Sepsis and The Innate Immune System

Question 1

Sepsis can be caused by the body’s reaction to meningitis, what type of rash would be spotted in this case?

Answer 1

Purpuric rash - non blanching.

Question 2

What is sepsis?

Answer 2

Life threatening organ dysfunction due to a disregulated host response to infection.

Question 3

What is septic shock?

Answer 3

Persisting hypotension requiring treatment to maintain blood pressure, despite fluid resuscitation.

Question 4

What is bacteraemia?

Answer 4

Presence of bacteria in the blood (with or without clinical features).

Question 5

Sepsis is recognised by the clinical assessment of patients who look sick or who have Early Warming Scores > 3 (from basic observation chart). Clinical features may suggest the source. What are some red flags and what should be done if Red Flag sepsis is spotted?

Answer 5

Red flags include a high respiratory rate, low blood pressure and unresponsiveness. Immediate action is required: send urgent investigations, inform a senior doctor for review and complete the Sepsis Six bundle.

Question 6

What makes up the sepsis 6 bundle?

Answer 6

Give oxygen, fluids and IV antibiotics.

Take lactate, urine output and blood cultures (before antibiotics administered).

Question 7

Give some examples of ‘urgent investigations’ in a case of Red Flag sepsis?

Answer 7

Full blood count (FBC), blood sugar, liver function test - CRP, coagulation studies and other microbiology samples (at site/source of infection).

Question 8

Neisseria meningitidis - how does it spread, what does it do and give 3 features?

Answer 8

Spread by direct contact with respiratory secretions, mostly colonises harmlessly.
Pili - small hair-like processes for enhancing attachment.
Polysaccharide capsule - promotes adherence and prevents phagocytosis.
Liposaccharide Endotoxin - triggers inflammation.

Question 9

Describe the inflammatory cascade.

Answer 9

Locally cytokines (TNFa and IL1) stimulate an inflammatory response to promote would repair and recruit RE system.
Systemically cytokines are released into circulation and stimulate Growth Factor, macrophages and platelets.
The goal is control of infection.

Question 10

What occurs in the inflammatory cascade during sepsis?

Answer 10

The infection is not controlled. Cytokines lead the activation of humoral cascades and the RE system –> circulatory insult with blood supply to vital organs compromised.

Question 11

What’s the link between sepsis and coagulation?

Answer 11

Cytokines initiate production of thrombin and this promotes coagulation. They also inhibit fibrinolysis, so the clotting cascade leads to microvascular thrombosis, which may cause organ ischaemia, dysfunction and failure.
Microvascular injury is the major cause of shock and multi organ failure.

Question 12

What could happen if lesions coalesce?

Answer 12

Progressive necrosis, as blood supply is prioritised to the vital organs.

Question 13

What are the supportive and specific treatments for sepsis?

Answer 13

Specific - antimicrobials - look for agent that’s likely to be active against pathogen, in age group and will reach the site - follow previously determined plan.
Supportive - physiological restoration with sepsis 6 - consider referral to ITU for regular monitoring and reassessment.

Question 14

List some life threatening complications of sepsis.

Answer 14

Irreversible hypotension, respiratory failure, acute kidney injury, raised intracranial pressure, ischaemic necrosis of digits/hands and feet.

Question 15

How might a diagnosis be confirmed in sepsis?

Answer 15

With a blood culture, PCR blood, lumbar puncture (if safe) - microscopy and culture of cerebrospinal fluid and PCR it (in a case with possible meningitis etc).

Question 16

Neisseria meningitidis is a gram _____ diplococcus with numerous serogroups. It’s polysaccharide capsular agent prevents ______ and its outer membrane acts as an ______. Up to __% of adults are carriers of meningococcal disease. It is spread by aerosols and ________ secretion. Acquisition –> clearance, carriage or ______.
In the U.K., group __ is the most common with a fatality rate of __%. Prevention 1 is ________ and 2 is prophylaxis. It is a _______ disease, which means cases must be reported to public health.

