CSP3 Flashcards
Define hypersensitvity
Damage to a patient caused by the immune system
Define allergy
Subdivision of hypersensitivity
- unecessary immune response against foreign antigen (type 1 hypersensitvity)
Type 1 hypersensitvity
IgE mediated
Mast cells
Anaphylaxis
Type 2 hypersensitvity
Autoantibodies against self structures
Type 3 hypersensitivity
Immune complex mediated
Type 4 hypersensitvity
T cells and macrophages
With out without granulomas
Type 5 hypersensitivity
Stimulatory autoantibodies
Graves’
What stimulates mast cells?
Antigen binding to IgE on surface
Complement activation = C5a, C3a
Nerves = axon reflex sensory nerves, substance P
Direct stimulation
Diagnostic test for anaphylaxis
Tryptase
C4 not consumed (low)
D dimers high
Causes of anaphylaxis
- arthropod venoms (bee, wasp, stings)
- drugs (ABs, insulin, ACTH, suxamethonium)
- foods (peanute, shellfish, egg, milk, latex, kiwi, alpha gliadin)
Differentials of anaphylaxis
MI PE Hyperventilation Hypoglycaemia Phaeo Angioedema
Define anaphylactoid reactions
Direct or indirect activation of mast cells without IgE
Still tryptase positive as involve mast cells
Same treatment as anaphylaxis
Triggers of anaphylactoid reactions
Vancomycin, NSAIDs, opiates, anaesthetic agents
Srawberries
Exercise, cold, trauma
Immune complex reactions to blood products
Scromboid reactions define
Massive ingestion of histamine from decayed mackerel/other oily fish
Tryptase negative as mast cells not involved
Urticaria
Chronic if >1 month but can be acute
Wheals/hives/raised itchy
Mast cells, histamine, leukotrienes
Dermis inflammation
Causes of urticaria
Allergic triggers
Direct contact - grass, latex
Allergic normally acute
Infections = viral, parasites
Autoimmune = vasculitis, SLE, type 3 hypersensitivity (normally chronic)
Autonomic = with heat/sweating, adrenergic with stress
Physical = sunlight/pressure/vibration/heat
Exercise: within hours of a meal
Hormonal: menstrual cycle link, steroid use
Mast cell disorders: urticaria pigmentosa
Iron/folate/B12 deficiency
Cold urticaria
Cryoglobulinaemia
Other autoimmune = SLE, leukaemia
Can cause Raynaud’s phenomenon
Can be inherited = C1AS1 gene mutation
Treatment of urticaria
Antihistamines - up to 4x recommended dose
Can add H2 antagonist (ranitidine)
Add montelukast
Progress to omalizumab (before was cyclosporin)
Treat lymphomas/autoimmune diseases accordingly
Non sedating antihistamines
Cetirizine
Loratidinde
Fexofenidine
Sedating antihistamines
Chloramphenamine
Define angioedema
Swelling of subcutaneous tissues
Causes of angioedema
Allergic (accompanied by urticaria)
Anaphylaxis/anaphylactoid syndromes
Hereditary
Hereditary Angioedema Type 1
C1 esterase inhibitor
Restraint on complement and bradykinin pathways
Hereditary Angioedema Type 2
C1 esterase inhibitor mutation
Hereditary Angioedema Type 3
Mutation of factor XII initiating bradykinin pathway and intrinsic clotting pathway
Acquired C1 esterase inhibitor deficiency
Angioedema but not hereditary as acquired
Autoimmune, haem malignancy, cryoglobulins, Heb C/B/Helicobacter
Idiopathy angioedema
Normal C1 esterase inhibitor level
treatment of angioedema
If allergic - same as anaphylaxis and urticaria
C1 inhibitor deficiency = anabolic steroids (tranexamic acid)/C1 inhibitor IV or SC
Idiopathic = tranexamic acid, icatibant SC inhibits bradykinin pathway
Allergic conjunctivitis, rhinitis, sinusitis
Type 1 hypersensitivity
IgE mediated
Antigens for allergic conjunctivitis/rhinitis/sinusitis
