CP Immunology - x6 lectures Flashcards
Define - sensitivity
[a/(a+c)]- measure of how good is the test in identifying people with the disease
Define Specificity
[d/(b+d)]- measure of how good is the test at correctly defining people without the disease
Define predictive value
[a/(a+b)]-The proportion of people with a positive test who have the target disorder
Define predictive value
d/(c+d) The proportion of people with a negative test who do not have the target disorder.
Normogram
probability of same finding in patients without disease
Types of diagnosis tests
Non specific - inflammatory markers
Disease specific - autoantibody testing, HLA typing
Non - specific markers of systemic inflammation
ESR CRP Ferritin Fibrinogen Haptoglobin Albumin Complement
Antinuclear antibodies ANA
- origins
LE phenomena detected by Hargraves in 1948
dsDNA identified in 1957
Anti-SM in 1966
Detection of dsDNA and ENA’s
Anti-dsDNA Crithidia luciliae assay (protosoa) Farr assay ELISA ENA’s Immunoblots Individual ELISA’s Combination of antigens >100 different antibodies described in SLE
Rheumatoid Factor
Antibody (IgM, IgG or IgA) directed against the Fc portion of IgG
Commonly found in rheumatoid arthritis but not diagnostic of the diseases (sensitivity and specificity around 70%)
Can be seen with other diseases in which polyclonal stimulation of B cells is seen (chronic infections)
High titters may be pathogenic in vasculitis
What is Anti-CCP (ACPA)
ACPA more specific for RA than Rheumatoid Factor (RF)
Similar Sensitivity to RF
useful prognostic marker
ACPA positive patients tend to have more severe and erosive disease
Anti-neutrophilic cytoplasmic antibodies (ANCA)
- when 1st described
- what specific for?
1982
autoantibody specific for Wegeners granulomatosis
Cytoplasmic cANCA
- what is visible under fluorescence
- what are the target antigens
- Granular fluorescence of neutrophil cytoplasm with nuclear sparing
PR3 (90%)
Azurocidin
Lysozyme (1%)
MPO
Perinuclear pANCA
- what is visible under fluorescence
- what are the target antigens
Nucleus only
MPO (70%) Azurocidin B-glucuronidase Cathepsin G (5%)* PR3
Clinical Utility of ANCA testing
histopathology = gold standard
-ve ANCA assay do no exclude AASV
+ve ANCA with no symptoms - do not continue to treat
Autoimmune Liver disease
Anti-mitochondrial Ab specific for primary biliary sclerosis
Anti-smooth muscle and anti-liver/kidney/microsomal (LKS) Abs, found in autoimmune hepatitis
Antibodies detected by IF screening using rodent tissue block (oesophagus, liver and kidney) and antigen specific ELISA
Autoantibodies - Type 1 Diabetes Melatis
Non pathogenic Several types: islet cell antibodies anti-GAD65 anti-GAD67 anti-insulinoma antigen 2 (IA-2) insulin autoantibodies (IAAs) Disappear with progression of disease and total destruction of β islet cells
role of autoantibodies in diagnosis of type 1 DM
Disease conformation
to identify relatives and patients at risk of developing autoimmune diabetes
Negative predictive value of ICA and IAA is almost 99%
Increased risk of disease development with greater number of different autoantibodies present and younger age of patient
Future of diagnostic testing for autoimmune diseases
Cytokines determination in serum
Detection of antigen specific autoimmune T and B cells
T-reg detection, ? measure of therapeutic response
Personalised medicine, genetic profiling to determine individual risk of the disease and to tailor the most appropriate therapy
Where is the most common genetic susceptibility for autoimmune disease?
