What are the relevant patient factors to travel related infections?
Calendar and relative time
Why is a patient's travel history important?
Imported diseases that are rare or unkown in the UK can occur, Infection DDx must be broadened to include infections endemic to areas travelled recently by patient
Different strains of pathogen are/have potentially:
Impacting on protection and detection
Antibiotic resistance differences
Guides necessary ward and lab based infection prevention
What are the key aspects of a patients travel history?
Where? (Be exact)
How (Direct or via?)
Specific risks (including sexual contact)
Preventative measures taken (E.g. Doxycycline)
What are the 4 main species of micro-organism that can cause malaria?
escribe the spread of malaria
Female mosquitos are the vector
No case to case spread
Where does malaria occur?
Africa, Asia, Middle east, South and Central America
Describe a typical malaria history
Fatigue and Malaise
Arthralgia (joint pain)
Fever, Chills and Sweats which cycle every 3rd or 4th day
All occuring 1-3 wks after bite (incubation period)
What might be the common findings of an examination of patient with malaria?
Resp distress (metabolic acidosis, pulm oedema)
Who is responsible for treatment of malaria?
Infectious disease physician
Describe malaria management
Blood smear to detect parasites
FBC, Urea and Electrolytes, LFTs, Glucose
Head CT if CNS symptoms
Treatment is species dependent:
- P. falciparum - quinine or artemisinin
- P. vivax, ovale, malariae - chloroquinine +/- primaquine
Describe a cycle of Malaria transmission/infection beginning from a mosquito biting an infected human
Mosquito acts as vector, infected blood passes into the mosquito gut and can be passed on via the mosquitos saliva
A mosiquto bites a human and the malarial parasite enters the blood through mosquito saliva
Parasite takes root in the liver (Exo-erythrocytic phase)
Parasite is released into the blood (Erythrocytic phase)
Mosquito can bite newl infected human and further pass it on
Outline the prevention of malaria
- Knowlegde of risk areas for regular or returning travellers
- Repellant, aqequate clothing, nets
- Chemoprophylaxis before travel
- Specific to region
Stats and continues before/after return
What is enteric fever?
General term for Typhoid and Paratyphoid fever
Describe the epidemiology of enteric fever worldwide and in the UK
Widespread in areas with poor sanitation
21 million cases per year, mostly children
500 cases/yr (travel related - mainly India)
What is the mechanism of infection of enteric fever?
Source is cases or carriers only
What is the causative organism for enteric fever?
Salmonella enterica serotypes
Commonly Salmonella typhii/paratyphii A, B or C
Aerobic gram negative rods
What are the virulence factors of Salmonella enterica subsp. that commonly cause enteric fever?
Gram negative endotoxin (VI antigen)
Invasin (to allow intracellular growth)
Fimbriae (small hairlike processes) allow adherence to ileal peyer's patches
What are the symptoms and signs of enteric fever?
Systemic disease w/ fever and headache
Complications can include haemorrhage and perforation of bowel
What investigation might be performed in a patient with suspected enteric fever?
What would be found in a patient with enteric fever?
FBC, WBCC, Urea and Electrolytes, LFTs, Blood and stool culture
Bacteria in blood and stool culture (S. Enterica subsp.)
What is the current treatment for enteric fever?
Ceftriaxone or azithromycin for 7-14 days
Describe the preventative measures for enteric fever
Food and water hygiene precautions (boil water etc)
Used for high risk travel and lab personnel
VI capsular polysaccharide antigen or live attenuated virus
Apart from enteric fever, what other common disease is caused by salmonella spp.?
Give common causative organisms, symptoms and complications
Widespread distribution including UK (non-travel related)
Commonly caused by S. typhirium/enteritidis
generally self limiting but bacteriaemia and deep seated infection may occur
What is zoonosis?
Any process whereby an infectious disease is transmitted from animal to human
Give an example of a zoonosis disease
Include the common causative organisms and it's distribution worldwide
Brucella abortus (cattle) and B. melintensis (goats and sheep)
Gram negative coccobascillus
With regards to brucellosis describe the:
Through skin breaks or the GI tract (Milk)
Non specific, febrile (undulant fever, rising and falling)
Generally from blood culture
Doxycycline and rifampicin
Why is travel history important in a patient that potentially has a severe/high risk disease?
