Acute Sepsis In ED / Innate Immunity

Question 1

What is SIRS?

Answer 1

Systemic inflammatory response syndrome is a response to a non-specific insult - e.g. ischaemia, trauma, infection, etc

Question 2

What are the clinical features of SIRS?

Answer 2

Two or more of: Temp: 38°C HR: >90bpm RR: >20/min (or pCO2 12 x 10^9/L

Question 3

What is bacteraemia?

Answer 3

Presence of bacteria in blood. Can be asymptomatic.

Question 4

What is septicaemia?

Answer 4

Generalised sepsis.

Question 5

What is sepsis?

Answer 5

Systemic response to infection: SIRS + documented or presumed infection.

Question 6

What is severe sepsis?

Answer 6

SIRS + organ dysfunction or hypoperfusion (e.g. hypotension).

Question 7

What is septic shock?

Answer 7

Severe sepsis (SIRS + organ dysfunction/hypoperfusion) + persistently low BP (despite giving IV fluid).

Question 8

What is a typical presentation of a person with meningococcal meningitis?

Answer 8

Previously fit and well, then suddenly non-specifically unwell with a high temperature but chills. Headache, nausea and photophobia are common

Question 9

What examinations would you carry out on a person you suspect to have meningococcal meningitis?

Answer 9

Same as SIRS (Temperature; HR / RR; FBC (paying attention to WBC, CRP) + BP).

Check for rashes (in cases of meningococcal meningitis likely to be purpuric or non-blanching) and neck stiffness.

Question 10

Anyone can differentiate between a non-blanching and a blanching rash. How would you do this?

Answer 10

The glass test. Press a clear glass over the rash. If it disappears it is blanching, if you can still see it it is non-blanching. Petechial rashes (found in cases of meningitis, thrombocytopenia and Ehlers-Danlos syndrome) are non-blanching.

Question 11

Which pathogen results in meningococcal meningitis?

Answer 11

Neisseria meningitidis, a gram negative diplococcus with a polysacchardie capsular antigen (preventing phagocytosis). The outermost membrane acts as an endotoxin. *(Group A-C, W-Z with B being the most common in the UK - 10% mortality rate - a vaccine is ready, not provided by NHS. There are vaccines for A, C, W and Y)*.

Question 12

How is neisseria meningitidis usually spread?

Answer 12

Spread by aerosols. This can be through: sneezing, coughing and even prolonged kissing. When acquired, the pathogen may be cleared, carried or invade.

Question 13

Do most people colonised by neisseria meningitidis develop meningococcal meningitis?

Answer 13

No - most people are harmlessly colonised. In those who are however, the disease is rapidly progressive and fatal if not diagnosed and treated promptly.

Question 14

What are other bacterial causes of meningitis?

Answer 14

Streptococcus pneumoniae (affect those in infancy as they have not developed immunity yet) can cause meningitis and is more easily spread.

Question 15

Although not common, meningitis can be caused by viruses. Which viruses can do this?

Answer 15

Mumps (although the MMR vaccine has practically eradicated viral meningitis), enteroviruses (normally mild stomach infection) and Herpes simplex virus.

Question 16

How can neisseria meningitidis be classified? What is the significance of this?

Answer 16

Gram -ve cocci. This means it has a lipopolysaccharide outer membrane, which acts as an endotoxin triggering inflamation.

Question 17

How does the pathogen neisseria meningitidis cause damage to its host?

Answer 17

In addition to the LPS acting as an endotoxin (triggering inflammation), the polysaccharide capsule promotes adherence and prevents phagocytosis. The pilus of the bacteria also enhances attachment.

Question 18

This diagram represents the membrane of a gram +ve bacteria and a gram -ve. Which one is which and why?

Answer 18

The top one is Gram +ve; the bottom one is Gram -ve.
Both have a plasma membrane and a peptidoglycan cell wall (with a periplasmic space in between).
The Gram -ve cell has a lipopolysaccharide capsule surrounding it, which acts as an endotoxin.

Question 19

What is an endotoxin?

Answer 19

A toxin that is released by a bacterial cell when it disintegrates.

Question 20

What is a toxin?

Answer 20

A poison, more often than not produced by pathogens. It acts as an antigen in the body.

Question 21

What is an antigen?

Answer 21

A toxin or foreign body which induces an immune response in the body, usually the production of antibodies.