HLA region
How can autoimmunity arise
failures in central or peripheral tolerance
causative assoications of autoimmune diseases
Sex (F»M)
Age - +++ elderly
Environment - infection, trauma, smoking
Give an example of a disease that illustrates home many complex factors are required to bring about an autoimmune inflammation
Rheumatoid arthritis
how does autoimmunity cause clinical disease
Autorective B cells and autoantibodies Directly cytotoxic Activation of complement Interfere with normal physiological function Autoreactive T cells Directly cytotoxic Inflammatory cytokine production General inflammation and end-organ dammage
Characteristics of organ specific autoimmune disease
Affect a single organ
Autoimmunity restricted to autoantigens of that organ
Overlap with other organ specific diseases
Autoimmune thyroid disease is typical
Characteristic of systemic autoimmune disease
Affect several organs simultaneously
Autoimmunity associated with autoantigens found in most cells of body
Overlap with other non-organ specific diseases
Connective tissue diseases are typical
Hashimotos thyroiditis
Destruction of thyroid follicles by autoimmune process
Associated with autoantibodies to thyroglobulin and to thyroid peroxidase
Leads to hypothyrodism
Grave’s Disease
Inappropriate stimulation of thyroid gland by anti-TSH-autoantibody
Leads to hyperthyrodism
myasthenic
anti-Ach receptor block the acetylcholine receptor
progressive muscle weakness over the course of the day
Pernicious anaemia
Failure of B12 absorption
Intrinsic factor inhibited by plasma cell secretion
B12 not to absorb
Non-specific markers of systemic inflammation
ESR CRP Ferritin Fibrinogen Haptoglobin Albumin Complement
Treatment for autoimmunity
Supportive
immunosuppression
preventative
Symptoms of systemic lupus erythmatosus (SLE)
photosensitive malar rash multiple mouth ulcers arthralgia alopecia pleural effusion
Anti-nuclear antibodies
nuclei of cells = sequestered antigen
- in SLE antibodies agains proteins and DNA in nuclei of cell created
- Anti-nuclear antibodies bind to skin cells that have been damaged by UV light
- Antinuclear antibodies and antigens = immune complex cause inflammation in ANY tissue
Lupus Nephritis
Immune complex deposition Inflammation Leaky glomerulus loss of renal function scarring irreversible renal failure
Treatment of SLE
Immunosuppression
What is vasculitis
inflammation of small vessels
3 types of ANCA vasculitis
Microscopic Polyangiitis (MPA)
Granulomatosis with Polyangiitis (GPA)
Eosinophilic Granulomatosus with Polyangiitis (EGPA)
Granulomatosis with Polyangiitis
AKA - Wegener’s Granulomatosis
Granuloma - mass inflammed tissue Destructive lesions in: Nose Sinuses Trachea Lung Orbits
Polyangiitis - inflammation vessels Inflammation of small vessels in: Skin Kidney Lung Gut
treatment - immunosuppression
Raynaud’s Phenomen
Primary
- common young F
- ANA negative
- Fairly harmless
Secondary
- ANA postive
- Associated scleroderma, SLE, etc
Scleroderma symptoms features internal organs involvement testing treatment
digital ulcers
lung fibrosis
skin fibrosis
raynauds
Fribrosis affects - lung, gut, kidneys
ANA - looking for anti centromere/anti Scl-70 antibodies
Immunosuppression - usually poor response
Connective Tissue Diseases
Immunity against ubiquious self antigens causes inflammation or fibrosis in ANY tissue
Define allergy and hyersensitivity
Undesirable, damaging, discomfort-producing and sometimes fatal reactions produced by the normal immune system (directed against innocuous antigens) in a pre-sensitized (immune) host.