Assessment of travel guides possible diagnosis
Also allows us to assess possibility of high risk infection being present
What precautions might be taken with someone with a suspected high risk of a travel related infection?
Requirement to consider isolation
Additional protections afforded to clinicians/lab staff handling high risk specimens
Give an example of two types of novel emergent viruses that caused pandemics
E.g. H1N1 swine flu in 2009
E.g. SARS-CoV in 2003 (severe acute respiratory syndrome)
Give examples of viruses, vectors and diseases that cause haemorrhagic fevers
Your examples may vary
Filoviridae - Bat - Ebola haemorrhagic fever
Flaviviridae - Mosquito - Dengue and Yellow haemorrhagic fever
What are the symptoms of Ebola?
Internal/external bleeding at 5-7 days
Describe the transmission of Ebola
Through direct contact with infected bodily fluids
What are the potential causes of traveller's diarrhoea?
What is the relevance of organism type/species to the symptoms experienced?
Different organisms can cause differnt types of stool found in diarrhoea
Name some web resources that you might use to look for information regarding any potential outbreaks of infections in areas your patient might have travelled?
What is influenza A and how is it spread/
Spreads via droplets/aerosols (commonly from a cough or sneeze)
What are the common symptoms of Infuenza A infection?
In severe cases Pneumonia
Describe how Infuenza A might be subtyped
Subtyped based on two proteins found on the surface of the viral envelope
Protein that causes RBCs to agglutinate (clump together)
A protein that cleaves the glycosidic bonds of neuraminic acid monosaccharides
Subtype of each (H and N) gives the overall subtype (E.g. H1N1)
Describe how Influenza A can cause pandemics
Gene mutation of antigens on envelope
The process by which two or more different strains of a virus, or strains of two or more different viruses, combine to form a new subtype having a mixture of the surface antigens of the two or more original strains.
These two processes in tandem produce new subtypes of virus that are occasionally highly virulent and +/- deadly, this leading to a pandemic
How would you manage a patient with Influenza A?
Oseltamivir (First ever Neuraminidase inhibitor)
Only in high risk patients (elderly, young, infirm) that present with onset of symptoms less than 48hrs ago
Only supportive treatment for otherwise healthy adults
What are the common symptoms of Legionella pneumophilia infections?
Bacterium causes Legionnairres' disease
A form of pneumonia
Symptoms also include:
Cough (dry or productive)
Diarrhoea and vomiting
What might be the labratory findings of a standard blood workup (FBC, WBCC, U&E, LFTs and Culture)?
Urea and electrolytes deranged (commonly hyponatraemia)
Impaired Liver function
Culture would reveal gram negative bascilli of L. pneumophilius
How is L. pneumophilia spread?
What is the source?
Spread via aerosol
Sources = Cases and soil
How does L. pneumophilia derange noraml innate immune function to aid in replication?
Once phagocytosed by macrophages lysosymes are unable to bind
L. pneumophilia remains in the macrophage where it can replicate
What are the common antibiotic clasess used to treat L. pneumophilia?
What is the response of a Naive T cell to a pathogen?
What are the two types of microbe as for as adaptive immune response is concerned?
Intracellular microbes (replicate intracellularly):
Extracellular microbes (replicate extracelullarly):
What is the initial cellular interaction of the adaptive immune system?
Antigen presenting cells react with T lymphocytes
What are the 3 processes involved in APC function?
Capture of microbe
Processing of microbe
Presentation of antigen to T lymphocytes
Where are APCs found?
Within lymphoid tissue:
Skin - SALT (Skin associated lymphoid tissue)
Mucous membranes (GastricALT, NasalALT, BronchialALT etc)
Lymphoid organs (Lymph nodes, spleen)
Circulation (Plasmacytoid and myeloid Dendritic cells)
How do APCs capture antigens?
Phagocytosis (whole microbe)
Micropinocytosis (Soluble particles - random process)
How do APCs recognise pathogenic cells?