Answer 16

Negative (coccus often found in pairs)
Phagocytosis
Endotoxin - kidney shaped bacterium
25 (commensalism in some people) 
Nasopharyngeal
Invasion
B
10
Vaccination
Notifiable

Question 17

The 6 most common signs of sepsis are what?

Answer 17

1. Mottled/discoloured skin
2. Severe breathlessness
3. Feeling like you’re going to die
4. Not passing urine for a day
5. Extreme muscle pain/shivering
6. Slurred speech/confusion

Question 18

What are the factors determining the outcome of the host-pathogen relationship?

Answer 18

Pathogen infectivity, virulence with mechanism of infection am the host’s immune response.

Question 19

What is the immune system and what are its roles?

Answer 19

Cells and organs that contribute to immune defences against infections and non-infectious conditions (self vs non-self).
Roles: pathogen recognition, containing/eliminating infection and regulating itself and remembering pathogens.

Question 20

What makes an infectious disease?

Answer 20

When a pathogen succeeds in evading or overwhelming a host’s immune defences.

Question 21

The immune system is split into innate and adaptive. Both halves work towards human survival. State some differences.

Answer 21

Innate/immediate protection takes seconds, lacks specificity and memory and has no change in intensity.
The adaptive/ long lasting protection on the other hand can take days, is specific, has immunologic memory and changes in its intensity.

Question 22

What is the innate immune system’s first line of defence and what are the different types?

Answer 22

Physical, physiological, chemical and biological barriers; these are factors which prevent entry and limit growth of pathogens.

Question 23

List some physical barriers involved in innate immunity.

Answer 23

Skin, mucous membranes of the mouth, respiratory tract, GI tract, urinary tract and bronchial cilia.

Question 24

List some physiological barriers involved in the innate immune system.

Answer 24

Diarrhoea (after food poisoning), vomiting (fp, hep, meningitis) - not just in GI infections, sneezing (sinusitis) where the goal is to expel microbes, but the symptoms may be from non infectious conditions.

Question 25

List some chemical barriers involved in the innate immune system.

Answer 25

Low pH (skin=5.5, stomach=1-3, vagina=4.4 - lactic acid produced by normal flora contributes to vaginal acidity) and antimicrobial molecules - IgA (tears, saliva, mucous membranes), lysozyme (sebum,perspiration, urine), mucus (at mucous membranes), B defensins (epithelium), gastric acid and pepsin.

Question 26

List some biological barriers involved in the innate immune system.

Answer 26

Normal flora: non-pathogenic microbes (usually) at strategic locations - absent in internal organs/tissue and not in blood, which compete with pathogens for attachment sites and resources, produce antimicrobial chemicals and synthesise vitamins.

Question 27

Give some examples of normal flora inhabiting the body, when do problems arise?

Answer 27

Staphylococcus aureus inhabits the skin and the nasopharynx houses streptococcus pneumoniae and neisseria meningitidis.
Clinical problems start when this flora is displaced from its normal location to a sterile location (by breaking the skin integrity, fecal-oral route or fecal-perineal-urethral route for women with UTIs, or poor dental work/hygiene.

Question 28

Serious infections may occur in high risk patients. Who may these be?

Answer 28

Asplenic patients, those with damaged or prosthetic valves or with previous infective endocarditis - all reasons for antibiotic prophylaxis. Or if the host is immunocompromised or when normal flora is pelted by antibiotics, normal flora may overgrown and become pathogenic (opportunistic infection).

Question 29

After the innate barriers as the first line of defence, what comes next?

Answer 29

Phagocytes, chemicals –> inflammation to contain and clear the infection.

Question 30

What are the basic steps of phagocyte-microbe interaction?

Answer 30

Recognition process and killing.

Question 31

What are the 2 main types of phagocyte in the body? Describe them.

Answer 31

Macrophages are present in all organs, they phagocytose and present microbial antigens to T cells, produce cytokines/chemokines.
Monocytes are present in the blood, get recruited to a site of infection and differentiate into macrophages.
Neutrophils are present in the blood (60% of blood leukocyte) and increase during infection, where they’re recruited to the site by chemokines, ingest and destroy pyogenic bacteria (get destroyed and so main component of pus).

