PBL 4: Infection and immunity Flashcards
Discuss the presentation, initial investigation, key differential diagnosis & initial management of fever
Defined as the elevation of core body temperature above the normal set-point
High temperature of 37.5°C or more
Occurs in infections or non-infectious conditions
Presentation
Temperature above 37.5°C
Sweats, shivering
Night sweats → associated with particular infections (e.g. TB, infective endocarditis)
low appetite
dehydration
Initial Investigation
If infection not specific, suggest…
Full blood count, including differential white count
Inflammatory markers - C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)
Chest X-ray and ECG - helps diagnose cause
Throat swab
Blood culture
Urinalysis
Key differential diagnosis
Very broad, further investigation and management are specific to the cause
Initial Management
Rest, fluids, paracetamol/ ibuprofen
Replacement of salt and water (if pt. drenching in sweat) with IV drip
Further management focused on cause
Concern heightens is temperature is very high / will not come down
Discuss the basic epidemiology, pathophysiology, presentation, investigation, management and prognosis of sepsis
Sepsis is a life threatening whole body response to an infection. The most important thing with sepsis is recognizing it as early as possible as that gives the patient the best possible chance.
If a patient is already in hospital a NEWS score is taken frequently:
Low risk is 4 or below
Medium is 5-6 or 3 on a single score
Above six is an emergency and a patient is usually moved to the ICU
Symptoms:
-Fever
-Loss of consciousness
-A change in mental state
-Brethlessness
Fast heartbeat
-Diarrhoea
-Fast breathing
-Cold and clammy skin
-Slurred speech
-Severe muscle pain
-being dizzy
-Nausea
Investigations:
A blood culture would be taken straight away which could give an indication to the bacteria causing the infection if not immediately obvious
Measuring serum lactate which is (level of lactic acid in blood) can give an indication of stress and can be useful in determining the severity of the infection
Testing urine output can be a good indicator of kidney injury if it is low and can be used as a marker to see how serious the sepsis is
A full blood count can let doctors identify quite early patients that are really at risk of sepsis( not sure where to put this doesn’t seem to fit in a good category)
A urea and electrolyte test can give info on any renal dysfunction
Risk factors:
Being over 65
Being immunocompromised
Having an indwelling line or catheter
Recently having surgery
Using drugs intravenously
Pregnancy
Complications:
You can go into septic shock which is where your blood pressure drops dangerously low and you can go into organ failure.
Approx 50% mortality rate
Small blood clots can form throughout the body blocking blood flow (in septic shock)
Treatment
Antibiotics given intravenously (immediately after diagnosis
Sometimes a ventilator
Give intravenous fluids
Recovery:
Recovery can last months or years (post sepsis syndrome)
Symptoms can be:
Feeling weak and tired
No appetite
More frequently ill
Changes in mood
Nightmares
PTSD
Swollen limbs
Joint pain
Prognosis
A majority of people recover from sepsis thats mild
Most people that get severe sepsis are at a higher risk for future infections
(some studies have found that) There is also a high death rate after hospital discharge compared to patients discharged with other diseases
Describe acute phase proteins and how they reflect inflammation
Class of proteins that increase or decrease in response to inflammation
Found in the plasma in the blood
Produced in the liver
Associated with innate immunity
Activated in response to inflammation or when Neutrophils and macrophages secrete cytokines (IL1, IL6 and TNF)
Two clinically relevant APP: CRP & ESR
C-reactive protein:
binds to Fc receptors of monocytes and neutrophils -> stimulates cytokine production
Works as an opsonin
Activates complement (CRP binds to receptors on damaged cells)
C3:
directly influences inflammation via complement cascade
Dilating arteries/ stimulating mast cells for histamine release/ chemotaxis of phagocytes/ opsoninsation of microbes
serum amyloid A
understudied but:
Synthesis of cytokines
Chemotaxis for neutrophils and mast cells
haptoglobin:
binds to haemoglobin - prevents iron loss
Antioxidant
fibrinogen
coagulation
ferritin
sequesters free iron
Discuss the function of B cells and how they contribute to the adaptive immune response
Summary of function:
B cells are the ‘snitches’ of the immune system.
They don’t kill antigens, they spot them, get them checked by t-helper cells, then get their mates (eosinophils, neutrophils and complement pathway etc.) to destroy the cell.