Grass pollens Tree pollens Seasonal exposure Animal danders House dust mite
Diagnosis of allergic conjunctivitis/rhinitis/sinusitis
Mainly History Seasonal = pollens, hayfever Skin prick IgE specific test May develop nasal polyps
Treatment for allergic conjunctivtis, rhinitis, sinusitis
Topical/systemic antihistamines
Topical mast cell stabilisers
Topical steroids
Antigen exclusion
Causes of rhinitis & sinusitis
Infections - common Vaso-motor rhinitis Non ellergic rhinitis with eosinophilia (NARES) Drusg = alpha agonist sprays, cocaine Irritant fumes/solvents Wegner's Septal deviation/foreign bodies Late pregnancy oestrogens CSF leak
Define atopy
Genetic predisposition to make IgE antibody against common environmental antigens
Associated with hayfever, childhood asthma and atopic dermatitis
Atopic dermatitis
Dry cracked itchy raised lesion Extensor surfaces first then flexures and cheeks Genetic component Filaggrin mutation IgE>1000 raised Staph infections of affected areas Increased eosinophils and mast cells
Aspirin sensitivity
Can cause angioedema
Triad = asthma, nasal polyps, sinusitis
Can enhance ability of other allergens to cause anaphylaxis
Nasal polyps
May need surgery
Topical steroids
Avoid aspirin and salicylates in food(tea/coffee/spices/tomatoes/cider/wine/mints)
Oral allergy syndrome
Itching and local swelling in oropharynx within minutes of eating
Rarely progresses to urticaria & angioedema and maybe anaphylaxis
IgE Type 1
Antigens for oral allergy syndrome
Fresh fruit/veg and cross react with pollens so often have hayfever too
treatment for oral allergy syndrome
Avoid foods
Cooked normally ok
Food allergy symptoms
Gut pain, bowel changes, vomiting Urticaria Angioedema Within minutes Anaphylaxis? Enteritis if eosinophillic gastropathy HISTORY crucial Skin prick tests avoidance Steroids
Latex allergy
Gloves, medical products, condoms Cross reactions = bananas/avacado/kiwi IgE mediated against latex protein (plant based) Contact urticaria Asthma Angioedema Anaphylaxis Rhino-conjunctivitis Skin prick Specific IgE testing
Drug allergies - penicillin
type 1 = anaphylaxis
2 = haemolytic anaemia
3 = serum sickness
4 = interstitial nephritis
+ erythema multiforme & Stevens Johnson
other drug allergies
Co-trimoxazole Sulphonamide Insulin = urticaria, anaphylactic like Anesthetics = measure tryptase DRESS syndrome = weeks after rash/fever/lymph, eosinophillia
Extrinsic allergic alveolitis
Type 3 inhaled foreign antigens occupational 6 hours after, worst at 24-48 fever, cough, SOB asthma may develop type 4 chronic exposure - interstitial pulmonary disease
Allergic bronchopulmonary aspergillosis
Type 3 & 1
Wheeze, cough, fever, haemoptysis
Can dev. bronchiectasis
High IgE and IgE
Serum sickness
Infused human or serum products Monoclonal AB Type 3 Fever, urticaria, vasc., lymph, poly-arthritis 7-14 days post primary exposure 1-3 days after secondary exposure
Contact hypersensitivity
Type 4 Nickel allergy topical drugs leather dyes chromium cement latex and rubber hair dyes/fragrance plants sunlight may be required to trigger sensitivity
Special tests overall
HISTORY!!! Skin prick tests Specific IgE in vitro tests Autoantibody screen Patch testing Tryptase D-dimers Complement - C3, C4, C1q, C2, C1q autoantibodies
Extracellular pathogen targets
Blood
Lymph
Interstitial spaces
Epithelial surfaces
Intracellular Pathogen targets
Cytoplasmic
Vesicular
When does adaptive immune response begin?
