Bacterial infections in the immunocompromised Flashcards
When should you think “could this patient have an immune deficiency”
- every patient who has an infection
- every infection can be viewed as a failure of the immune system
for the majority of infections…
there is a reasonable explanation why the infection occurred e.g.
- Cellulitis - dry skin, infection as portal of energy
- UTI - urinary stasis
- LRTI - architectural or cilia issues
When do you investigate further for immune deficiency
- Consider an immune defect in all patients with infections but particularly in those with infections that are
- recurrent
- severe
- unusual
one aspect of the immune system will…
affect susceptibility to some but not all micro-organisms thus if you have one defect of the immune system you might only be defect to some infections
multiple …
immune defects can and often do co-exist
What is a pathogen
a micro-organism that causes disease
What is a commensal organism
- A microorganism that derives benefit from another organism without causing damage
- e..g Staphylococcus epidermises, pneumocystis jiroveci
What is a primary pathogen
An organism that can cause disease in a healthy host
e. g.
- staphylococcus aureus , Streptococcus pneumonia
What is an opportunistic pathogen
- Pathogen that is generally only able to cause disease in the setting of a weakened immune system and which rarely cause disease in healthy individuals
E.g. - Staphylococcus Epidermidis, Pneumocystis Jiroveci
What is primary immunodeficiency
- Immune defect that the patient is born with
- often due to genetic mutation
- often but not always manifest in childhood
What is secondary immunodeficiency
Immune defect that is associated with or related to another condition
What are the types of secondary immunodeficiency
- Iatrogenic
- Non-iatrogenic
What is an Iatrogenic immunodeficiency
- Immune suppression due to treatment for another condition e.g. steroids, chemotherapy, biologics
What is a non-iatrogenic immunodeficiency
Immune suppression related to a disease process
- cancer
- diabetes
- malnutrition
- infections e.g. HIV, sepsis, post measles
What are the basics of the immune system
- Physical barriers - Skin and mucous membranes
- Innate immune system - phagocytes and complement cascade
- Humeral immunity - B cells and antibodies
- Cell mediated immunity - T cells and cytokines
What is the main function of physical barriers
Prevent the invasion of micro-organisms
Name the main physical barriers
Skin
- low pH
- low free water
- antimicrobial peptides
- cell sloughing
Gut Mucosa
- low pH
- antimicrobial peptides
- cell sloughing
- commensal flora
- tight junctions
Respiratory tract
- ciliated epithelium
- antimicrobial peptides
- cell sloughing
- resident commensals
Urinary tract
- urethral sphincter
- one way flow
- antimicrobial peptides
- cell sloughing
Vagina
- Commensal flora
- pH
What can damage the skin and cause entrance to bacteria
- Surgery, cannula, burns, trauma
Which organisms
- Skin flora
- perineal flora
- environmental usually by inoculation
What can damage the gut mucosa and what organisms infect it
- Chemotherapy, broad spectrum antibiotics (alter the normal flora of the GI tract)
- translocation of normal commensal flora ( gram negative, candida, anaerobes)
What can damage the respiratory tract and which organisms can infect it
- Intubation
- commensals from the respiratory tract and upper GI
- e.g. S.aureus, gram negative, candida
What can damage the urinary tract and which organisms can infect it
- urinary catheter
- perineal flora (gram-negative, candida)
What can damage the vaginal mucosa and which organisms can infect it
- Broad spectrum antibiotics
- candida
How can you prevent damage to physical barriers
- prevent surgical site infection
- prevent line infection = preparation, inspection, care
- catheter associated infection - insertion, secure, need
- ventilator associated pneumonia - PPI, position, cuff
How do you recognise a pathogen
- Pathogen recondition receptors such as TLRs and C-type Lectins recognise PAMPs which are present on pathogens therefore recognise the pathogen
Phagocytes express..