How many immunopathological classifications
- coombs and gell 1963
- extended classification
4
5
Explain type 1 reaction
e.g. pollen
Anaphylactic IgE exogenous antigen 15-30min response basophils and eosinophil
Explain type 2 reaction
e.g. penicillin
cytotoxic IgG IgM cell surface antigen mins - hours response antibody and compliment
Associated disease
Erythroblastosis fetalis
Goodpasture’s nephritis
Explain type 3
e.g. Mould
Immune complex IgG, IgM soluble antigen 3-8 hours response complement and neutrophils
associated disease
- SLE
Explain type 4
e.g. poison Ivy
delayed type None antibody tissues and organs antigen 48-72 hours monocytes and lymphocytes
How do allergies develop
Barrier dysfunction sensitization changes in T cell subsets, dominated by Th2 IgE ALLERGY
Immune response to parasitic disease
Increased levels of IgE Total Specific to pathogen – cross-reactive Tissue inflammation with: eosinophilia & mastocytosis Basophil infiltration Presence of CD4+ T cells secreting: IL4, IL5 & IL13
hygiene hypothesis
Stimulation by microbes is protective
Epidemiological data – Increase in Allergy
Animal Models – T1DM, EAE, Asthma
Increased atopy (Asthma) after anti-parasitic Rx
Prevention of autoimmunity (Crohn’s) by infections
Pro-biotics in pregnant women
Mechanism – Th1 Th2 deviation
genetic influence on allergic immune response
Polygenic diseases Cytokine gene cluster IL3,5,9,13 IL12R; IL4R FceRI IFNg; TNF
NOT sufficient for disease
ONLY susceptibility
Immune responses
- Allergens
Antigens that initiate an IgE-mediated response
First encounter results in innate & IgM response
Immune response
- conventional immune response
Allergen requires processing
Presentation to T cells & cytokine release
Results in delineation of T-helper subsets into different types
IgE mediated Allergic response
Immunopathogenesis IgE Ab mediated mast cell and basophil degranulation- release of preformed and de novo synthesized inflammatory mediators Clinical features Fast onset (15-30 min) Wheal and flare Late phase response Eosinophils Central role for Th2 T cell
Role of Th2 T cell
Multiple cytokine release
Innate inflammatory response
Drive for immunoglobulin production
what is the ATOPIC triad
Asthma
rhinitis
eczema
Allergic Rhinitis
Nasal congestoin, mucus, polyps, nasal inflammation, tonsillar and adenoidal enlargement
Perennial/seasonal
House dust mite, animal danders, pollens
Treatment - Antihistamines, nasal steroids
Allergic Asthma
Airway inflammation, airway constriction and hyperactivity
In childhood - Aeroallergic stimuli- house dust mite
Immediate symptoms IgE mediated
Damage to airways - late phase response
Damaged airways - Hyper reactive to allergic stimuli
Atopic Dermatitis
Contact - allergic/non allergic
Clinically - intense itching, blistering, weeping
House dust mite - TRIGGER
Treatment - topical steroids, moisturisers
Anaphylaxis
an acute potentially life threatening IgE mediated systemic hypersensitivity reaction
Diagnosis of anaphylaxis
History Specific IgE (>0.35 KuA/L) Skin prick test (>3mm wheal) SPT Video Intra-dermal test Oral challenge test – Gold standard Basophil activation test Component resolved diagnostics
Basophil activation test
cross-linking of membrane-bound IgE, basophils upregulate the expression of specific activation markers such as CD63, CD203c and the expression of the inhibitory receptor CD300a. The exact mechanisms that govern basophil degranulation remain elusive, but it has been demonstrated that phosphorylation of p38 MAPK exerts a pivotal role in cell activation.
Treatment for anaphylaxis
Antihistamine, steroids, adrenaline
Immunotherapy - for life threatening reactions, severe hayfever, animal fur
Not good - multiple allergies, food, allergic rashes
Food allergy
MAJOR FOOD ALLERGENS Water soluble glycoproteins 10 - 60 kd COW’S MILK EGG LEGUMES - PEANUT; SOYBEAN; TREE NUTS FISH CRUSTACEANS / MOLLUSCS CEREAL GRAINS
clinical manifestations of food allergy
Gastrointestinal vomiting, diarrhoea, oral symptoms Respiratory (upper & lower) rhinitis, bronchospasm Cutaneous urticaria, angioedema role of food in atopic dermatitis unclear Anaphylaxis
Pattern Recognition receptors PRR
Toll-like receptors (TLR’s), NOD-like receptoes (NLR’s), RigI-like receptors (RLR’s) C-type lectins (CLR’s), scavenger receptors
Antimicrobial peptides
-Defensins, -defensins, cathelin, protegrin, granulsyin, histatin, secretory leukoprotease inhibitor, and probiotics
Cells
Macrophages, dendritic cells, NK cells, NK-T cells, neutrophils, eosinophils, mast cells, basophils, and epithelial cells
Complement components
Classic and alternative complement pathway, and proteins that bind complement components
cytokines
Autocrine, paracrine, endocrine cytokines that mediate host defense and inflammation, as well as recruit, direct, and regulate adaptive immune responses
B Lymphocytes
develop potential to secret antibodies: humoral immunity
Killer/cyotoxic T lymphocytes
lymphocytes are able to kill. Cellular immunity
helper T lymphocytes
secrete growth factors (cytokines) which control immune response: Help B lymphocytes and T lymphocytes (Helper T cells are target of HIV
suppressor T lymphocytes
may damp down immune response
binding of antibodies to antigens does the following
Neutralizaion agglutination of microbes precipitation of dissolved antigens activation of complement system leads to cell lysis enhances phagocytosis
Immunodeficiency
where the immune system is not effective enough to protect the body against infection
Can be argued that infection is always the result of transient immunodeficiency.