Innate immune response begins first
Then reaches threshold where pathogen level increases where adaptive is activated
Immune response from a cute
- wound bleeds washing out foreign bodies
- resident macrophages and injured tissue initiate inflammatory response
- interleukins and cytokines activated- specificaly IL1,6,8 and TNFalpha
How are interleukins actiavted?
TLR recognise pathogen features
TLR1 & 2
Gram positive
bacterial products
yeast
TLR3
dsRNA
TLR4
LPS
Gram negative
TLR5
Flagellin
TLR6
Complex
With TLR2
TLR7 & 8
ss RNA
TLR9
bacterial DNA
What do interleukins then do?
Inflammation Driving innate immune response Fluid enters site Clot forms sealing wound NK cells, neutrophils, macrophages and IgM attracted
How does innate immunity initiate adaptive
Dendritic cells phagocytose bacterial antigen
Become APC
How does a dendritic cell mature?
Immature releases LPS which is detected by TLR4
Moves from tissues to lymph nodes
What do dendritic cells do once matured?
Activate naive T cells binding to them via MHC
CD4+ differentiate to either Th1 or Th2 effector cells
CD4+ to Th1
Via IL12
CD4+ to Th2
Via IL4
What produces IL4
Parasitic worms via IgE
What produces IL12
Dendritic cell
Function of Th1 cells?
Produce IFNgamma which:
cell mediated immunity
helps cytotoxic T cells and macrophages
Function of Th2 cells?
Produce IL4,5,13
Humoral Immunity
Help B cells for antibody production via plasma cell production
TB Leprosy
Th1 dominant response IFN-gamma Activated macrophages Low organism number Limited disease
Lepromatous Leprosy
Th2 dominant response IL4,5,13 Hyperglobulinemia High no. of organisms Disseminated disease
Cutaneous leishmaniasis
boils
Th1 dominant
limited
Visceral lieshmaniasis
Black Fever
Th2 dominant
Disseminated
Miliary TB
Th2 dominant
Disseminated
Memory cells
Fraction of activated T and B cells become memory cells
Provide long lasting immunity
Stored in bone marrow and lymph nodes
Features of bronchial asmtha
Mucus hypersecretion
Airway inflammation
Bronchial hyper-responsiveness
Acute attacks of SOB and airway obstruction due to SM contraction
2 phases of asthms
1 = early bronchospasm 2 = late inflammation
Spasmogens examples asthma early phase
Histamine
Methacholine
Histological asthma chages
Goblet cell hyperplasia
Thick sub-basement membrane
Cellular infiltrate
IgE production is asthma
Dendritic cells present allergen to T and B cells at LN
- T helper switch to B cells via IL4,13 and CD14 on B cells bind to ligand on T cells
Role of IgE in asthma
Binds to IgE receptors on mast cells via FcR1
Binds to low affinity receptors on lymphocytes, eosinophils, platelets and macrophages via FcR2
Role of mast cells
Release mediators:
- histamine
- leukotrienes
- cytokines
Early effects of mediators
bronchospasm
OEdema
Airflow obstruction
Late effects of mediators
Airway inflammation
Airway obstruction
Airway hyper-responsiveness
Eosinophils
- originate in bone marrow
- IL3 and 5 regulate
- leukotriene source
- contain proteins which damage epithelium
Terminal differentiation of eosinophils
By GM-CSF & IL5
- IL5 prolongs survival
- Increased IL5 associated with tissue eosinophilia
- Anti-IL5 therapy = mepolizumab, reslizumab
Lymphocytes
Surface activation markers
CD4+ Th1 - IL2 and IFNgamma
Th2 - IL4,5,6,9,13
GATA-3 mRNA
TF confined to Th2 in asthmatics
Factors favouring Th1 phenotype
Presence of older siblings
Early exposure to day care
