreatic islet cells
What type of T cells are there?
CD3+, CD4+ (TH1 and TH2 cells)
CD3+, CD8+ (cytotoxic T cells or TC)
What is the function of CD8+ T cells?
Protect against intracellular pathogens
What is the function of CD4+ T cells?
Provide help for antibody production and regulate immune response
What cytokines are produced by CD4+ cells?
TH1 cells: TNFalpha, IFNgamma
TH2 cells: IL-4, IL-5, IL-10
How are naive CD4 T cells activated?
Professional antigen presenting cells engulf foreign material and bring to lymph nodes. Here they begin to present antigens which are bound to MHC class II allowing CD4+ cells that express the specific TCR cells against the peptide/MHC complex to activate. Verification that it is a foreign cell and not self, must then come from CD28 on the T cell and B7 on the APC (co-stimulatory molecules).
What happens to a CD4+ T cell that is not verified?
It becomes anergic - will not respond to any foreign cells in the future. Eventually apoptose
How are naive CD8 cells activated?
Same as CD4+ BUT MHC I instead of MHC II are presented by APC
What are the functions of CD4+ TH1 cells?
Cell-mediated immunity against intracellular microbes
Killing of infected cells - cytotoxic T cells, natural killer cells
Phagocytosis - macrophages (IFNgamma)
Antibody production (B cells) - IgG1-3
What do CD8+ cells produce that kill infected cells?
Perforins
Granzymes
What are the functions of TH2 CD4+ T cells?
Humoral immunity against extracellular microbes
Killing of parasites - eosinophils (IL-5)
Antibody production - B cells (IgG4)
Mast cell activation - IgE
Mucosal protection - IgA
How are naive B cells activated?
By CD4+ T helper cells through immunological synapse.
T cell independent - Type 1 - B cell binds to antigen and receives secondary activation by toll-like receptors. Then limited to IgM antibodies that are specific TLR-binding antigen
Type 2 - Antigens that are expressed on the surface of pathogens with an organised and repetitive form can activate B cells by cross-linking of antigen receptors in a multi-valent fashion. Many bacteria have repeating carbohydrate epitopes that stimulate B cells, cross linking their IgM antigen receptors, leading to IgM synthesis in the absence of T cell stimulation.
What are some characteristics of the humoral response?
Fast Strong Long duration High affinity Isotype switch
What are the functions of IgG antibodies?
Fc-dependent phagocytosis
Complement activation
Neonatal Immunity
Toxin/virus neutralisation
What is the function of IgA antibodies?
Mucosal immunity
What are the functions of IgE antibodies?
Immunity against helmiths
Mast cell degranulation (allergies)
What is the function of IgM antibodies?
Complement activation
What medical achievements have been derived from study of the adaptive immune system?
Disease prevention - vaccination/active immunisation Immunoglobulin therapies - immune deficiencies Immediate protection - passive immunity (antibody transfer) Diagnostic tests (antibody based) - infectious diseases, autoimmune diseases, blood type and HLA types
