Session 3 - Acute Sepsis and Innate Immunity

Question 1

What is sepsis?

Answer 1

Sepsis is a life threatening organ dysfunction due to a dysregulated host response to infection.

Septic shock is persisting hypotension requiring treatment to maintain blood pressure despite fluid resuscitation.

Question 2

What are the symptoms of sepsis?

Answer 2

• Respiratory rate higher than 25 breaths/min
• Need for oxygen to keep O₂ saturation above 91%
• Systolic BP is less than 91mmHg
• Heart rate is greater than 130 bpm
• No urine output for over 18hrs
• Responds only to voice or pain (otherwise unresponsive)
• Non blanching rash - mottled skin or ashen looking and cyanotic
• Neutropenia or chemotherapy within the last 6 weeks

Question 3

What are possible complications of sepsis?

Answer 3

• Irreversible hypotension
• Respiratory failure
• Acute kidney injury and renal failure
• Raised intracranial pressure
• Ischaemic necrosis of the extremities

Question 4

What possible infections can cause sepsis?

Answer 4

All infections could cause sepsis, but here are some to be more specific:

• pneumonia
• UTI
• abdominal infections
• wound infection
• device related infection
• meningitis

Question 5

What investigations would you take to diagnose sepsis and the underlying infection?

Answer 5

• Blood culture
• PCR of blood culture bacteria
• Lumbar puncture (if it is safe)
  
  • Microscopy and culture of CSF
  • PCR of CSF

Question 6

Describe the helpful mnemonic for sepsis

Answer 6

Slurred speech

Extreme shivering/ muscle pain

Passing no urine

Severe breathlessness

I feel like I might die.

Skin mottled or discoloured

Question 7

What is the sepsis 6 bundle?

Answer 7

Actions that should be completed in 1 hour after the diagnosis of sepsis.

• Give high flow oxygen
• Take blood cultures
• Give IV antibiotics
• Give a fluid challenge
• Measure lactate
• Measure urine output

Question 8

What supportive care would you give to someone with sepsis?

Answer 8

• Referral to the ITU
• Utilise the sepsis 6 bundle
• Montior the patient with regular reassessments

Question 9

What specific treatment would you give to someone with sepsis?

Answer 9

• Use an agent that is likely to be active against the pathogens that have caused the primary infection
• The agent should be able to get to the site of infection

Question 10

Describe in brief, the layout of the immune response

Answer 10

Pathogen recognition: receptors on the cell surface

Containing and eliminating the infection: killing and clearance mechanisms

Regulating itself: minimum damage to the host

Remembering pathogens: preventing the disease from recurring

Question 11

What are the two forms of immunity and what do they do?

Answer 11

Innate immunity: provides a broad and immediate response.

Adaptive immunity: follows innate immunity and is more specific, providing long lasting protection.

Question 12

What are the two lines of defence in innate immunity?

Answer 12

First line of defence: innate barriers

Second line of defence: phagocytes and chemicals that help in the inflammatory response

Question 13

What are the innate barriers we have against infections?

Answer 13

• Physical Barriers
• Physiological barriers
• Chemical barriers
• Biological barriers

Question 14

Explain and give examples of physical barriers in innate immunity

Answer 14

Physical Barriers - actually physically blocking the infection from entering the body

Examples: Skin, mucous membranes, bronchiole cillia

Question 15

Explain and give examples of physiological barriers in innate immunity

Answer 15

Physiological Barriers - barriers that intend to expel the pathogen from the body

Examples: vomiting, diarrhea, sneezing, coughing

Question 16

Explain and give examples of chemical barriers in innate immunity

Answer 16

Chemical Barriers - intend to kill the pathogens before it can enter the body

Examples: low pH found on the skin, in stomach acid, and in the vagina

Antimicrobials found in tears, lysozymes, mucus, gastric acid

Question 17

Explain and give examples of biological barriers in innate immunity

Answer 17

Biological Barriers - non pathogenic microbials present on specific and advantageous surfaces

Examples: E. coli in the gut, Staphylococcus aureus on the skin, and Neisseria meningitidis in the nasopharynx

Question 18

Briefly outline the second line of defence in the innate immune response

Answer 18

Phagocytes get involved in attempting to destroy the pathogen.

Phagocytes are signalled to where the microbes are and will attack them.

Question 19

What phagocytic cells are involved in the innate immune response?

Answer 19

• Macrophages
• Moncytes
• Neutrophils
• Basophils/Mast cells
• Eosinophils
• Natural Killer cells
• Dendritic cells

Question 20

What do macrophages do in the innate immune response?