Some facts:
Originate from bone marrow
Have receptors for specific antigens on their surface
They circulate through the blood and lymph to B cell areas in lymphoid tissue
When they react with the specific antigen they are activated:
Divide
Some B cells become plasma cells, continually secreting antibodies
Others become memory cells for future interaction with the antigen
Activation of B cells:
An antigen can, rarely, be T independent. In this case, it does not need to be checked by T helper cells before activating B lymphocytes
Normally:
Antigen is T dependent
B cell processes and fragments antigen
Fragments of antigen is then presented to a t helper cell
Once the t helper cell confirms it is foreign, T cells secrete lymphokines, triggering B cells to divide
Response to antigen of B cells: (Relate to vaccines)
When the antigen is first presented to the body:
Initially, IgM is mainly secreted (innate immune system)
Then, by 11 days [IgG]~[IgM]
(Where IgM is an innate immunoglobulin, IgG is part of the adaptive system)
When the antigen is second presented to the body:
Response is much more rapid, evident in 3 days
The majority of antibodies are IgG
There is a slower decline in antibody production
IgG: in blood supply, circulating, attaching to pathogens
IgE: getting rid of parasites on skin and mucosal surfaces. Relates to MAST and eosinophil cells
IgA: secreted across mucosal surfaces to pick up pathogens before they enter the body
B cells make antibodies that enter the blood like bullets to find pathogens.
Discuss the function of T cells and how they contribute to the adaptive immune response
T cells are produced in the thymus gland.
Antigen-antibody diversity is a key feature of the adaptive immune system. It allows the identification of different pathogens.
Gene rearrangement is the key feature of adaptive immunity, gene rearrangement only takes place in B and T cells.
In T cells it occurs in their receptors and is a different process to gene rearrangement in immunoglobulins. It allows you to acquire an immune response and this allows your immune system to adapt.
Each cell has a different variable region because each cell has carried out a different gene rearrangement. Each cell can only rearrange genes once.
Cells that have rearranged the right gene can bind to an antigen. Antigen binding triggers cell division, which is known as clonal expansion.
The variable region binding to antigen causes proliferation.
Clonal expansion generates large numbers of cells making the same receptor. The other cells die.
T-cells do not recognise antigens directly, they recognise infected cells.
Antigens are broken down within cells and small parts of them are sent to the plasma membrane on a conveyor belt. This is called antigen presentation. This involves MHC proteins.
Helper T cells recognise pathogens processed by antigen presenting cells, macrophages and dendritic cells.
This is what allows the T helper cell to proliferate.
T-cells must be able to bind to antigens presented on B-cell to see if they agree on the antibody to be produced.
Activated T-cell then sends a signal to the B cell to proliferate.
Co-stimulation induces cytokine secretion from the T-cell. Cytokines then lead to the B-cell proliferating.
T cells continue to bind to memory B cells, causing the proliferation of more B cells stimulating the production of more memory cells and plasma cells.
Describe the mechanism of phagocytosis
phagocytes eat and kill the bacteria
Phagocytic Pattern recognition (PRR) on the phagocyte identify PAMPs on the pathogen swallowing it and trapping it in a phagosome
PAMS bind to TLR
Phagosome binds with lysosome to form phagolysosome
Specific phagolysosome granules (protease, hydrolase) kill microbes while decreasing the pH
Azurophilic granules (Hydrolases and oxidative enzymes) activate acidic environment to kill more microbes
NAPDH oxidises O2 into superoxide ion creation
bsuperoxide dismutase converts superoxide into H2O2 to kill organism
If there is a large number of pathogen that enter then signalling PRR are activated
Activated signalling PRR cause phagocytes to release cytokines
Describe the different cells of the innate immune response and how they respond to infection
Neutrophil: Phagocytosis and bacteriocidal mechanisms
Eosinophils: killing parasites
Macrophage: Phagocytosis, bacteriocidal mechanisms; antigen presentation
MAST cell: Release of histamine and other mediators
Natural Killer cell: apoptosis of virally infected cells
Macrophages first in
Describe the process of antigen presentation
Summary
Lies at the interface between innate and acquired immunity.
1. infected cells release virus,
2. Innate recognition by TLR
3. Antigen representing cells
4. Antigen representation to T Cells
An antigen-presenting cell (APC) is an immune cell that detects, engulfs, and informs the adaptive immune response about an infection.
Antigen presenting cells include macrophages, B cells, and the various dendritic cells.
A pathogen is detected to APC’s will phagocytose the pathogen and digest it to form many different fragments of the antigen.
Antigen fragments will then be transported to the surface of the APC, where they will serve as an indicator to other immune cells.
Dendritic cell may present on the surface of other cells to induce an immune response, acting as an antigen-presenting cell.
Macrophages also function as APCs.