Extracellular pattern recognition receptors (PRRs) recognise extracellular pathogens via pathogen associated molecular patterns
Intracellular PRRs recognise intracellular pathogens via PAMPs
Give some types of APCs and where they are found
Dendritic cells - Lymph nodes
Langehans' cells - Skin
Macrophages - various tissues
B cells (recognise antigen in native form) - Lymphoid tissues
What are the differences in response of an APC when it encounters intracellular or extracellular microbes?
Extracellular PAMP is recognised by extracellular PRR leading to activation of humoral immunity (Antibodies and complement)
Intracellular PAMP is recognised by PRR leading to activation of cell-dependent immunity (Cytotoxic T cells, macrophages and antibodies)
What class of molecules do APCs present to T lymphocytes?
Present Major Histocompatibility Complex (MHC) class I/II
Also known as Human Leukocyte Antigens (HLA)
Describe the differences between MHC I and MHC II molecules
Class I presented by all nucleated cells
Class II presented by professional APCs (dendritic cells, macrophades, B cells etc)
Class I molecules presented when peptides from intracellular microbes are detected by APC
Class II molecules presented when peptides from extracellular microbes are detected by APC
Responsive T cells:
Class I molecules present to CD8+ T cells (Extrcellular)
Class II molceules present to CD4+ T cells (Intracellular)
What are the key genetic features of the HLA genes?
Both parental genes expressed
Increases the number of MHC molecules we can express, stregthening immunity
Different alleles among different individuals
Increases presentation of different antigens in the population
Outline the differences in structure of MHC Class I and II molecules
Alpha 1, 2 and 3 regions on peptide 1
Beta 2 microglobulin subunit on peptide 2
Peptide binding site between Alpha 1 and 2 units on peptide 1
Alpha 1 and 2 units on peptide 1
Beta 1 and 2 units on peptide 2
Peptide binding site is between the two peptides
How specific is the binding of MHC molecules to processed peptides?
Broad specificity (can present a large number of peptides)
Outline the process of MHC Class I presentation on cell surface from the entry of a virus into the cell
Virus wil replicate and produce proteins
These proteins are recognised as useless and directed to proteasomes where they are cleaved into small peptides
These peptides are transported to the ER where MHC class I molecules can be found, if there is a match, the two form a complex
This complex is exported to cell membrane to await recognition by CD8+ T cell
Proteasome action is not confined to viral proteins, it can cleave self proteins, why does this not lead to autoimmune disease in a health person?
Self proteins are recognised by MHC Class I molecules but the complex is not recognised by CD8+ T cells and do not lead to activation
Outline the process of MHC class II presentation on the cell surface from entry of Exogenous antigens into the cell
Exogenous antigen from extracellular microbe is endocytosed
Lysosome fuses with endosome and antigen is digested into small peptides
MHC class II bearing vesicle exported from ER fuses with endosome
If MHC II recognises a peptide the complex is exported to the cell membrane to be recognised by a CD4+ cell
Describe why patients with HIV might vary in their disease progression
Exhibit HLA genes such as B27, B51 and B57
These are linked to the presentation of not mutating peptides that are key to virus survival
This leads to a sustained and effective CD4+ response to HIV as the virus cannot mutate these key peptides without losing the ability to replicate/infect cells etc
These patients are also known as Elite controllers or long term non-progressors due to this ability to effectively control viral replication
Exhibit HLA genes such as B35 and are commonly homozygotes for HLA-I alleles
Linked to the presentation of non-key peptides that the virus can readilty mutate
This leads to decreased recognising of the HIV virus and hence decreased CD4+ response hence rapid progression of disease
What is the relevance of HLA molecules to medical treatment?
HLA mismatch between donor organ and recipient leads to recipient immune system attacking donor tissue (Organ rejection)
Graft versus host:
Grafted tissues such as skin begins to attack recipient cells
Give some conditions in which there is an HLA type link
HLA-B27 found in 90% of patients
Insulin dependent Diabetes Mellitus:
HLA-DQ2 found in 50-75% of patients
Dendritic cells can present MHC molecules unusually in response to certain stimuli, explain this
Intracellular microbes can trigger a dendritic cell to present with MHC class I and II molceules hence activating CD4+ and CD8+ cells
CD4+ cells activated in this way are a differnt type of CD4+ cells to that seen in humoral immunity
Where do T cells mature?