TB, measles, Hep A
Rural environment
Factors favoring Th2 phenotypes
Widespread AB use Western lifestyles Urban environment Diet Sensitization to house dust mites and cockroaches
Define immunodeficiency
Suboptimal resistance to infectious disease
Primary & secondary
Primary immunodeficiency
Genetically mediated = X linked agammaglobulaemia, Di George
Idiopathic = Common variable immune deficiency
Secondary Immunodeficiency
Infections = AIDS Malignant = lymphoma, myeloma, leukaemia Metabolic = DM Trauma = burns Treatment caused = cytotoxic drugs, glucocorticoids, irradiation AB loss = nephrotic syndrome
- more common than primary
B lymphocyte & AB deficiency
Pneumococcus Haemophilus Staphylococcus Moraxella Strep Neisseria Mycoplasma Enteroviruses Norovirus Rhinovirus
Otitis Media Sinusitis LRTI Meningitis Septicaemia Septic arthritis Osteomyeltiis Abscess
X Linked Agammaglobulaemia
- no antibodies
- no B lymphocytes
- defective tyrosine kinase gene for B lymphocytes
- very rare
- boys>
- 2nd 6m of life with chest infections/ear/sinusitis
- will get worse infections if not treated -> bronchiectasis
- die in childhood or early adulthood if not treated
- can also get viruses
Treatment of X linked agammaglobulaemia
AB replacement - almost all IgG
AB when necessary
Then normal lifespan
Common Variable Immune Deficiency
- not common
- any time presents
- small degree of inherited
- B lymph normal/low/absent
- low AB
- impaired immunisation response
- T lymph may be affected
- autoimmunity associated?/granulomatous disease?
- get infections like X linked
- severity depends on AB levels
- Need AB replacement ASAP
Isolated AB class deficiency
IgA = low or absent with normal IgG and IgM
- at any time
- often healthy otherwise
- RTI, intestinal infections
- v. rare IgM inherited deficiencies, aut recessive in consanguineous families
Secondary AB deficiency causes
- drugs
- nephrotic syndrome = urine low
- protein losing enteropathy = loss into bowel lumen
- malignancies = lymphomas (with T lymp defect)
- cytotoxic therapy + immunosuppressive = with T lymph deficiency and neutrophil deficiency
- rituximab = B lymphocyte depletion so specific AB deficiency
Fungi causing T lymphocyte deficiency
Pneumocystis jeroveci Candida Cryptococcus Histoplasma Skin
Protozoa causing T lymphocyte deficiency
Cryptosporidium = diarrhoea
Toxoplasma
Viruses causing lymphocyte deficiency
Herpes Simplex, Zoster
CMV
EBV
HHV 8
Mycobacteria causing T lymphocyte deficiency
Atypical
Di George Syndrome
Primary T lymph deficiency cause
- chromosome 22 partial deletion
- pharyngeal 3rd & 4th arch defects
- no thymus or parathyroids
- vessel abnormalities
- facial abnormalities
- complete thymus absence = complete T lymph absence
- often incomplete thymus = T lymph gradually improves with age
Nucleoside phosphorylase and adenine deaminase deficiency
T lymph deficiency primary cause
- enzymes specific to T lymph
AIDS
- caused by HIV
- T lymph deficiency
- retrovirus
- CD4 targeted
- now antiretroviral treatment
Diagnostic test of AIDS
AB to HIV
p24 viral antigen
HIV RNA
Neutropenia
- oral soreness/gingivitis/pharyngitis
- then URTI/LRTI
- soft tissue infections and abscess
- septicaemia
Bacteria causing neutropenia
Gram negative aerobic rods = pseudomonas, E Coli, entrobacteria, enterococci
Non beta haemolytic strep
Staph - epidermidis, saprophyticus
Fungi causing neutropenia
Candida spp.
Aspergillus spp.
