Immunology and Microbiology Flashcards
What kinds of local host factors predispose an individual to opportunistic infections?
Anatomical defects
- example: short urethra in females leading to UTIs
Surgical and other open wounds
Burns
Catheterisation (bladder or IV)
Foreign bodies in the body
- example: sutures that contain foreign material provides an environment supportive of opportunistic growth
What kinds of systemic host factors can predisposes an individual to opportunistic infection?
Extremes of Age (via loss of immune function)
Leucopenia
Malignancy
Malnutrition
Diabetes
Liver Disease
Certain infections (i.e immunocompromising HIV infection)
Treatment with antimicrobials (i.e antibiotics to clostridium difficile or altering protective microflora)
Primary immunodeficiencies
Are endogenous or exogenous microbes the most common source of opportunistic infections?
Opportunistic infections are most commonly the result of engoenous /self microbiota
What does the term nosocomial refer to?
Are nosocomial infections more difficult to treat?
Nosocomial refers to microbes and infections typically aquired in an institutional setting.
Institutions include hospitals, aged care facilities etc.
Nosocomial microbe strains are often multiresistant to drug treatments -> are more difficult to treat
Describe the Pseudomonas family of bateria
Pseudomonas are gram negative rods
- Aerobes or facultative anaerobes
- Motile - posses flagelli for movement
- Some species produce pigments -> pyocyan pigment = turquoise/green pus with a foul odour
- Non-fermenting and non-sporing
- Catalase and oxidase positive
- Wide-spread
- Low nutritional requirements
What is the most common and medically significant species of Pseudomonas?
How can this species be subtyped?
Pseudomonas Aeruginosa
Pseudomonas Aeruginosa is further classified according to serotype and seldomly biotype. In epidemiological studies; the species is subtyped into strains via multilocus sequence typing (MLST)
What is the medical significance of Burkholderia Pseudomallei
Burkholderia Pseudomallei is a from a related genera to Pseudomonas.
It causes meliodosis
The symptoms of melioidosis depend on the site of the infection and this can vary. Often it starts as a chest infection with shortness of breath, productive cough and fever
It is a particularly prevalent cause of pneumonia in the Northern Territiory
List three opportunistic pathogens that commonly infect patients with cystic fibrosis
Pseudomonas Aeruginosa
Burkholderia Capacia
Stenotrophomonas Pseudomallei
Describe the epidemiology of Ps. Aeruginosa
Is an environmental microbe widespread throughout nature - especially moist environments
Transient coloniser of skin, mucous membranes and GIT
Is an opportunistic pathogen - particularly in cystic fibrosis patients
An important nosocomial pathogen:
- Traditionally associated with burns and febrile neutropenia
- Currently associated with pneumonia, UTI and sepsis
Aquired from environment and spread on hands and fomites
- Some strains can spread between cystic fibrosis patients
Discuss the resistance associated with Ps. Aeruginosa
All strains of Ps. Aeruginosa are intrinsically resistant to many antibiotics and weak disinfectants
Resistance is also readily aquired from other bacterial via horizontal gene transfer
What diseases are caused by Ps. Aeruginosa?
Superficial Infections:
Skin: wound infections, otitis externa and folliculitis (infection of hair follicules)
Eye: keratinitis, corneal ulcer
Deep or Systemic Infections
Pulmonary: Nosocomial pneumonia, chronic infection in CF patients
Other: UTI, endocarditis, osteomyelitis and septicaemia (immunocompromised patients)
Describe the pathophysiology of Ps. Aeruginosa
- Adheres weakly to intact epithelium via flagella, pili and LPS
- LPS and flagellin bind toll-like receptors; this also upregulates immune system cytokine production
- LPS core binds to CFTR
- In normal people, binding pseudomonas to CFTR is protective -> holds bacteria for macrophages to detroy it. This process is lost in cystic fibrosis patients who have a mutated CFTR gene/protein.
- Once adherent, bacteria produce biofilm
* Ps. Aeruginosa capsule assists adherence and the formation of biofilm.
NOTE: Invasion only occurs in very large numbers
How do the properties of Ps. Aeruginosa change when in biofilm?
Ps. Aeruginosa undergo changes in gene expression when in biofilm. This is a result of quorum sensing.
- Non-motile
- More capsule material / mucoid phenotype
- More adherent
- Less invasive
- Shorter LPS (no O-antigen)
- Slowed growth
- Increased resistance to antibiotics
What factors contribute to the elevated spread of Ps. Aeruginosa
- Reduced PMN / Febrile Neutropenia
- Flagella - more motile
- Production of Exoenzymes: proteases. haemolysins, elastases and phospholipases
- Exotoxins: exotoxin A, exotoxin S and exotoxin U inhibit phagocytosis
- LPS-CFTR mediated invasion - particularly into the cornea
What happens in patients with Cystic Fibrosis?