Question 22

What is the inflammatory cascade initiated by?

Answer 22

Endotoxins binding to macrophages

Question 23

There are three ‘stages’ in the inflammatory cascade. What are these?

Answer 23

LOCAL –> SYSTEMIC –> SIRS

Question 24

What happens in the LOCAL stage of inflammation?

Answer 24

Cytokines (TNFs and ILs e.g. TNf-a and IL-1) are released (as a result of binding of endotoxins to macrophages) to stimulate an inflammatory response, which promotes wound repair and the reticuloendothelial system

Question 25

What is the reticuloendothelial system (or the mononuclear phagocyte system)?

Answer 25

Part of the immune system located in reticular connective tissue that contains phagocytic cells (monocytes and macrophages that accumulate in the lymph nodes and the spleen and Kupffer cells of the liver)

Question 26

How does local inflammation progress to be systemic?

Answer 26

Cytokines are released into circulation stimulating growth factor, macrophages and platelets. The body is aiming to restore homeostasis.

Question 27

How would SIRS come about?

Answer 27

Progression of systemic inflammation when the body cannot restore homeostasis. The cytokines initiate production of thrombin - promoting coagulation. They also inhibit fibrolysis. Leads to microvascular (major cause of shock) thrombosis and increased risk of organ ischaemia, dysfunction and failure.

Question 28

What investigations might you do in someone with meningitis?

Answer 28

FBC, Urea and Electrolytes Blood Gases / PCR Analysis Blood Sugar Liver Function Tests CRP

Question 29

What is 'The Sepsis Six'?

Answer 29

Bundle given to patients within 1 hour of developing sepsis: 1. High flow O2 2. Take blood (and other, e.g. pus) cultures 3. Administer empiical IV antibiotics 4. Measure serum lactate 5. Start IV fluid resuscitation 6. Accurate urine output measure

Question 30

In a case of meningitis, what is the antibiotic of choice?

Answer 30

Usually ceftriaxone - as it penetrates into the CSF and is effective against the majority of causative pathogens.

Question 31

What are some of the life-threatening complications of meningitis?

Answer 31

Life-threatening hypotension, Respiratory failure, AKI, Raised intracranial pressure, ischaemic necrosis of peripheries.

Question 32

How would you confirm a diagnosis of meningitis?

Answer 32

``` Blood culture and a PCR of the blood. Lumbar puncture (only performed once checking contraindications), culturing the CSF (with PCR if necessary). Appearance - turbidity and colour - Microscopy and Gram Staining will be carried out on the CSF. ```

Question 33

How can meningitis be prevented?

Answer 33

Vaccination Prophylaxis (given to close contacts)

Question 34

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

Answer 34

Patient: Level of host response Pathogen: Number of organisms present Mechanism of Infection: Virulence

Question 35

What is the immune system?

Answer 35

Cells and organs that contribute to immune defences against infectious and non-infectious conditions.

Question 36

What is an infectious disease?

Answer 36

When the pathogen succeeds in evading and / or overwhelming the host's immune defences.

Question 37

What are the roles of the immune system?

Answer 37

Pathogen recognition Containing / eliminating the infection Regulating itself - minimum damage to self Remembering pathogens - prevent recurrence of disease

Question 38

What does innate immunity confer to the immune response?

Answer 38

``` Fast response (seconds), recognising groups of pathogens. Lacks memory and cannot change intensity. ```

Question 39

What does adaptive immunity confer to the immune response?

Answer 39

Slower response (3-4 days), specific to one pathogen. It has immunologic memory and increases its intensity.

Question 40

What is the first line of defence of the innate immune system?

Answer 40

The innate barriers which include: Physical Physiological Chemical Biological

Question 41

What are some examples of physical barriers?

Answer 41

Skin Mucosal membranes - Mouth, Respiratory/GI/Urinary tract Bronchial cilia

Question 42

What are some examples of physiological barriers?

Answer 42

Diarrhoea - Food Poisoning, Allergies Vomiting - Food Poisoning, Hepatitis, Meningitis Coughing - Pneumonia Sneezing - Sinusitis

Question 43

What are some examples of chemical barriers?

Answer 43

Low pH - Skin (5.5), Stomach (~2), Vagina (4.4) Antimicrobial molecules - IgA (found in tears, saliva), Lysozyme (sebum, perspiration, urine), Mucous (mucous membranes), Beta-defensins (epithelium), Gastric acid + Pepsin

Question 44

What are some examples of biological barriers?