Dermatophyte fungi
Primary causes of neutropenia
Rare genetic syndromes: Cyclical neutropenia Severe congenital neutropenias Kostmann syndrome Chronic benign neutropenia
Secondary causes of neutropenia
Marrow aplasia Haem malignancies Drugs - cytotoxic therapy Autoimmune - anti-neutrophil AB Infections
Chronic granulomatous disease
Neutrophil function defects
- X linked recessive
- boys
- childhood presentation
- pneumonia/infective arthirits/abscess/skin infections
- end as granulomas
Test for chronic granulomatous disease
Nitroblue tetrazolium test
OR
Dihydrorhodamine test
Normal phagocytes decolourise dyes, patients’ do not
Treatment fro chronic granulomatous disease
AB
IFN
Bone marrow transplant
Leukocyte Adhesion Deficiency (LAD)
Very rare aut recessive CD18 deficiency Associates with CD11 forming beta 2 integrin (neutrophil adhesion molecule) Failure of umbilical cord to slough
Test for LAD
CD11/18 expression measured
Treatment for LAD
AB
Bone marrow or stem cell transplant
Possible mechanisms for diabetes causing infections
Neutrophil function impaired
Microcirculation impaired
Body fluids more nutritious for bacteria
Complement defects
Genetic
Lupus like picture
Meningitis danger
Often healthy individual
Low C3
Bacterial infections
Tests for complement defects
C3 and C4 routine
C1q
C2
Factors H,I,B
Angioedema
ACEi can cause
Absent/small spleen
Congenital
Infarcted in SC
Hyposplenism in coeliac
Removed for hereditary spherocytosis and lymphoma, trauma, idiopathic thrombocytopenia, hypersplenism
Typical infections causing absent/small spleen
Septicaemia Pneumococcus Haemophilus Meningococcus Malaria
Treatment for absent/small spleen
Prophylaxis AB = pen V or macrolide
Vaccines - pneumococcal, meningococcal, Haem Infl.
Better before splenectomy
Carry INFO CARD
Defects of anatomical innate immune system
CF Bronchiectasis Urinary Outflow Obsrtuction Cilia defects = Kartagener's syndrome and smoking Burns/wounds Poor phlebotomy, catheterisation Indwelling lines
Reticular Dysgenesis
- severe combined immune deficiency
- rare genetic syndrome
- only red cells and platelets present in blood
- few days of life before overwhelming infection
- sterile isolation needed until bone marrow transplant
SCID
Severe combined immune deficiency
- have phagocytes
- no B or T lymph
- 2 years of life with AB support in sterile isolation
- need bone marrow transplant
Hyper IgM syndrome
- very rare
- inherited defect
- loss of signal from activated CD4 T helper cells to APCs
- no B cell class switching
- High IgM, low G and A
- pneumocystis carinii
- mutation of CD40 ligand on T lymph is commonest cause, X linked
- CD40 lack on APC is rarer cause, aut recessive
Hyper |gE syndrome
Job’s syndrome if STAT3 mutation
- eosinophilia
- facial and skeletal abnormalities
- eczema, staph infec, candida, pneumonia
Wiskott-Aldrich syndrome
X linked
- defective cytoskeletal protein found in haemoapoetic cells
- thrombocytopenia = bleeding
- affects B and T lymph & phagocytes
- ear, sinuses infections, lymphomas
Chediak-Higashi syndrome
- defect moving material into lysosomes
- phagocyte affected
- affects production of cytolytic granules in T lymph and NK cells
- neutropenia
- peripheral neuropathy
- bacterial infections and fungi
Ataxia telangectasia
aut recessive defect in ATM gene for DNA repair - whites of eyes = telangectasia - T & B lymph affected - infections, lymphoma, leukaemia
Secondary causes of combined defects
- common
- gluco-corticosteroids
- azathioprine
mycophenolate
MTX
Ciclosporine
Tacrolimus
Inflixmab block TNF
Ix for immunodeficiency diseases
FBC
ESR & CRP
U&E, LFT, bone profile, TFT
C3 & C4, C1q, C2, C1 esterase inhibitor
Mannose binding ligand
Immunoglobulins - IgG, A, M
Specific AB to infections before and after immunisations,
CD3,4,8,19,56
Measure T lymph proliferation response to stimulation
Neutrophils number
genetic tests
Infections = cultures, swabs, HIV, Hep B and C, EBV, CMV, imaging
Define commensal organism
Micro-organism that derives benefit from another organism without causing damage
Define primary pathogen
Cause of disease in healthy hosts
Iatrogenic causes of immunodeficiency
2ry cause
Treatments - steroids, chemo
Non iatrogenic causes of immunodeficiency
2ry cause
due to disease process
Which organisms damage skin barrier and how?