CF patients have a defect in CFTR which leads to abnormal ion transport, thickened mucus and impaired mucocilliary function
Ps. Aeruginosa and Staph are not inhibited by high salt concentrations
The biofilm state of Ps. Aeruginosa confers resistance to mechanical removal and are less visible to the innate immune system
DNA secreted by bacteria and released from dying cells thicken the mucus further
The bacterial variant that persist are the Pseudomonas bacteria in the biofilm form (the less virulent form)
How is Ps. Aeruginosa controlled?
Ps. Aeruginosa cannot be eradicated from the environment; management must be directed towards preventing infections in the first instance:
- Practice high levels of hand hygiene
- Reduce the risk of susceptible patients to exposure by suitable management of burns, neutropenia, catheters etc.
- Be alert for infections and treat early
- Use contact lenses appropriately
- Life long monitoring and treatment of CF patients
What is the definiion of pyrexia of unknown origin (PUO)?
- Prolonged illness (2-3 weeks duration)
- Fever (>38.3 degrees) on several occasions
- No diagnosis after intelligent investigations
Discuss the homeostasis and normal values of body temperature
Body temperature is kept within a narrow homeostatic range to ensure optimal conditions for metabolic and neuronal activity is maintained.
The average oral temperature range is 35.8-37.8
Body temperature varies in a diurnal pattern -lower in morning and higher in the afternoon (0.5-1.0 variation)
Body temperature is regulated in the anterior hypothalamus by temperature sensitive neurons -> controls the balance between heat loss and production:
- Heat loss via peripheral vasodilation, sweating and reduced physical activity
- Heat conservation via peripheral vasoconstriction, piloerection abd warmth seeking behaviour
- Heat generated through shivering and the release of thyroid hormones, glucocorticoid and/or catecholamines
At what temperature is a fever deemed to occur?
A fever is characterised by:
- Early morning oral temperature > 37.2
- Oral temperature >37.8 any time of the day
There is a margin of error with methods of measuring internal blood pressure as it is difficult to obtain a direct measure:
- Oral temperature < core body temp by 0.5
- Axillary temp < core body temp by 1.0
- Ear probe temp closer to core temp.
*
Describe the processes involved in a febrile response
Why do we have a febrile response?
A febrile response or fever is a mechanism in which the body regulates the immune system to an infective challenge
A rise in core temperature “switches on” a range of immune, endocrine and physiologically mechanism around their optimum activity levels of 39.5 degrees
BUT… it is expensive, in terms of energy, to maintain such a level of metabolic activity to keep temperature at a febrile level,
View attached image outlining the processes leading to fever formation.
What is rigor within the context of a febrile response
Rigor is the feeling of intense coldness which accompanies the onset of a febrile illness.
It occurs because the hypothalamic set point for temperature has been elevated by PGE2and LPS interactions -> but the body has not yet meet this temperature (giving sensation of coldness) before initiating heat elevating behavious including:
- uncontrollable shivering
- striking loss of pallor in face + limbs
- pilo-erection (goose-bumps)
Rigor leaves the sufferer exhausted with a high fever >39 degrees.
What signs and symptoms should alert you to a serious cause of acute fever?
Fever is a common presenting illness of which infection is the most common etiology. These will generally be self limiting viral infections.
Identifying fever occuring as a result of severe and life-threatening infections is crucial. Signs and symptoms of emergency infections include:
- rapid onset/evolution of illness
- rigors
- severe muscle pain
- impaired conscious state
- shock
- cyanosis
- tachyypnoea
- vomiting
- severe headache
- rash
- jaundice
What populations of patients are at risk of developing severe febrile/infectious illnesses?
- Returning from overseas travel
- Asplenic patients
- Neutropaenic patients
- Elderly
- Diabetic
- IVDU
How should life-threatening acute febrile illness be managed?
Investigations
- FBE, CRP, renal function and liver function
- Blood cultures + urine cultures
- Chest x-ray
Empirical IV antibiotics
- if bacterial infection is likely
Admit or prolong stay in ED for observation and review the following day
Important: CRP only raises after the 1st 6-12 hours of infection so patients with severe illnesses can have normal WBC and CRP counts on examination early in disease course
- beware of “normal CRP & WBC” or “improvement with panadol and/or IV fluid” in these patients
What process of clinical reasoning should be applied to pyrexia or unknown origin (PUO)?