receptors for and can be activated by complement and antibodies - tis links together different aspects of the immune system
What is the main role of phagocytes
- defect against extracellular pathogens
How does a phagocyte kill pathogens
Phagocytosis and intracellular killing
- Phago-lysosmoe fusion and reactive oxygen specific
Release of extraceullar substances
- antimicrobial peptides, NETs
What are the problems associated with phagocyte
defects in numbers or function
What are primary problems associated with phagocytes
- Chronic granulomatous disease
- defects in neutrophil migration and granule release
What are secondary problems associated with phagocytes
- Disease related e.g. AML, Aplastic anaemia, diabetes
- Chemotherapy-associated neutropenia
- impaired neutrophil function e.g. corticosteroids
What is the impact of phagocyte issues
- Increased susceptibility to range of infections
Bacterial
- often associated with breaches in cutaneous and mucosal integrity - gut commensals, line infections, wound infection
Fungal
- candida from GI tract
- Aspergillus from the air
How do you manage phagocytes
- lower index of suspicion for infection
What are the pathways in the complement system
- Classical pathway
- mannose binding lectin pathway
- alternative pathway
What is the classical pathway
C1q binds to antibody-antigen complex
What is the mannose binding lectin pathway
- Binds to repeating sugars
What is the alternative pathway
failure to inactivate the intrinsic activation
What is the role of the complement system in immunity
- trigger other aspects of the immune system - mainly against bacteria
- kill pathogens
What are the three ways the complement system responds
- Opsonisation - complement receptors on phagocytes
- chemotaxis - complement receptors on phagocytes
- Direct killing - C5-9 membrane attack complex
What are primary complement problems
- defect in amount and or function of complement components
What are secondary complement problems
Eculizumab
- monoclonal antibody vs C5
- used for PNH and acute rejection
Autoantibodies e.g. in myeloma
What happens if the complement pathway doesn’t work
- There is a high degree of redundancy in immune pathways around initial immune recognition and immune activation
- the overall impact of complement defects is limited
- defective membrane attack complex is associated with significantly increased risk of Neisseria meningitides infection
How does the humeral immunity system responds to pathogens
- Activated B cells produce antibodies
Binding of antibodies to the antigen leads to
- neutralisation - block binding of pathogens to cels
- complement activation - antigen-Antibody complexes bind to C1q which triggers the classical complement cascade
- opsonisation - Fc portion of the antibody recognised by receptors on phagocytes which leads to increased phagocytosis
- Antibody dependent cytotoxicity: Fc portion of antibody is recognised by NK cells which leads to release of pre-formed granules leading to death of the target cell
What are the types of antibody binding
- blocking
- CDC
- ADCC
- opsonisation and phagocytosis
What is the main roles of humoral immunity
Enhanced killing of extracellular pathogens
- Bacteria and fungi
- parasites (IgE vs multi-cellular helminths)
- +/- virally infected cells
What causes primary humoral immune defects
- Range of primary immunodeficiencies associated with impaired humoral immune response
- SCID, CVID, IgA deficiency
What are the causes of secondary humoral immune defects
- Disease related: CLL
- treatment related: corticosteroids, rituximab
- transplantation: Solid and stem cell
- splenectomy
What organisms tend to evade phagocytosis and complement
- Streptococcus pneumonia
- haemophilus influenza
- Neisseria meningitis
these are encapsulate organisms meaning that they have a thick capsule which helps them avoid phagocytosis and complement
What does IgA deficiency predispose to
- Prediposes to GI infection such as Protozoa (Giardia and cryptosporidium), Bacteria (e.g. Campylobacter) and viruses (e.g. Norovirus)
How do some cells evade the immune system
Cover themselves in carbohydrate capsule
- so no peptide is available
- these are encapsulated bacteria
- essentially invisible to T cells as they only recognise peptides
T cells can only recognise..
Peptides - so T cells can only help B cells when the antigen is a peptide
How have B cells evolved to recognise carbohydrate capsule pathogens
- subset of B cells have evolved to recognise the repeating carbohydrate motifs that make up the capsule of these bacteria
- they are able to be activated without T cell help
- T cell independent
Where do the subset of B cells live that can recognise carbohydrate covered pathogens
- They live in the marginal zone of the spleen and are called splenic marginal zone B-cells
What happens to individuals with no spleen
- individuals with no spleen or with a spleen that doesn’t work will not have any splenic marginal zone B cells
- so therefore they are at increased risk of infection due to encapsulated organisms (S.pneumo, HiB, N.men)
- they are also at risk of more severe infection due to a number of other pathogens e.g. Capnocytophaga, babesiosis and malaria
What are the two types of T cells
- T helper cells - CD4+
- Cytotoxic T cells - CD8+
What are the difference between the two types of T cells
T helper cells
- recognise antigen presented by APC using MHC II antinges from pathogens that have been phagocytksed
- e.g. antigens from pathogens that have been phagocytosed
Cytotoxic T cells