Answer 20

• Present in all organs
• Ingest and destroy microbes through phagocytosis
• are APC (present antigens to T cells in adaptive immunity)
• Produce cytokines and chemokines

Question 21

What do monocytes do in the innate immune response?

Answer 21

• Present in the blood
• Recruited at the site of infection where they then differentiate into macrophages

Question 22

What do neutrophils do in the innate immune response?

Answer 22

• Present in the blood and increase in numbers during infection
• Led by chemokines to the site of infection
• Ingest and destroy pyogenic bacteria (Staph. aureus, and Strep. pyrogenes)

Question 23

What do basophils do in the innate immune response?

Answer 23

• Are one of the early actors in inflammation through vasomodulation
• Also important in allergy responses

Question 24

What do eosinophils do in the innate immune response?

Answer 24

• Provide defence against mutli cellular parasites (worms)

Question 25

What do natural killer cell do in the innate immune response?

Answer 25

* Kill all abnormal host cells (either virus infected or malignant)

Question 26

What do dendritic cells do in the innate immune response?

Answer 26

* Antigen presenting cells to the T cells

Question 27

What are the two mechanisms that allow phagocytes to target microbes?

Answer 27

PAMPs and PRRs Opsonin proteins and Opsonin receptors

Question 28

What do PAMPs do?

Answer 28

PAMPs are pathogen-associated molecular patterns that sit on the surface of the microbial. They are recognised by the relevant phagocytic structures, PRRs, pathogen recognition receptors. This allows phagocytes to act and target the pathogens.

Question 29

What do opsonins do?

Answer 29

Similar to PAMPs, but requires the pathogen to be opsonised first. Pathogens are opsonised by the binding of IgG molecules or Cb3 molecules to their surface. Phagocytes have receptors that recognise IgG and Cb3, when they detect these molecules it signals to the phagocyte to engulf and destroy the microbe.

Question 30

Outline the process of oxygen dependent phagocytosis

Answer 30

* Chemotaxis and adherence of the microbe to the phagocyte * The phagocyte to then ingests the microbe * This leads to the formation of a phagosome * Oxygen consumption increases * This leads to a respiratory burst that produces oxygen containing molecules that are anti-microbial * Phagosome will then fuse with a lysosome to form a phagolysosome * The enzymes in the phagolysosomes will ingest the microbe * A residual body is formed, which contains indigestible materials * The waste materials are discharged

Question 31

What is the complement system?

Answer 31

A series of proteins that enhance the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism. It also promotes inflammation, and attacks the pathogens plasma membrane. Can be activated in different ways but resulting mechanism is the same.

Question 32

How is the complement system activated?

Answer 32

There are 2 activating pathways: * Alternative pathway (activates in th early stage) * MBL pathway (activates at a later stage)

Question 33

How does the alternative pathway activate the complement system?

Answer 33

The alternative pathway is initiated by cell surface microbial constituents. Example: endotoxins on E. coli

Question 34

How does the MBL pathway activate the complement system?

Answer 34

The MBL pathway is initiated when MBL binds to mannose containing residues of proteins found on many microbes.

Question 35

What happens in the complement system?

Answer 35

Both pathways activate the same protein cascades in terms of antimicrobial actions: * C3a and C5a: guides the phagocyte towards the microbe by attracting neutrophils and macrophages with the relevant receptors * C3b and C4b: are opsonins that will stick to the microbe and attract phagocytes * C5 to C9: killing of pathogens and the membrane attack complex

Question 36

What is the role of innate immunity and the inflammatory response?

Answer 36

When a phagocyte comes into contact with a microbe, it begins the production and release of the following cytokines: Tumour Necrosis Factor-a (TNFa), Interleukin-6 (IL-6), and Interleukin-1 (IL-1) This results in a variety of responses in terms of fighting infections.

Question 37

What actions do the activation of TNFa, IL6, and IL1 cause that help the body fight an infection?

Answer 37

* In the liver, they release C-reactive protein * activates the complement system and promotes phagocytosis * In the liver, they release MBL * activate the MBL portion of complement activation * In the bone marrow, results in the mobilisation of neutrophils * this is the reason for the raised neutrophil count in an FBC * Cause the following actions in the inflammatory response: * vasodilation * vascular permeability * adhesion of inflammatory molecules to microbes so phagocytes can phagocytose * In the hypothalamus, increase of body temperature leading to fever