week 4 transplant and infection in immunocompromised people Flashcards
What technique identified blood group substances in the cell membrane of all vascular endothelial cells, and certain epithelial cells?
Immunofluorescent staining
What type of isoagglutinins do normal individuals have?
Have naturally occurring anti-A or anti-B
What is the prognosis for transplants performed between blood group incompatible individuals?
Poor outcome
What is MHC?
Set of genes found in all vertebrate species
What is the function of MHC?
Important role in immune function, disease susceptibility and reproductive success.
Where are the proteins of MHC expressed and what is there function?
Proteins encoded by the MHC are expressed at the cell surface and function to present ‘self’ and ‘nonself’ antigens for inspection by T cell antigen receptor
How many MHC molecules on a average cell?
50,000 – 100,000 MHC molecules on the average mammalian cell –> big target for the immune system to see if the cells are foreign or not
What is the role of MHC in transplantation?
Role in histocompatibility, major influence on graft survival.
What does Histocompatibility mean?
Compatibility between the tissues of different individuals, so that one accepts a graft from the other without giving an immune reaction.
Is MHC polymorphic?
Very
What 3 divisions is MHc divided into?
class I region encodes HLA-A, B, C (‘classical’) antigens
class II region encodes HLA-DR, DQ, DP antigens
class III region encodes HSP70, TNF, C4A, C4B,
Which of the classes of MHC is not important in transplantation?
class 3
On what chromosome is MHC found?
Short arm of chromosome 6 (6p21.3
Class 1 and 2 MHC genes are roughly how many kb?
Class 1 - 3-6kb
Class 2 - 4-11kb
What is the human version of MHC?
Human Leucocyte Antigens
On what cells is class 1 MHC found?
found on all nucleated cells –> involved in endogenous antigens
On what cells is class 2 MHC found?
primarily expressed on B lymphocytes but expression can be induced on T lymphocytes and other cells
What is the structure of HLA class 1 and 2?
Membrane bound glycoproteins Have a rough structure of different domains making up a discrete protein binding groove
How is HLA inherited?
Mendelian inheritance
En-bloc from each parental chromosome
Each individual inherits two antigens at a given locus.
Codominant expression. All of the inherited antigens are displayed on the cell surface
Is the level of HLA same throughout the body and what affect does this have?
The level of expression of HLA is at different levels across tissues, has implications for the transplanted tissue
What makes MHC highly polymorphic?
Large number of allelic variants at each locus
How is the high polymorphic state of MHC maintained?
Allelic variation maintained at population level due to survival advantage
Why is it significant that there is high polymorphism in MHC?
Significant in terms of capacity of individual to mount an immune response in response to an antigenic challenge
What are the different types of HLA Matching?
Serology (Broad)
Serology (Split)
Molecular (Low)
Molecular (High)
What is the process of forein MHC recognition in direct recognition during transplantation?
1) WBC of donor migrate to the recipient
2) Donor WBC interacts directly with recipient T cell, presenting transplant Ag
3) Recipient T cell now recognises donor antigens
4) T cells proliferate and kill donor tissue Only happens in transplant situation, an unusual immunological process
What is the normal immunological process when the transplant tissue is rejected?
Indirect recognition?
1) Foreign Ag presented to recipient T cells by recipient APCs 2) Recipient T cells now recognise donor antigens and proliferate 3) Donor tissue killed This is a normal immunological process
What is sensitisation?
Any event which elicits an HLA directed immune response
Why is sensitisation important in tissue transplant?
Aswell as determining donor HLA, need to determine the HLA to which the recipient has already been exposed and ‘sensitised’ and see if the recipient is already sensitised to any donor HLA
What process make someone more prone to sensitisation?
Pregnancy –> any women gone through pregnancy will become sensitised to foregin HLA
Blood transfusion
Transplantation
How is sensitation tested?
Serum screening
Crossmatching
What does the cRF% tell you in terms of sensitisation in transplant?
CrF% tells you Tells you the percentage of donors that would be inaccessible to a recipient based on the recipients pre-sensitisation
What happens in Hyperacute rejection?
Anastamosis between donor and recipient vessel 2) Recipient blood flows in and binds to HLA on donor vascular cells 3) Get activation of clotting cascade 4) And complement activation 5) Lose endothelial integrity and damage to donor tissueGet coagulation, the new organ gorgeous in blood becomes necrotic disseminated intravascular coagulation can kill the patient
What two process are activated in hyperaacute rejction?
Activate clotting cascade
Activate complement
What are the chances of 2 siblings being perfectly matched?