Usually secondary to the effects of external factors
Some are primary immunodeficiencies caused by genetic defects in individual components of the immune system.
The type of infection is a guide to underlying cause.
Laboratory tests confirm.
Acquired Immunodeficiency
Many causes; transient or long-lasting; minor or major.
Stress
Surgery/burns
Malnutrition
Cancer – especially lymphoproliferative disease
Immunosuppressive effect of drugs inc. cancer therapy
Lymphocytes
Neutrophils
Primary Immunodeficiency
Very rare
Extensively studied - give important clues to the working of the immune system - experiments of nature.
Often diagnosed in early childhood but can present in adult life
Recurrent infection often suggests immunological problem
Chronic Granulomatous disease
Osteomyelitis Pneumonia Swollen lymph nodes Ginigivitis Non-malignant granulomas Inflammatory bowel disease
Defects in b cells
Lead to different degrees of loss of antibody secretion.
Usually leads to recurrent bacterial infection with pyogenic organisms.
Usually diagnosed at around 1-2 years since maternal IgG protects.
Treat with antibiotics then iv IgG For life.
Most are very serious
some less serious e.g IgA deficiency.
1 in 5-700 not severely immunodeficient
Primary B cell deficiencies
Common Variable Immunodeficiency X-linked agammaglobulinaemia Autosomal recessive Hyper IgM syndrome IgA Deficiency IgG Subclass Deficiency Transient Hypogammaglobulinaemia of infancy
Defects in T cells
Usually more dramatic since B cells also need T cell help.
Symptoms are recurrent infection with opportunistic infections, bacteria, viruses,
Fungi (candida), protozoa (pneumocystis).
Defects in both B and T
Severe Combined Immunodeficiency (SCID) syndromes
Combined Immunodeficiency syndromes
Bone Marrow Transplantation curative
Gene therapy
Primary T cell deficiencies
Severe Combined Immunodeficiency syndromes
Adenosine Deaminase Deficiency
Purine Nucleoside Phosphorylase Deficiency
MHC Class II Deficiency
Wiskott-Aldrich Syndrome
Define immunomodulation
The act of manipulating the immune system using immunomodulatory drugs to achieve
a desired immune response.
A therapeutic effect of immunomodulation may lead to immunopotentiation, immunosuppression, or induction of immunological tolerance.
Name 7 mechanisms of immumodulation
Immunization Replacement therapy Immune stimulants Immune suppressants Anti-inflammatory agents Allergen immunotherapy (desentization) Adoptive immunotherapy
Define Immunomodulators
Medicinal products produced using molecular biology techniques including recombinant DNA technology
what are the classes of immunomodulators
Substances that are (nearly) identical to the body’s own key signaling proteins
Monoclonal antibodies
Fusion proteins
Describe Adalimumab
Human IgG1, monoclonal Ab,
constant human domain Fc but with human variable domain in Fab’ region
Describe Infliximab
Chimeric mouse human IgG1 monoclonal antibody,
human constant domain and murine variable domain
Describe Etanercept
Fusion Protien, Fc-TNFR3 extracellular domain,
Describer Cetrolizumab
humanised monovalent Fab-PEG - contains polyethylene glycol (PEG) moiety, human constant domains and human constant domains with murine variable domain
Define Passive Immunization
transfer of specific, high-titre antibody from donor to recipient. Provides immediate but transient protection
Problems with passive immunisation
risk of transmission of viruses
serum sickness
types and uses of passive immunisation
pooled specific human immunoglobulin animal sera (antitoixins and antiveninins)
Uses
Hep B prophylaxis
Botulism, VZV in pregnancy, diphtheria, snake bites
Define active immunisation
simulate development of protective immune response and immunological memory
What is active immunogenic material
Weakened forms of pathogens
Killed inactivated pathogens
Purified materials (proteins, DNA)
Adjuvants
What are problems with active immunisation
Allergy to any vaccine component
Limited usefulness in immunocompromised
Delay in achieving protection
What are replacement therapies and immune stimulation
-Pooled human immunoglobulin (IV or SC) Used in Rx of antibody deficiency states
-G-CSF/GM-CSF