Describe the T cell receptor
Used to recognise MHC I and II molecules
Huge genetic diversity required to recognise all MHC molecules
Genetic diversity comes about via a process called gene rearrangement
Creates a variable region within the TCR protein that binds to MHC
What are the types of T cell?
Called T helper cells
Cytotoxic T lymphocytes (CTL)
What are the common immune features on a T cell membrane?
T Cell receptor - For binding to processed peptide on MHC
CD3 - Co-receptor involved in signal transduction
CD4 protein - Recognises MHC class II molecules directly conferring specificity
CD8 protein - Recognises MHC class I molecules directly conferring specificity
Describe the activation of Naive CD4+ cells
Naive TH-0 CD4+ cells bind to an APC presenting MHC class II molecules in 3 ways:
CD4 bind directly to MHC II
TCR binds to the peptide presented by MHC II
CD28 on the T cell binds to B7 protein on the APC
APC releases cytokines that stimulate one of two outcomes:
If the MHC II is presenting extracellular microbe fragments then the TH-0 lymphocyte becomes TH-2 or TH-17 for best humoral response
If the MHC II is presenting intracellular microbe fragments (such as in the case of dendritic cells) then the TH-0 lymphocyte becomes TH-1 for best cellular immune response (TH-1 goes on to interact with CD8+ which is activated in tandem with CD4+)
What is co-stimulatory activation of T cells?
Binding of TCR and CD4+/8+ is not enough to fully activate a T cell and therefore an extra recptor/ligand binding pair is required to bind to fully activate
E.g. B7 and CD28 for CD4+ cells
Describe the T cell response to intracellular microbes
APC (Dendritic cell) presents MHC I and II molecules and acessory activation proteins such as B7 that activate both CD4+ (into TH-1) and CD8+ cells
CD8+ cells are not fully activated and require interaction with TH-1 cells to fully activate
CD8+ cells are now fully activated CTLs that will bind to infected MHC class I presenting cells and release cytotoxic proteins that lead to death of the infected cell (E.g. Perforins and Granzymes)
Label the boxes
Describe what is demonstrated by this graph
Top then bottom:
HIV Viral load is dependent on CD4+ number
The higher the CD4+ the better the body can control viral replication and hence lower viral load
What is concept is demonstrated by these two graphs?
Shows that long term survivors of HIV (on the left) have a consistently higher level of CD8+ cells which combat the HIV infected cells
In patients which cannot control the virus the CD8+ cells drop rapidly and viral load rises quickly
Apart from activation of CD8+ T cells what is the response to intracellular microbes?
TH-1 cells which activate CD8+ cells also activate:
- Produces antibodies
- Leads to opsonisation, neutralisation, complement activation
- Phagocytic activity
- Kills opsonised microbes
Describe the typical primary and secondary antibody reactions to infection
Antibodies are largely pentameric IgM and small amount of IgG
IgM contributes to opsonisation
Reflects naivety to the pathogen
Antibodies are largely IgG with some IgM
IgG is a more effective antibody, it opsonises, activates complement and initiates antibody dependent cell cytotoxicity
Larger total amount of antibody
Reflects a learned response to pathogen, high amount of specific IgG
Apart from activation of CD4+ cells, what is the adaptive immune response to extracellular microbes?
TH-2 Cells activate:
Eosinophils - Killing of parasites
B Cells - Release antibodies
Mast Cells - Mediate local inflammation, can trigger allergic reaction
TH-17 Cells activate:
Neutrophils - Phagocytosis of bacteria
Outline the range of Antibodies relesed in reaction to etracellular microbe and give their functions
Antibody dependent cell cytotoxicity
Mediation of allergic reaction
Give some examples of medical advances derived from study of the adaptive immune system
Treatment of immune deficiency
Passive immunisation (antibody transfer)
Antibody based diagnostic testing:
Blood type and HLA typing