Answer 44

Normal flora - Non pathogenic microbes in strategic locations (Nasopharynx, Mouth/Throat, Skin, GI Tract). Compete with pathogens for attachment sites and resources. Some produce antimicrobial chemicals and synthesize vitamins (K, B12 etc). They are absent in internal organs

Question 45

What are some examples of normal flora that inhabit the skin?

Answer 45

Staph aureus Strep pyogenes Candida albicans Clostridium perfringens

Question 46

What are some examples of normal flora that inhabit the nasopharynx?

Answer 46

Strep pneumoniae Neisseria meningitidis Haemophilus infleunzae

Question 47

How can clinical problems arise from normal flora?

Answer 47

If normal flora is displaced from its normal location to a sterile (or other) location. If patient is immunocompromised or suppressed (due to antibiotics), normal flora can overgrow, becoming pathogenic.

Question 48

Give examples of how normal flora can become pathogenic through being displaced from its site of origin to a sterile location.

Answer 48

Breaching skin integrity: Burns, surgery, IV lines / drug users Faecal-oral route: Foodborne Infection Fecal-perineal-urethral route: UTIs (women)

Question 49

Give an example of how normal flora can become pathogenic through being displaced from its normal location.

Answer 49

Poor dental hygiene / work: Serious in high-risk patients (asplenic, patients with damaged / prosthetic heart valves - possible infective endocarditis) - Antibiotic prophylaxis is given. Common to have harmless bacteraemia (due to dental extraction, gingivitis etc.)

Question 50

Briefly explain how Infective Endocarditis could come about? What pathogens are prominent causes?

Answer 50

Staph aureus and Strep pyogenes are the most common causative pathogens of infective endocarditis. These pathogens can be inoculated into the body through poor dental work / hygiene. If the patient has damaged / prosthetic heart valves (or a history including infective endocarditis) the pathogen is more likely to adhere to the valves and not be cleared (the damaged / prosthetic valves do not have cilia). The valves do not have their own blood supply. Thus it is difficult to transport WBCs to the site and fight infection.

Question 51

Normal flora may overgrow due to the host being immunocompromised. What common presentations could cause this?

Answer 51

Diabetes AIDS Malignant diseases Chemotherapy (neutrophils)

Question 52

Patients are often given antibiotics. This can lead to a patient becoming immunosuppressed. Normal flora, now, easily outcompetes the pathogens. In some cases, this can lead to an overgrowth of the normal flora which can be harmful. What common presentations could cause this? What type of pathogens result in these presentations.

Answer 52

Severe colitis caused by Clostridium Difficile Vaginal thrush caused by Candida albicans These are opportunistic pathogens

Question 53

The first line of defence of the innate immune response is innate barriers - what is the second line of defence?

Answer 53

Phagocytes & Chemicals --\> Inflammation Together will contain and clear the infection.

Question 54

What are the main phagocytic cells?

Answer 54

Macrophages - present in all organs; ingest and destroy micro-organisms (phagocytosis); present microbial antigens to T helper cells (adaptive immunity); produce cytokines and CHEMOKINES. Monocytes - present in blood (5-7%); recruited at infection site and differentiate into macrophages. Neutrophils - present in blood (60% of leukocytes); increase in number during infection; recruited by CHEMOKINES to site of infection; ingest and destroy pyogenic bacteria: Staph aureus and Strep pyogenes.

Question 55

What is pus?

Answer 55

Pus normally presents as the body's immune system attempts to fend off an infection. It is an accumulation of dead neutrophils.

Question 56

What non-phagocytic cells are involved in innate immunity?

Answer 56

Basophils / Mast cells Eosinophils Natural Killer cells Dendritic cells

Question 57

What are basophils / mast cells functions? How do they differ?

Answer 57

Early actors of inflammation Important in allergic responses They are very similar in both appearance and function. There is one key difference: basophils are found in the blood, mast cells are tissue-resident cells (e.g. mucosal tissue)

Question 58

What do eosinophils do?

Answer 58

Give defence against multi-cellular parasites (helminths).

Question 59

What are Natural Killer Cells?