Act on bone marrow to increase production of mature neutrophils
-IL-2 (Stimulates T cell activation- rarely used)
-α-interferon (Main use in treatment of Hep C)
-β-interferon (Used in therapy of MS)
-γ-interferon
Can be useful in treatment of certain intracellular infections (atypical mycobacteria), also used in chronic granulomatous disease and IL-12 def
What can be used for Immunosuppression
Cortocosteroids Cytotoxic/ agents Anti-proliferative/activation agents DMARD’s Biologic DMARD’s
how do corticosteroids work
Decreased neutrophil margination
Reduced production of inflammatory cytokines
Inhibition phospholipase A2 (reduced arachidonic acid metabolites production)
Lymphopenia
Decreased T cells proliferation
Reduced immunoglobulins production
what are the side effects of corticosteroids
Carbohydrate and lipid metabolism Diabetes Hyperlipidaemia Reduced protein synthesis Poor wound healing Osteoporosis Glaucoma and cataracts Psychiatric complications
What are cortico steroids used for
Autoimmune diseases CTD, vasculitis, RA Inflammatory diseases Crohn’s, sarcoid, GCA/polymyalgia rheumatica Malignancies Lymphoma Allograft rejection
What are T cell targeted immunosuppression straregies
Anti- IL-2 receptors mAbs
CyA Tacrolimus
Sirolimus
Azathioprine MMF
What drugs target lymphocytes
Antimetabolites
- Azathioprine (AZA)
- Mycophenolate mofetil (MMF)
Calcineurin inhibitors
- Ciclosporin A (CyA)
- Tacrolimus (FK506)
M-TOR inhibitors
-Sirolimus
IL-2 receptor mABs
- Basiliximab
- Daclizumab
What do Calcineurin inhibitors do
CyA
Binds to intracellular protein cyclophilin
Tacrolimus (FK506)
Binds to intracellular protein FKBP-12
Mode of action
Prevents activation of NFAT
Factors which stimulate cytokines (i.e IL-2 and INFγ) gene transcription
T cell effects
Reversible inhibition of T-cell activation, proliferation and clonal expansion
Sirloins *(rapamycin)
how does it work
Macrolide antibiotic
Also binds to FKBP12 but different effects
Inhibits mammalian target of rapamycin (mTOR)
Mode of action
Inhibits response to IL-2
T cell effects
Cell cycle arrest at G1-S phase
Side effects of calcineurim / mTOR
Hypertension Hirsutism Nephrotoxicity Hepatotoxicity Lymphomas Opportunistic infections Neurotoxicity Multiple drug interactions (induce P450)
What are the clinical uses of calcineurim/mTOR
Allograft rejection
Autoimmune diseases
Antimetabolites, how do they work?
-AZA
-MMF
T and B cell effects
Inhibit nucleotide (purine) synthesis
AZA
Guanine anti-metabolite
Rapidly converted into 6-mercaptopurine
MMF
Non-competitive inhibitor of IMPDH
Prevents production of guanosine triphosphate
T and B cells effects
Impaired DNA production
Prevents early stages of activated cells proliferation
What does Methotrexate MTX do
What does Cyclophosphamide
Folate anatagoinists
Cross link DNA
What are the cytotoxic side effects
ALL Bone marrow suppression Gastric upset Hepatitis Susceptibility to infections Cylophosphamide Cystatis MTX pneumonitis
What are the clinical uses of cytotoxic drugs
AZA/MMF
Autoimmune diseases (SLE, vasulitis, IBD)
Allograft rejection
MTX
RA, PsA, Polymyositis, vasculitis
GvHD in BMT
Cyclophosphamide
Vasculitis (Wagner’s, CSS)
SLE
What are biologic DMARD’s
- Disease modifying anti rheumatic drugs
Anti-cytokines (TNF, IL-6 and IL-1) Anti-B cell therapies Anti-T cell activation Anti-adhesion molecules Complement inhibitors
Anticytokines
Anti-TNF
Anti IL-6
Anti IL-1
Anti-TNF
First biologics to be successfully used in therapy of RA (5 different agents now licensed)
Used in a number of other inflammatory conditions (Crohn’s, psoriasis, ankylosing spondylitis)
Caution: increase risk of TB
Anti-IL-6 (Tocilizumab)
Blocks IL-6 receptor
Used in therapy of RA and AOSD
May cause problems with control of serum lipids
Anti-IL-1
3 different agents available (anakinra, rilonacept and canakinumab)
Used in treatment of AOSD and autoinflammatory syndromes
Rituximab
Chimeric mAb against CD20- B cell surface
First approved in ’97 for treatment of chemotherapy resistant DLCL
Many uses:
Lymphomas, leukaemias
Transplant rejection
Autoimmune disorders
Adoptive Immunotherapy
2 examples,
uses