- Onset and duration
- Seek localising symptoms
- Establish severity
- Is there really a fever?
- Obtain information and review all results
- Look for clues - past history, family history, medications
- Country of origin
- Travel history
- Occupation, animal exposure
- Sexual history and IV drug use
Epidemiologically, which populations of individuals are at greater risk of developing PUO?
Patients with the following risk factors have a greater incidence of PUO:
- occupation / animal exposure (birds, farms visits)
- country of origin (TB, typhoid, denge, malarial vivax exposure)
- travel - local or OS (even in last two years)
- contact with toddlers (nappies - cytomegalovirus in young baby urine + faeces contracted by parents who develop 2-3 week fever + foetal abnormalities if mother is preganant again)
- risk for Subacute bacterial endocarditis (SBE) (heart murmer, prosthetic valve, pacemaker, IVDU)
- new sexual contacts
- new medications
What investigations should be run in a prolonged fever?
FBE
- atypical lymphocytosis
- neutrophilia
- exclude malaria (particularly OS travel within last few years
_ESR _
- is non-specific
- high with prolonged bacterial infection or vasculitis
- very high in autoreactive immune diseases
CRP
- very high (>200) suggest bacterial infection/inflammation
Chest X ray
- Atypical pneumonia
_Blood + urine cultures _
What are the four most common categories of illnesses that lead to PUO
Infection
Connective Tissue Disorders
Malignancies
Other
List the important **infectious **causes of PUO
Subacute bacterial endocarditis (esp. viridans strep)
- low grade mouth inhabiting organisms lodge on abnormal heart valves. Presents with low grade history of aches alongside fever. Can present with embolism events. Blood cultures + ECG to diagnose
**Tuberculosis **
Intra-abdominal abscess
- may or may not present with abdominal pain or nausea
HIV related opportunistic infection
- like cryptococcus or MAC
Other
- EBV, CMV, Q fever, malaria
Describe the important **connective tissue disorders **that can result in PUO
**Polymyalgia rheumatica **
- extremely high ESR
Vasculitis
Systemic Lupus Erythromatosis
Acute Thyroiditis
- accompanied by muscle stiffness
Gramulomatous Disease
- sarcoidosis, Crohn’s Disease or idiopathic granulomatous hepatitis
Describe the important malignancy illnesses that can lead to PUO
Lymphoma
**Renal Cell Carcinoma **
Hepatoma
Atrial Myxoma
(Note: rarely GI malagnancies)
What additional investigations should be run in PUO following investigations for acute and prolonged pyrexia?
- Repeat and review basic bloods, including blood cultures
- MSU - looking for glomerular RBC
- ANA, Rheumatoid factor, ANCA
- Iron studies (serum ferritin)
- LDH, beta 2 microglobulin
- HIV serology
- Consider serology for EBV, CMV, brucellosis, Q fever, psittacosis, bartonella, syphilis
- Consider TB - Mantoux/gamma IFN assay - not very useful
Discuss the relationship between PUO and immunocompromised HIV or transplantation victims
Immunocomprimised patiets with these conditions ([CD4+] < 200 microlitres) are susceptible to PUO conditions.
Infections are responsible for 80% of these PUO cases -> mycobacterium avium complex is the dominant pathogen
Other causes include Non-hodgkins lymphoma, medications or non-HIV specific endocarditis or syphilis
What applications are immunisations used for?
- To prevent infection
- To treat an infection
- To prevent or treat non-infectious conditions e.g. cancer
- To modify immune responses e.g allergy desensitisation
- Modify physiological processes (more in animals)
What are the three types of immunisation?
Active
Passive - antibodies
Passive - immune cells
Discuss the principles that underpin passive immunisation with Ig
Passive immunisation with Ig is useful in the **prevention and treatment **of many conditions
Ig is sourced from humans (ideally), horses and monoclonal synthesis
There are two types of passive Ig immunisation:
Pooled:
- Ig derived from the plasma of blood donations which is collected form a product to prevent/treat disease
Hyperimmune:
- Screen people for high levels of desired Ig and aquire supplies of Ig from them to be stored for treatment
Passive immunisation with Ig is short lived - immunisation for the life of the antibody molecules ***- and potentially hazardous **due to possible interactions with host cells *
Provide some examples of passive immunisation
Pooled Gamma-Globulin
-
Agammaglobulinaemia
- human origin -> prevention of disease
-
Measles
- human origin ->prevention and modification of disease severity during incubation period
Hyperimmune Globulin
- Hepatitis B
- Varicella
- Rabies
- Tetnus
- Diptheria
- Bites / Stings
mAb
- Autoimmunity
- mouse + human origin -> treatment of condition
What types of **living immunising agents **are used in in active vaccines?