- recognise antigens presented by any cell type using MHC I molecules e.g. antigens from within cell cytsole and are designed to detect intracellular pathogens such as viruses
How do T cells recognise pathogens
- Naive T cells become activated when they recognise there antigen that matches their specific T cell receptor
- T cells require a 2nd single which includes other receptors expressed on the surface of the APC, or cytokines within the localenvironemtn
- the balance of factors at the time the the naive T cel encounters its antigen will either promote or inhibit activation of naive T cells
What does a TH1 cell do
Stimulate APC to kill intra-cellar pathogens by enhancing phagolysosome fusion, production of ROS etc
e.g. TB, salmonella, histoplasmosis, leishmania, toxoplasma
What does a TH2 cell do
Stimulate B cells to make antibodies to act against extracellular pathogens
What does a TH17 cell do
Stimulate epithelial cells to produce antimicrobial peptides to counter pathogens encountered at epithelial and mucosal surfaces
e.g. the skin and respiratory tract
What do CD8 cells do
Kill human cells that are expressing non self antigens including
- antigens derived from pathogens that are infecting and replicating inside the human cell e.g. viruses
- antigens derived from aberrant host cell pathways e.g. malignancy
What are the mechanisms of CD8 cells killing pathogens
- Perforin - makes spores in the cell membrane
- Fas ligand - induces apoptosis
What are the primary cell mediated immune defects
- Most are combined immune deficiencies as T cells are important for B cell development e.g. SCID, IgM, Di-Geroge
What are the secondary cell mediated immune defects
- Disease related: Infection (HIV), malignancy
- treatment related - anti-rejection mediation, steroids, Anti-TNF, stem cell transplant, radiotherapy
- malnutrition
what is the main driver of rejection in a solid organ transplant initially
cell mediated immunity
- mainly via presentation of non self MHC to CD4+ T helper cells by APC and B cells
Describe the order of rejection from the immune system in a solid organ transplant
Initially cell mediated immunity
- mainly via presentation of non self MHC to CD4+ T helper cells by APC and B cells
T cell activation is followed by secretion of cytokines, chemokine and adhesion molecules to promote local inflammation
- this leads to immune mediated damage of the graft
What is the main target of anti-rejection therapies
Main target is the removal or inhibition of T cell activation
- Anti-thymocyte globulin (ATG) and anti-lymphocyte globulin (ALG)
- anti- CD52 - alemtuzumab
name the anti rejection therapies that are used in solid organ transplantation
Inhibition of T cell activation
- anitmetabolites - azathioprine and mycphenolate
- these interfere with DNA synthesis in lymphocytes
Calcineurin inhibitors
- tacrolimus and cyclosporine
- these interference with cell signalling in T cells
mTOR inhibitors
- Limus and everolimus
- interfere with cell signalling in T cells
Inhibition of co stimulation (IL-2 signalling)
- belatacept
Corticosteroids
Why does immune suppression occur with haemipoietic stem cell transplant (HSCT)
- the underlying condition being treated e.g. aplastic anaemia or AML
- chemotherapy to treat the underlying condition prior to HSCT
- chemotherapy to get risk of the current immune cells int he recipient so that the incoming donor stem cells are not rejected
- prevention and treatment of the graft v host
what are the three main time periods in HSCT
- Pre engraftment - transplantation to approximately day 30 - immune system suppressed enough to have the transplantation occur
- Early post-engraftment - from engraftment to day 100 - this is when the transplanted cell begin to make cells
- Late post-engraftment - after day 100
What are the infection risks in an allogenic stem cell transplant
- transplanted cells come rom someone else
- vulnerable to infection from all three time periods
What are the infection risk sin the autologous stem cell transplant
- Transplanted cells come from the patient
- no risk of graft versus host disease
- risk of infection due pre engraftment and early post-engraftment
what are the main issues in pre-engraftment in HSCT
- mucositis
- lines
- neutropenia
- and lymphopenia which arises in day 30
What are the main issues in early post-engraftment in HSCT
- ongoing lymphopenia
- development of graft versus host disease
What are the main issues in late post-engraftment in HSCT
- Slow recover of T and B cells
- graft versus host disease and requirement of immunosuppression
What do you take in a history of someone who has an immunodeficiency
History of pressing complaint
- details of current and past immuno suppression
- details and timing are important - when was the transplant, what immunosuppression drugs are Theon
- prior infection and microbiology results
- vaccines and prophylaxis and are they taking the prophylaxis
- co-mordbities and current medication
How do you investigate immunodeficiency
- routine - FBC, U+E, LFT, CRP
Microbiology and virology
- blood cultures - ideally 2 sets, ideally from the lumen of any line and peripheral
- urine
- resp viral PCR
others directed by symptoms and signs
- stool sample
fungal biomarkers
Imaging
- as directed by signs and symptoms
How can you prevent an person with immunosuppression from becoming ill
- treat the immunodeficiency or try to reduce it
- replacement what is missing - e.g. immunoglobulin replacement
- try to generate a protective response to pathogens the patient may be at risk of acquiring - immunise the patient ideally before the immunosuppression occurs