Bone marrow transplant (BMT) Stem cell transplant (SCT) Uses Immunodeficiencies (SCID) Lymphomas and leukemias Inherited metabolic disorders (osteopetrosis) Autoimmune diseases
Immunomodulators for allergy
examples
Immune suppressants
Allergen specific immunotherapy
Anti-IgE monoclonal therapy
Anti-IL-5 monoclonal treatment
allergen specific immunotherapy indications mechanisms routes side-effects
Indications:
Allergic rhinoconjutivitis not controlled on maximum medical therapy
Anaphylaxis to insect venoms
Mechanisms:
Switching of immune response from Th2 (allergic) to Th1 (non-allergic)
Development of T reg cells and tolerance
Routes:
SC or sublingual for aero-allergens
Side-effects:
Localised and systemic allergic reactions
What is Omalizumab
mAb against IgE
Used in Rx of asthma
Also useful in Rx of chronic urticaria and angioedema
May cause severe systemic anaphylaxis
What is Mepolizumab
mAb against IL-5
Prevents eosinophil recruitment and activation
Limited effect on asthma
No clinical efficacy in hypereosinophilic syndrome
Who discovered MHC
Peter Alfred Gorer
What is MHC
- set of genes found in all vertebrate species
- expressed at cell surface and function to present self/nonself antigens for T cell antigen receptor inspection
- highly polymorphic
- 50,000 – 100,000 MHC on average cell
The Human MHC
6p21.3
3.6Mbp long
aka Human Leucocyte Antigens complex
3 regions
class 1 - HLA-A,B,C (classical antigents
Class 2 - HLA-DR,DQ,DP antigens
Class 3 - HSP70, TNF, C4A, C4B,C2,BF, CYP21
Class 1 genes 3-6kb
Class 2 genes 4-11 kb
Where are class 1 and class 2 antigens found
Class 1
all nucleated cells
Class 2
primarily B lymphocytes, can be inducted on T lymphocytes
Both membrane bound glycoproteins
What are Class 1 associated with what are class 2 associated with
Class 1 - MHC encoded 45kb heavy chain non covalently associated with non polymorphic B2 micro globulin
Class 2 - MHC encoded 31-34 kd associated with A chain non covalently assoicated with 26-29 kd B chain
How is HLA inherited
Mendelian inheritance, codominant expression, all inherited antigens are displayed on cell surface - HLA phenotype
Why is HLA polymorphism significant
capacity of individual to mount immune response in response to antigenic challenge
HLA Matching
Serology - Broad
HLA-A2, A9; B27, B15, DR1, DR2
Serology - Split
HLA-A2, A23(A9); B27, B62(B15); DR1, DR15(DR2)
HLA-A2, A24(A9); B27, B63(B15); DR1, DR16(DR2)
Molecular - Low
HLA-A02, A23; B27, B15; DRB101, DRB115
HLA-A02, A24; B27, B15; DRB101, DRB1*16
Molecular - High
HLA-A02:01, A23:01; B27:01, B15:01; DRB101:01, DRB115:01
HLA-A02:02, A23:02; B27:02, B15:02; DRB101:02, DRB115:02
What is sensitisation
any even which elicits a HLA direceted immune response,
pregnancy, blood transfusion, transplantation
looked for by
serum screening
cross matching
What is a hyper acute rejection
Activation clotting cascade, activation of complement
What are the innate defences of the body
Skin, interferons, compliment, lysozyme, mucous membranes,
normal commensal flora
what are the classification of immunodeficiencies
congenital/primary
acquired/secondary
Neutrophil defects
Qualitative
Chemotaxis – rare, congenital, inadequate signalling, abnormality in receptors or NE movement
–Killing power - 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
Neutorphil defect
quantitative
eg - cancer treatment, bone marrow malignancy, aplastic anaemia caused by drugs
“Neutropenic”
Esp. imp. when 50% will dvlp an infection. Highly lethal if not treated quickly with correct antibiotics – empirical therapy, >50% those with Pseudomonal infections will die in 24hrs if not treated
T cell deficiencies
Congenital – rare
Acquired – drugs e.g. ciclosporin after transplantation (decreases graft versus host disease and rejection), steroids
Acquired – viruses e.g. HIV
T cell deficiencies caused by opportunistic pathogens examples bacterial, viral, fungal
May be intracellular
BACTERIAL – Listeria monocytogenes (food), Mycobacteria – MTB, MAI
VIRAL – e.g. leukaemia and transplanted pnts - HSV, CMV (pre–emptive treatment), VZV. Serological testing, prophylaxis and treatment with e.g. aciclovir and ganciclovir
FUNGAL – e.g. Candida spp., Cryptococcus spp.