Question 32

Aside from marcrophades, monocytes and neutrophils, which cells are involved in innate immunity?

Answer 32

Basophil/Mast cell are early actors of inflammation for vasomodulation and are important in allergic responses.
Eosinophils provide defence against multicellular parasites (worms).
Natural killer cells kill abnormal host cells.
Dendritic cells present microbial agents to T cells to trigger specific/adaptive/acquired immunity.

Question 33

How do pathogens get recognised by phagocytes?

Answer 33

Microbial structures called PAMPs (pathogen associated molecular patterns) made of carbohydrates/lipids/proteins/nucleic acids exist on the pathogen’s surface.
PRRs (pathogen recognition receptors - most common are ‘Toll like receptors’) recognise these. Phagocytes have a variety of PRRs for flexible recognition.

Question 34

What’s the purpose of opsonisation?

Answer 34

Coating proteins/opsonins bind to microbial surfaces leading to enhanced attachment of phagocytes (and so clearance of microbes).

Question 35

Give some examples of types of opsonins.

Answer 35

Complement proteins - C3b, C4b, antibodies - IgG, IgM, acute phase proteins - CRP and mannose binding lectin tMBL. They are essential in clearing encapsulated bacteria.

Question 36

After recognition of pathogens, there is engulfment and degradation by which phagocytotic killing mechanisms?

Answer 36

Oxygen dependent pathway (respiratory burst) - produces toxic oxygen products to kill pathogens e.g. Nitric oxide, hydrogen peroxide and hydroxyl.
Oxygen independent pathway - includes lysozymes, proteolytic and hydrolysis enzymes.
Phagosome + lysosome = phagolysosome

Question 37

What are complement pathways and the 2 ways they’re activated?

Answer 37

20 serum proteins (C1-9 most important).
Alternative pathway - initiated by cell surface microbial constituents (endotoxins).
MBL initiated when it binds to mannose containing residues of proteins found on many microbes.

Question 38

After the complement cascade is activated, what happens?

Answer 38

C5a and C3a recruit phagocytes, C3b and C4b opsonise pathogens, C5-C9 kill pathogens/are part of the membrane attack complex.

Question 39

What groups of chemicals are involved in the innate immune system?

Answer 39

The complement system and cytokines.

Question 40

What are the roles of chemokines/cytokines?

Answer 40

Chemoattraction, phagocyte activation, inflammation.
Actions of macrophage derived TNFa and IL-1 and IL-6:
Make liver produce CRP and MBL (complement activation).
Mobilise neutrophils in bone marrow.
Cause inflammatory reactions of vasodilation, vascular permeability, adhesion molecules and attraction of neutrophils.
Make hypothalamus increase body temperature.

Question 41

Summary of innate immunity:
Innate _____ breached —> entrance and colonisation of _____, complement, ______ (PRR) and mast cell activation - phagocytosis and _______ production, vascular changes and chemoattraction of _____ and ______, fever from ________ and ______ phase response from liver, then local inflammation (signs of which are …).

Answer 41

Barrier
Pathogen
Macrophage
Cytokines
Neutrophils and monocytes
Hypothalamus
Acute
Rubor, calor, Dolor, tumor and loss of function

Question 42

What changes in the innate response could lead to clinical problems?

Answer 42

Reduced phagocytosis from a decreased spleen function.

Decreased neutrophil number or function.

Question 43

What are purposes of the 1st and 2nd lines of defence in innate immunity?

Answer 43

1st (barriers) - limit entry and growth of pathogens.

2nd (phagocytes and cytokines) - contain and eliminate infection.

Question 44

What is the function of acute phase protein CRP?

Answer 44

Opsonin-mediated phagocytosis.

Question 45

Neisseria meningitidis, has a polysaccharide capsule that’s an important virulence factor, why?

Answer 45

It prevents phagocytosis and contributes to the host’s inflammatory response.

Question 46

The chemical composition of Neisseria meningitidis’ capsule defines its serogroup, some of which have the antigenic capsule used as part of their vaccine(ACWY), but serogroup B vaccine does not trigger a good response with this method, what is used instead?

Answer 46

A number of subscapular antigens.