Flora
Perineal flora
Bacillus fungi
Via surgery, trauma, burns, cannula
Which organisms damage mucosa barrier and how?
Normal commensal flora translocate Gram negative Candida Aerobes Via chemo, broad spectrum AB
Which organisms damage resp tract barrier and how?
Intubation
From GI and URT secretions
Candida
Gram -ve
Which organisms damage urinary tract barrier and how?
Catheter
Perineal flora
Gram -ve
Candida
Which organisms damage vaginal barrier and how?
Broad spectrum AB
Candida
What diseases cause primary caused phagocyte defects?
Chronic granulomatous disease
Neutrophil migration defects
What diseases cause secondary cause phagocyte defects?
AML Aplastic anaemia Diabetes Chemo associated neutropenia Corticosteroids - impair neutrophil function
Which organisms usually cause disease in phagocyte defects?
S. aureus Pseudomonas Aspergillus Zygomycetes Normal commensals
Prevention of disease due to phagocyte defects
Prophlactic AB early = quinolones
Antifungals
IFNgamma
Vaccinations
What things cause secondary complement defects?
Eculizumab
Myeloma auto antibodies
Impact of complement defects
Increased risk of neisseria meningitis
Meningococcal meningitis
Menigococcal sepsis
Prevention of disease due to complement defects
Proph AB
Vaccinations
Causes of primary humoral immune defects
IgA defciiency
Hyper IgM
Causes of secondary humoral immune defects
CLL
Splenectomy
Corticosteroids
Rituximab
Impact of humoral immune defects
Strep pneumoniae
H. influenzae
Neisseria meningitis
(encapsulated organisms if IgG deficiency)
GI pathogens (protozoa) if IgA deficiency
Prevention of disease in humoral immune defects
Proph AB
AB replacement = immunoglobulins from blood
Splenectomy infection prevention
Vaccination - before splenectomy better
Prop AB = pen V
Causes of primary cell mediated immune defects
Combined
Di-George
Hyper IgM
Causes of secondary cell mediated immune defects
HIV Malignancy Anti-rejection therapy Steroids Anti-TNF Stem cell transplant Radiotherapy Malnutrition
Impact of cell mediated immune defects
HIV targets CD4 cells = T helper response poor Mycobacteria, salmonella, listeria Cryptococcus, PCP, histoplasma CMV Toxoplasma
Prevention of disease in cell mediated immune defects
Aciclovir for viral
Cotrimoxazole for fungal and latent TB
Immunisations
Avoid live vaccines!