T cell deficience caused by Cryptoporidium pram
- route
- recovery
- treatment
– Sporozoa – oocysts shed by cattle/humans.
Faecal oral route.
Most patients recover after prolonged illness of up to 3 wks.
May take much longer in T-cell deficient pnts – if at all. Symptomatic treatment only (in most cases)
T cell deficiency causes by Toxoplasma gondii
- Family
- route
- presentation
Sporozoa.
Cats. Humans infected by contact with cat faeces/ or from e.g. transplanted heart with the bradyzoites present.
May present with lesion in brain and neurological signs.
(most immunocompetent pnts are asymptomatic)
T cell deficiency causes by Stronglyoides stercoralis
- Family,
- Route
- presentation
- suspected in which patient (pnts) groups
Nematode.
Larvae penetrate skin, migrate. Normal pnts aymptomatic or rash of Larva Currens but immunocompromised get multiplication, huge invasion of tissues, eosinophilia.
May get Gram negative septicaemia as larvae move. Suspect in pnts from tropical countries or old POW pnts.
What is hypogammaglobulinaemia
Antibody problems
Congenital - rare
Acquired – multiple myeloma, chronic lymphocytic leukaemia, burns
Usually encapsulated bacteria e.g. S. pneumoniae in the resp. tract or e.g. Giardia lamblia or Cryptosporidium in GIT
what is complement deficiency
Hereditary, rare
Encapsulated bacteria. Need complement to help kill organisms. Earlier defect in pathway then greater no. of orgs may infect.
Classical and Alternative
e.g. C5-8 then Neisseria meningitidis is important – lysis not achieved via membrane attack complex as MAC not formed. 50-60% pnts will have 1 episode of disease in life
Frequent, serious S. pneumoniae infections as poor quality opsonisation
Why would you need a splenectomy?
What are the implication of a splenectomy
Spleen - source of complement and antibody producing B-cells, removes opsonised bacteria from blood.
Causes - traumatic, surgical or functional e.g. sickle cell anaemia
Streptococcus pneumoniae, Haemophilus influenzae type B, N. meningitidis, malaria
Implications
High mortality, vaccination, prophylactic penicillin, education – seek help if unwell
Immunocompromised after organ transplantation
Liver in HCV/paracetamol OD (solid organ transplants)
Stem cells in haematological malignancy.
Anti-rejection treatment suppresses cell mediated immunity to stop effects of cytotoxic and natural killer cells. Degree of immunosuppression varies on how closely the donor and recipient are matched.
Management of infection in immunocompromised patients
Treat the known infection – empirical, need specimens from likely site of infection to guide therapy
E.g. remove catheters
Reverse defect if possible/stop immunosuppression
How to investigate infections
History and examination
Urgent diagnosis and treatment
Blood cultures. Occasionally bone marrow cultures
Respiratory samples – esp. induced sputa, bronchoalveolar lavage and lung biopsy. Microscopy - Gram, ZN, fungal and silver stains. Viral immunofluorescence. Bacterial culture including Legionella, TB. Fungal culture, viral culture +/- PCR. Histology.
Other samples as systems suggest e.g. urine
Serology samples (e.g. Toxoplasma spp.) +/- PCR. Aspergillus antigen +/- PCR
(surveillance cultures)
Imaging studies e.g. X ray/CT chest, MRI
How to prevent infection in immunocompromised patients
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