1 in 4
What are the chances of 2 siblings being completely mismatched?
1 in 4
What are the chances of 2 siblings being partially matched?
1 in 2
Give examples of Innate defences
Skin
Interferons, complement, lysozyme, acute phase proteins
Mucous membranes (tears, urine flow, phagocytes)
What is the possible outcome when normal gut flora is disrupted by broad spectrum antibiotics?
C. difficile and Candida spp can be caused.
What other factors other than broad spectrum antibiotics can disrupt the normal gut flora?
Extremes of age, pregnancy, malnutrition
What are the 2 Classification of immunodeficiencies?
Congenital or primary
Acquired or secondary
What are the two defects of neutrophils?
Qualitative defects (e.g. lose ability to kill or chemotaxis) or Quantitative defects (less present) --> not enough NE
Which of the two defects of neutrophils is more common?
Quantitative defects
Qualitative defect of chemotaxis causes problems in what process? How common is it and how is it acquired?
Inadequate signalling,
Abnormality in receptors
NE movement
Rare and congenital
Qualitative defect of neutrophils causes defect in killing power. What disease does it cause and why? What does the patient become at risk of?
Inherited
Chronic Granulomatous Disease.
NE fail to mount a respiratory burst in phagocytosis. Deficient in NADPH oxidase so hydrogen peroxide not formed.
At risk of Staph. aureus infections
What are the causes of quantitative neutrophil defet?
cancer treatment, bone marrow malignancy, aplastic anaemia caused by drugs
At what point is the level of neutrophils so low that the person is at extreme risk of infection?
What is Neutropenic ?
The presence of abnormally few neutrophils in the blood, leading to increased susceptibility to infection.
Another name for quantitative defect of neutrophils
What percentage of pople will get a infection with quantitative defect?
> 50% will dvlp an infection. Highly lethal if not treated quickly with correct antibiotics – empirical therapy,
What infection will cause over 50% of people with quantitative defect to die within the 24hrs of getting the infection?
Pseudomonal infections
What bacterial infections are neutropenic patients at risk of?
Gram negative bacilli (e.g E. coli),
Gram positive cocci (e.g. S. aureus ) -
Often normal flora E.g. Coagulase negative staph
What fungal infections are neutropenic patients at risk of?
Candida spp. , Aspergillus spp.
What is the treatment for neutropenic?
Broad spectrum Ab.
An aminoglycoside and an antipseudomonal penicillin
What is the reason for giving antipseudomonal penicillin to a person with neutropenic?
Due to the risk of pseudomonal infection
What is 2nd line of defence for neutropenic pateints?
Carbapenem, then antifungals, remember viruses
What is the use of granulocyte stimulating factors for neutropenic patients?
Drugs to give that make the immune system working again
How common is congential T cell defeciency?
Rare
What are the causes of acquired T cell defeciency ?
Drugs e.g. ciclosporin after transplantation (decreases graft versus host disease and rejection), steroids
Viruses e.g. HIV
What bacterial infections are patients with T cell defeciency at risk at?
Listeria monocytogenes (food), Mycobacteria – MTB, MAI
What are the common viral infections when a person has T cell defeciency?
Herpes simplex virus , Cytamegalovirus , Varicella zoster virus
What is the treatment for people who are T cell defecient and have a viral infection?
Serological testing, prophylaxis and treatment with aciclovir and ganciclovir
What are the common fungal infections when a person has T cell defeciency?
Candida spp., Cryptococcus spp.
What is the fungus causes meningitis in patients with HIV?
Cryptococcus spp.
What two protozoa infections are common in patients with T cell defeciency?
Cryptosporidium parvum and Toxoplasma gondii
What family are Cryptosporidium parvum and Toxoplasma gondii from?
Sporozoa
How is Cryptosporidium parvum spread and how does it infect humans?
Oocysts shed by cattle/humans.
Faecal oral route.
How long does symptoms last on healthy people and people with T cell defeciency who are infected by Cryptosporidium parvum ?
Normal healthy people can be ill to up to 3 weeks
People who are T cell defecient can take a lot longer or may not recover at all
What is the treatment for Cryptosporidium parvum ?
Symptomatic treatment only
How is Toxoplasma gondii spread and how does it infect humans?
By cats
Humans infected by contact with cat faeces/ or from transplanted heart with the bradyzoites present.
What symptoms may be present from a person infected with Toxoplasma gondii?
May present with lesion in brain and neurological signs
What is a common parasitic infection of people who are T cell defecient?
Strongyloides stercoralis
What family is Strongyloides stercoralis from and how does it spread?