Answer 59

They are a type of lymphocyte which kill all abnormal host cells (virus infected or malignant). Lymphoid progenitor cells (lymphoblasts) can differentiate into B-lymphoctes, T-lymphocytes and Natural Killer Cells.

Question 60

Where do B lymphocytes mature? What about T lymphocytes?

Answer 60

B-cells mature in the bone marrow. T-cells mature in the thymus.

Question 61

Where is the thymus?

Answer 61

The anterior superior mediastinum - in front of the heart, behind the sternum. It is an important organ in the immune system.

Question 62

What are dendritic cells?

Answer 62

Predominantly found in the skin and in other sites in contact with the external environment (inner lining of nose, lungs etc). They present microbial antigens to T cells. Langerhans cells are a type of dendritic cell (not to be confused with the islets of Langerhans).

Question 63

Pathogen recognition must take place for the phagocyte-microbe interaction to take place. How does this come about?

Answer 63

Pathogen will have PAMPs (pathogen-associated molecular patterns) present: carbs, lipids etc. Phagocyte will have PRRs (pathogen recognition receptors) - 4 types - toll-like being the most significant (e.g. TLR4 = LPS; TLR2 = Peptidoglycan) Opsonins (coating proteins) bind to microbial surfaces leading to enhanced attachment of phagocytes and clearance of microbes (e.g. C3b, IgG). Vital to clear encapsulated (gram negative) bacteria (e.g. strep pneumoniae, neisseria meningitidis, haemophilus influenzae)

Question 64

What proceeds pathogen recognition by phagocytes?

Answer 64

Engulfment and debridement of pathogens.

Question 65

Describe some of the key stages of phagocytosis?

Answer 65

Adherance of microbe to phagocyte - Chemotaxis (release of cytokines/chemokines assist) Ingestion of microbe by phagocyte - becomes a phagosome, then a phagolysosome. This phagolysosome is then digested by enzymes of the phagocyte. Indigestible material - residual body - released as waste.

Question 66

How do phagocytes kill microbes?

Answer 66

Through either oxygen-dependent or independent pathways.

Question 67

What are the oxygen-dependent killing mechanisms that phagocytes can use to kill microbes?

Answer 67

Respiratory burst. Reactive Oxygen Species (e.g. H2O2, OH, NO, O2-) are released which are toxic to the microbes.

Question 68

What are the oxygen-independent killing mechanisms that phagocytes can use to kill microbes?

Answer 68

Lysozyme Lacto/Transferrin Cationic proteins Proteolytic and hydrolytic enzymes

Question 69

What is the complement system?

Answer 69

20 serum proteins (C1-C9 most important) with different antimicrobial actions. C3a and C5a: Recruitment of phagocytes C3b-C4b: Opsonisation of pathogens C5-C9: Killing of pathogens through the Membrane Attack Complex (leads to cell lysis)

Question 70

What are the 2 activating pathways of the complement system?

Answer 70

Alternative pathway: initiated by cell surface microbial constituents (e.g. LPS on gram negative bacteria) MBL pathway: Salmonella spp. and Candida albicans have cell surface proteins containing mannose residues. Pathway initiated by Mannose-binding lectin (MBL), present in the blood, binding to them.

Question 71

What are the anti-microbial actions of macrophage-derived TNF-alpha / IL-1 / IL-6?

Answer 71

Liver: increased CRP & MBL (enhancing opsonisation) Bone Marrow: neutrophil mobilisation Inflammatory Actions: vasodilation, more adhesion molecules - greater attraction of neutrophils Hypothalamus: Increased body temperature

Question 72

How can sepsis be a result of infection?

Answer 72

1. Infection 2. Microbial Toxins 3. Overreaction of TLR-4 (neutrophils, endothelium, monocytes) and complement 4. Excessive Systemic Inflammatory Response (cytokine shower / coagulopathy / vasodilation / capillary leak = tissue / organ hypoperfusion) 5. Sepsis / Septic Shock

Question 73

Reduced phagocytosis causes results in clinical problems. How could this come about?

Answer 73

Asplenia/Hyposplenia Decreased neutrophil count: Chemotherapy / Drugs / Leukaemia / Lymphoma (normal 2.5-7.5 x 10^9 / L; \< 1: significant problems) Decreased neutrophil function: Chronic granulomatous disease (no respiratory burst); Chediak-Higashi syndrome (no phagolysosomes)

Question 74

Summary Of Innate Immunity

Answer 74