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DJ - ESA 3 - Infection > Acute Sepsis In ED / Innate Immunity > Flashcards

Acute Sepsis In ED / Innate Immunity Flashcards

1
Q

What is SIRS?

A

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

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2
Q

What are the clinical features of SIRS?

A

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

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3
Q

What is bacteraemia?

A

Presence of bacteria in blood. Can be asymptomatic.

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4
Q

What is septicaemia?

A

Generalised sepsis.

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5
Q

What is sepsis?

A

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

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6
Q

What is severe sepsis?

A

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

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7
Q

What is septic shock?

A

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

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8
Q

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

A

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

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9
Q

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

A

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.

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10
Q

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

A

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.

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11
Q

Which pathogen results in meningococcal meningitis?

A

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)*.

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12
Q

How is neisseria meningitidis usually spread?

A

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

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13
Q

Do most people colonised by neisseria meningitidis develop meningococcal meningitis?

A

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

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14
Q

What are other bacterial causes of meningitis?

A

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

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15
Q

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

A

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

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16
Q

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

A

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

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17
Q

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

A

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.

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18
Q

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

A

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.

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19
Q

What is an endotoxin?

A

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

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20
Q

What is a toxin?

A

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

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21
Q

What is an antigen?

A

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

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22
Q

What is the inflammatory cascade initiated by?

A

Endotoxins binding to macrophages

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23
Q

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

A

LOCAL –> SYSTEMIC –> SIRS

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24
Q

What happens in the LOCAL stage of inflammation?

A

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

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25
Q

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

A

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)

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26
Q

How does local inflammation progress to be systemic?

A

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

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27
Q

How would SIRS come about?

A

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.

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28
Q

What investigations might you do in someone with meningitis?

A

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

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29
Q

What is ‘The Sepsis Six’?

A

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
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30
Q

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

A

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

31
Q

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

A

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

32
Q

How would you confirm a diagnosis of meningitis?

A 
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.
33
Q

How can meningitis be prevented?

A

Vaccination
Prophylaxis (given to close contacts)

34
Q

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

A

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

35
Q

What is the immune system?

A

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

36
Q

What is an infectious disease?

A

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

37
Q

What are the roles of the immune system?

A

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

38
Q

What does innate immunity confer to the immune response?

A 
Fast response (seconds), recognising groups of pathogens.
Lacks memory and cannot change intensity.
39
Q

What does adaptive immunity confer to the immune response?

A

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

40
Q

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

A

The innate barriers which include:
Physical
Physiological
Chemical
Biological

41
Q

What are some examples of physical barriers?

A

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

42
Q

What are some examples of physiological barriers?

A

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

43
Q

What are some examples of chemical barriers?

A

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

44
Q

What are some examples of biological barriers?

A

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

45
Q

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

A

Staph aureus
Strep pyogenes
Candida albicans
Clostridium perfringens

46
Q

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

A

Strep pneumoniae
Neisseria meningitidis
Haemophilus infleunzae

47
Q

How can clinical problems arise from normal flora?

A

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.

48
Q

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

A

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

49
Q

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

A

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.)

50
Q

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

A

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.

51
Q

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

A

Diabetes
AIDS
Malignant diseases
Chemotherapy (neutrophils)

52
Q

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.

A

Severe colitis caused by Clostridium Difficile
Vaginal thrush caused by Candida albicans

These are opportunistic pathogens

53
Q

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

A

Phagocytes & Chemicals –> Inflammation

Together will contain and clear the infection.

54
Q

What are the main phagocytic cells?

A

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.

55
Q

What is pus?

A

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

56
Q

What non-phagocytic cells are involved in innate immunity?

A

Basophils / Mast cells
Eosinophils
Natural Killer cells
Dendritic cells

57
Q

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

A

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)

58
Q

What do eosinophils do?

A

Give defence against multi-cellular parasites (helminths).

59
Q

What are Natural Killer Cells?

A

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.

60
Q

Where do B lymphocytes mature? What about T lymphocytes?

A

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

61
Q

Where is the thymus?

A

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

62
Q

What are dendritic cells?

A

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).

63
Q

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

A

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)

64
Q

What proceeds pathogen recognition by phagocytes?

A

Engulfment and debridement of pathogens.

65
Q

Describe some of the key stages of phagocytosis?

A

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.

66
Q

How do phagocytes kill microbes?

A

Through either oxygen-dependent or independent pathways.

67
Q

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

A

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

68
Q

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

A

Lysozyme
Lacto/Transferrin
Cationic proteins
Proteolytic and hydrolytic enzymes

69
Q

What is the complement system?

A

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)

70
Q

What are the 2 activating pathways of the complement system?

A

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.

71
Q

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

A

Liver: increased CRP & MBL (enhancing opsonisation)

Bone Marrow: neutrophil mobilisation

Inflammatory Actions: vasodilation, more adhesion molecules - greater attraction of neutrophils

Hypothalamus: Increased body temperature

72
Q

How can sepsis be a result of infection?

A
  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
73
Q

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

A

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)

74
Q

Summary Of Innate Immunity

A

DJ - ESA 3 - Infection (12 decks)

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