_Unattenuated _
- uses full strength / active pathogens for vaccination that are either obtained from another species or administered via an un-natural route so as to not induce infection/disease
Empirically attenuated
- Don’t know why the pathogens become less virulent
- Take pathogen and grow under abnormal conditions to cause adaptation to new environment = inability to grow in human environment yet retains antigens to trigger immunogenicity
- Difficult to acquire licences now for these vaccines
Rationally attenuated
- Designed vaccines that remove the virulence of pathogens
Reassortments
- Clone genes of multiple microbes into an attenuated microbe -> expresses antigens and develop resistance to multiple microbes
Antigen expressed on living vectors
- Express pathogen antigens on a living vector that is incapable of causing disease
Provide some examples of **living unattenuated vaccines **
Respiratory adenovirus (different route)
Rotavirus (different host)
Provide some examples of living empirically attenuated vaccines
_Viruses _
- Polio
- **Measles **
- Mumps
- Rubella
- VZV
- Rotavirus (rotarix)
- Yellow fever
_Bacteria _
- BCG (Bacillus Calmette–Guérin) vaccine for tuberculosis
- Typhoid (Ty21a)
Provide examples of living rationally attenuated vaccines
Cholera (CVD 103-HgR)
- made it resistant to mercury to use as a marker for the strain
- allowed proof of effect + protection against indemnity
Other vaccines are in development -> likely to be the main type vaccine in the future
Provide examples of reassortment vaccines
**Rotavirus **
Influenza
**Note: **both of these virus families have segmented genomes that easily facilitate the conglomerate vaccination of multiple strains
What are the five types of **non-replicating **vaccines?
- Inactivated virions or bacterium
- Purified product or component of pathogens (may be modified)
- Product of cloned gene
- Synthetic immunogen (experimental)
- DNA vaccine (experimental)
Provide examples of inactivated vaccines
Viruses
- Polio (Salk IPV)
- Influenza
- Hepatitis A
- Japenese encephalitis
- Rabies
Bacteria
- Cholera
- Typhoid
- Pertussis
- Q Fever
Provide examples of **component vaccines **
Viruses
- Hepatitis B
- purified from plasma traditionally but now manufactured from yeast with recombinant DNA
- HPV
Bacteria
-
Pertussis (acellular)
- constucted from 3-5 components including pertussis toxin, filamentous haemagglutinin and pertactin
- Diptheria toxoids
- Tetanus toxoids
-
Capsular Polysaccharides
- 23vPPV (Pneumococcal polysaccharide vaccine) - modified vaccine
- Vi (Salmonella Typhi vaccine)
- Hib vaccine (haemophilus influezae B)
- MenCCV (meningococcus vaccination as part of schedule)
- MenCV (meningococcus vaccination for travellers)
What are the advantages and disadvantages of living vaccines?
_Advantages _
-
Broader immune response
- there are more antigens in the body to mount a response against + more natural immune response
-
Local immunity (sometimes)
- Get immunity at site of infection by the particular organism
- Ease of administration
Disadvantages
-
Disease
-
Back mutations
- living viruses can regain function in the human environment
- Polio vaccine type 2 has a single point mutation that can revert back
- Spread
- pathogen can spread to immunocompromised individuals before the patient can mount an immune response
- Contamination
- other viruses may be included in the tissue culture that the virus is grown on
-
Back mutations
- **Failure **
- Dead
- Living viruses are required to be kept alive - needing a “cold chain” of supply
- Pre-existing immunity
- mount an immune response to the live vaccine which destroys it
- This is often the result of passive immunity (e.g. mothers Ab) - is transitory so the patient does not acquire immunity
- This is why the live measles vaccine is given at 1 y.o
- Interference
- Dead
What are the advantages and disadvantages of killed vaccines?
Advantages
- Stable
- Contamination is unlikely
- Can’t spread
- Safe for immune deficient (not going to replicate and cause disease)
Disadvantages
- Weaker immune responses
- High doses required
- **Need adjuvants **
- this can lead to side effects
- Expensive
What types of factors determine at which stage a person is given a particular vaccine?
The time at which an individual is likely to contract an illness is a major determinant of immunisation timing; for example:
- HepB at the time of birth because it can be acquired in the labour/birthing process
- **23vPPV **at the age of 50
Whether an individual has maternal Ab resistance to a live vaccine:
- **Measles **vaccine given after 1 year of life after maternal antibodies are lost = avoids maternal antibody destruction of measles vaccine.