Before activation and differentiation, B cells can also function as APCs.
After phagocytosis by APCs, the phagocytic vesicle fuses with an intracellular lysosome forming phagolysosome.
Within the phagolysosome, the components are broken down into fragments; the fragments are then loaded onto MHC class I or MHC class II molecules and are transported to the cell surface for antigen presentation
Antigen peptides are presented to T cells by APCs in association with MHC class II molecules.
APCs express MHC on their surfaces, and when combined with a foreign antigen, these complexes signal a “non-self” invader. Once the fragment of antigen is embedded in the MHC II molecule, the immune cell can respond.
Partially digested into peptide fragments and then displayed on the surface of the APC associated with an antigen-presenting molecule such as MHC class I or MHC class II, for recognition by certain lymphocytes such as T cells.
Helper T- cells are one of the main lymphocytes that respond to antigen-presenting cells.
Peptide antigens can be generated in the cytosolic compartment of the cell or in the endosomes:
Peptide antigens generated in the cytosolic compartment of the cell, such as from viruses and bacteria that replicate in the cytosol, bind to class I MHC molecules for presentation to CD8 + T cells.
Peptide antigens generated in endosomes from the endocytic uptake of extracellular antigens, such as toxins, or from microbes captured in endosomes, such as after the phagocytic uptake of certain bacteria by macrophages, bind to class II MHC molecules for presentation to CD4 + T cells
List 2-3 microorganisms which cause infections which commonly present to primary care
Escherichia coli (E.coli) => most common cause of Urinary Tract Infections (UTIs)
· Streptococcus pyogenes => causes sore throats (strep throat) which is mostly common in children (5-10 years old)
· Rhinovirus => Most common cause of common cold and can enter the body through nose, mouth, eyes
Describe the diagnostic modalities available in primary care for the diagnosis of infection
· Diagnostic Test for Urinary Tract Infection:
o Different diagnostic methods for men and women of different ages and if they are catheterised
o Women <65 years old:
– Exclude other possible causes of urinary symptoms so check for STIs
– Check for risk of sepsis
– Symptoms: dysuria (discomfort/burning with urination), nocturia (waking up at night with urge to urinate) or cloudy urine
· 2 or more = likely to have UTI so consider antibiotics
· 1 = UTI possible so urine dipstick used to increase diagnostic certainty
· 0 = Less likely to be UTI so use urine dipstick if other severe urinary symptoms present (e.g., frequency, urgency, haematuria (blood in urine)
– Urine dipstick informs diagnosis but sent for culture to confirm diagnosis
o Men <65 years old:
– Check for STIs
– Check for sepsis, prostatitis (inflammation of prostate gland)
– Take mid-stream urine sample for culture to confirm the diagnosis (urine dipstick unreliable for this)
· UTIs less likely to occur in men so it is better to get diagnosis confirmed
– Consider antibiotics after
o Catheterised adults or >65 years old:
– Do not use urine dipsticks as they become more unreliable with increasing age over 65 and if an individual is catheterised
– Most likely to be asymptomatic
– Make sure to check for sepsis
– Check for other urinary symptoms
– Symptoms suggest UTI => send urine culture
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/927195/UTI_diagnostic_flowchart_NICE-October_2020-FINAL.pdf
· Diagnostic Test for Helicobacter pylori:
o Test for H. pylori when:
– Patients with uncomplicated dyspepsia (indigestion) cannot be treated with changes to lifestyle or antacids after having done one course of PPI
– Patients with history of gastric or duodenal ulcer/bleed
– Patients with unexplained iron-deficiency
o Non-Invasive Tests:
– Urea Breath Test (UBT) => most accurate, needs prescription and staff time to do
– Stool Helicobacter Antigen Test => “pea-sized” piece of stool sent to laboratory
– Serology => testing with blood (not as accurate), detect IgG antibody but cannot differentiate active from past infection
o Refer to endoscopy, culture, and susceptibility testing if after 2 courses of antibiotics patients is still HP positive
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/828593/HP_Quick_Reference_Guide_v18.0_August_2019_change_highlighted.pdf
· Diagnostic Test for Fungal Skin and Nail Infections:
o Many nail problems can look like fungal infections send samples before starting any long-term treatments
o Take samples for fungal infections when:
– Considering oral treatment
– There is a severe case
– First line of treatment is ineffective
– Diagnosis is uncertain
o Take sample by scraping skin with blunt scalpel blade
o For nails samples, take full thickness clipping of infected nail
o For hair samples, take scalp scrapings it will usually pull out hair stumps (plucking from root does not produce best samples)