Nematode.
Larvae penetrate skin, migrate.
What is the symptoms of healthy patients and patients with T cell defeciency when they are infected by Strongyloides stercoralis ?
Normal patients are aymptomatic or rash of Larva Currens ( condition of itchyness)
T cell defecient patients: get multiplication, huge invasion of tissues, eosinophilia.
In a patient who is immunocompromised what secondary bacteria infection may they get from Strongyloides stercoralis?
May get Gram negative septicaemia as larvae move.
In which patients should you suspect strongyloides infection?
1) Pnts from tropical countries 2) Old POW pnts
What is Hypogammaglobulinaemias?
Abnormal low levels of all classes of immunoglobulins
Is Hypogammaglobulinaemias congenital?
Yes but its very rare
What are the acquired causes of Hypogammaglobulinaemias?
multiple myeloma,
chronic lymphocytic leukaemia,
burns
What is the common bacterial infection of a person with Hypogammaglobulinaemias?
S. pneumoniae in the respiratory tract
Haemophilus influenzae type B, N. meningitides
What is the common parasitic infection of a person with Hypogammaglobulinaemias?
Giardia lamblia or Cryptosporidium in GIT
What is the treatment of Hypogammaglobulinaemias?
Immunoglobulin replacement
Is complement defeciency acquired or Hereditary?
It is Hereditary but rare
Why can’t patients with complement defeciency deal with encapsulating bacteria?
Need complement to help kill organisms. Earlier defect in pathway then greater no. of orgs may infect.
Why will a patient with complement defeciency get frequent serious S. pneumoniae infections?
Due to infections poor quality opsonisation
Why is it difficult in dealing with Neisseria meningitidis for a compement defecient patient?
If you have problem with C5-8 then Neisseria meningitidis is important – lysis not achieved via membrane attack complex as MAC not formed.
50-60% patients will have 1 episode of disease in life
Pateints with complement defeciency of C5-8 will commonly get infected by what bacteria?
Neisseria meningitidis –> gram negative bacteria
What is the role of the spleen in the support of the immune system?
Spleen - source of complement and antibody producing B-cells, removes opsonised bacteria from blood.
What are the caues of Splenectomy?
Causes of the removal of spleen - traumatic, surgical or functional e.g. sickle cell anaemia
What 4 infections are patients who have had Splenectomy are at a particular risk of acquiring?
Streptococcus pneumoniae,
Haemophilus influenzae type B,
N. meningitidis,
Malaria
What are the 3 preventive/treatment measures for a person wtih splenectomy?
vaccination,
prophylactic penicillin,
education
What is Biologics?
Antibodies or other peptides which inhibit inflammatory cytokine signals
Give examples of Biologics?
Tumour necrosis factor or TNF, inhibiting T-cell activation, or depleting B-cells.
What does biologics increae the risk of?
Risk of tuberculosis, herpes zoster, Legionella pneumophila, and Listeria monocytogenes
Should patients with T cell deficiency be given vaccines?
No
What infections can take place at different points during a transplantation?
1) The initial disease (e.g. HBV, liver transplant)
2. Surgery and hospital admission (e.g. ventilator acquired pneumonia, S. aureus wound infection)
3. Organ receipt (e.g. Toxoplasmosis, CMV), patient matching
4. Opportunistic infection during initial immunosuppression (initial 3/12, e.g. CMV, Aspergillus)
5. Later opportunistic infection (after 3/12, e.g. Zoster, Listeria)
What is the treatment protocal for a person who is immunocompromised and gets an infection during transplantation?
Treat the known infection – empirical, need specimens from likely site of infection to guide therapy
Remove catheters or other possible infection risks
Reverse defect if possible/stop immunosuppression
How do you investigate infections for people who are immunocompromised?
History and examination
Urgent diagnosis and treatment
Blood cultures. Occasionally bone marrow cultures
Respiratory samples – esp. induced sputa, bronchoalveolar lavage and lung biopsy.
Other samples as systems suggest
Serology samples
Imaging studies
What are the measures in preventing infection in people who are immunocompromised?
Hand washing /aseptic technique / protective isolation / HEPA air filtration (allografts)
Vaccines (avoid live vaccines in T-cell deficient)
Prophylactic antimicrobials (e.g. penicillin, septrin, aciclovir) and passive immunoglobulin
Special diet
Is a splee a secondary or primary lymphoid organ?
Secondary lymphoid organ
What is biologics used for?
Used in treating Rheumatoid arthritis
What type of patients will need stem cell transplant?
Patients who have had leukaemia
