Sepsis and The Innate Immune System Flashcards
Sepsis can be caused by the body’s reaction to meningitis, what type of rash would be spotted in this case?
Purpuric rash - non blanching.
What is sepsis?
Life threatening organ dysfunction due to a disregulated host response to infection.
What is septic shock?
Persisting hypotension requiring treatment to maintain blood pressure, despite fluid resuscitation.
What is bacteraemia?
Presence of bacteria in the blood (with or without clinical features).
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?
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.
What makes up the sepsis 6 bundle?
Give oxygen, fluids and IV antibiotics.
Take lactate, urine output and blood cultures (before antibiotics administered).
Give some examples of ‘urgent investigations’ in a case of Red Flag sepsis?
Full blood count (FBC), blood sugar, liver function test - CRP, coagulation studies and other microbiology samples (at site/source of infection).
Neisseria meningitidis - how does it spread, what does it do and give 3 features?
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.
Describe the inflammatory cascade.
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.
What occurs in the inflammatory cascade during sepsis?
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.
What’s the link between sepsis and coagulation?
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.
What could happen if lesions coalesce?
Progressive necrosis, as blood supply is prioritised to the vital organs.
What are the supportive and specific treatments for sepsis?
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.
List some life threatening complications of sepsis.
Irreversible hypotension, respiratory failure, acute kidney injury, raised intracranial pressure, ischaemic necrosis of digits/hands and feet.
How might a diagnosis be confirmed in sepsis?
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).
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.
Negative (coccus often found in pairs) Phagocytosis Endotoxin - kidney shaped bacterium 25 (commensalism in some people) Nasopharyngeal Invasion B 10 Vaccination Notifiable
The 6 most common signs of sepsis are what?
- Mottled/discoloured skin
- Severe breathlessness
- Feeling like you’re going to die
- Not passing urine for a day
- Extreme muscle pain/shivering
- Slurred speech/confusion
What are the factors determining the outcome of the host-pathogen relationship?
Pathogen infectivity, virulence with mechanism of infection am the host’s immune response.
What is the immune system and what are its roles?
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.
What makes an infectious disease?
When a pathogen succeeds in evading or overwhelming a host’s immune defences.
The immune system is split into innate and adaptive. Both halves work towards human survival. State some differences.
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.
What is the innate immune system’s first line of defence and what are the different types?
Physical, physiological, chemical and biological barriers; these are factors which prevent entry and limit growth of pathogens.
List some physical barriers involved in innate immunity.
Skin, mucous membranes of the mouth, respiratory tract, GI tract, urinary tract and bronchial cilia.
List some physiological barriers involved in the innate immune system.
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.
List some chemical barriers involved in the innate immune system.
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.
List some biological barriers involved in the innate immune system.
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.
Give some examples of normal flora inhabiting the body, when do problems arise?
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.
Serious infections may occur in high risk patients. Who may these be?
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).
After the innate barriers as the first line of defence, what comes next?
Phagocytes, chemicals –> inflammation to contain and clear the infection.
What are the basic steps of phagocyte-microbe interaction?
Recognition process and killing.
What are the 2 main types of phagocyte in the body? Describe them.
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).
Aside from marcrophades, monocytes and neutrophils, which cells are involved in innate immunity?
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.
How do pathogens get recognised by phagocytes?
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.
What’s the purpose of opsonisation?
Coating proteins/opsonins bind to microbial surfaces leading to enhanced attachment of phagocytes (and so clearance of microbes).
Give some examples of types of opsonins.
Complement proteins - C3b, C4b, antibodies - IgG, IgM, acute phase proteins - CRP and mannose binding lectin tMBL. They are essential in clearing encapsulated bacteria.
After recognition of pathogens, there is engulfment and degradation by which phagocytotic killing mechanisms?
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
What are complement pathways and the 2 ways they’re activated?
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.
After the complement cascade is activated, what happens?
C5a and C3a recruit phagocytes, C3b and C4b opsonise pathogens, C5-C9 kill pathogens/are part of the membrane attack complex.
What groups of chemicals are involved in the innate immune system?
The complement system and cytokines.
What are the roles of chemokines/cytokines?
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.
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 …).
Barrier Pathogen Macrophage Cytokines Neutrophils and monocytes Hypothalamus Acute Rubor, calor, Dolor, tumor and loss of function
What changes in the innate response could lead to clinical problems?
Reduced phagocytosis from a decreased spleen function.
Decreased neutrophil number or function.
What are purposes of the 1st and 2nd lines of defence in innate immunity?
1st (barriers) - limit entry and growth of pathogens.
2nd (phagocytes and cytokines) - contain and eliminate infection.
What is the function of acute phase protein CRP?
Opsonin-mediated phagocytosis.
Neisseria meningitidis, has a polysaccharide capsule that’s an important virulence factor, why?
It prevents phagocytosis and contributes to the host’s inflammatory response.
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?
A number of subscapular antigens.