When to suspect primary immunodeficiency
- infectiosn requiring IV AB
- FH of it
- 4 or more new ear infections in 1 year
- 2 or more new sinus infections in 1 year
- 2 or more months on at least 2 AB
- 2 or more pneumonias within 3 yrs
- frequent deep skin abscesses
- thrush/skin fungal infection >6m
- 2 or > deep infections within 3 yrs
Chronic persistent infection define
Infection maintained by continuous replication of a virus
Chronic latent infection define
Persistent or life long infection maintained by pool of latently infected cells (non replicating)
Viral infections in cell mediated immune deficiency
Herpes = Simplex, Varicella zoster, CMV, EBV Paramyxoviruses = RSV, measles, parainfluenza Papillomarviruses = HPV Polyomaviruses = BK, JK
HSV
Herpes Simplex Virus
- nearly always HSV-1
- genital herpes HSV-2
- direct contact spread with lesions
- swab lesion PCR
- Tx = aciclovir
HSV Primary infection
asymptomatic
Maybe = fever, pharyngitis, ulceration and lymphadenopathy
HSV Secondary recurrence
Very common
Prodromal tingling
Localised painful blisters
Resolve 5-7 days
Varicella Zoster
Most have had exposure
Diagnosis = swab area
Varicella Zoster Primary Infection
Chickenpox Fever + generalised rash Sporadic Spring-summer peak Highly infectious via resp droplets and lesion shedding - most infectious 1-2 days before rash
Varicella Zoster Reactivation
Shingles In immunosuppressed May be multidermatomal Encephalitis Infectious until all lesions crusted Uncomplicated in healthy Severe with pneumonitis otherwise
Treatment of HSV and VZV
Treat immunocompromised always
Antivirals = reduce symp, duration, shedding, complications
If VZV have pneumonitis, encephalitis, eye disease = IV treatment
ACE Viruses
Adenovirus, CMV, EBV
- major hazard for allogeneic HSCT
- primary infection and reactivation
- transmitted from donor
CMV
- virus in saliva, urine, breast milk
- common in childhood
- usually minimal symptoms and self limiting
- mononucleosis like
- remains latent in blood and bone marrow cells and can reactivate when suppressed
- important causes of congenital abnormalities
- pathogen of solid organ and bone marrow transplant patients
CMV diagnosis
Pre transplant serology
Post transplant monitoring for viraemia/infection
CMV infection vs. disease
Infection - lab evidence of virus activity - primary and re-infection Disease - clinical evidence of disease - syndrome - organ specific
CMV management
PROPH - anti-viral after transplant regardless
Pre-emptive = start antiviral therapy at first indication of active CMV replication after transplant (if bone marrow and SCT)
EBV
- herpes virus establishes latency
- most of pop have past infection
- in immunosuppressed = lymphoma (transplant and HIV patients) and post transplant lymphoproliferative disorder (first year)
Risk Factors of PTLD
<5 yrs Antirejection Therapy Tacrolimus >ciclosporin CMV seromismatch Small bowel/heart/lung/liver/renal/BM/pancreas transplants EBV seronegative prior to transplant
PTLD Symptoms
Fever unexplained GI upset Lymphadenopathy Tonsillar hypertrophy IM Hepatic/splenic enlargement Anaemia Graft dysfunction
Adenovirus
3 main syndrome - resp (mild, self limiting), keratoconjunctivitis, gastroenteritis
- immunosuppressed
- transplant (RF = child, severe GvH disease, cord blood transplant, liver, heart)
Adenovirus in immunosuppressed
Asymptomatic viral shedding/ end organ disease/ disseminated more than 2 sites
Management of adenovirus in immunosuppressed
Screening via blood = urine PCR
Reduction of immune suppressed
Polyomarviruses
JC and BK
Early life acquired
Initial viraemia = kidney seeding = latency
Reactivation due to viruria = viraemia = end organ disease
Asymptomatic
3 syndromes of polomarviruses
BK virus associated haemorrhagic cystitis
BK virus associated nephropathy
JC-PML
Define confidentiality
Agreement that gives the confider the right to expect discretion from the confidant as well as guardianship of the information received
Define confidential information
Info disclosed to the professional about the patient before or after death which has a nature of confidence or seen by the patient as having such a nature
Patient identifiable data
When does confidentiality cease to exist
Only when no representatives can give consent or refuse disclosure
How long should health records be retained for?
8 years min.
25 for maternity/obstetric
Why do we have duty of confidentialtiy?
- no trust otherwise = no info. = no care = no business
- unpleasant legal/professional consequences
- precondition of autonomy
When can confidentiality be relaxed?
- patient gives explicit consent to disclose for purposes of epidemiology/research/education, to relatives
- must be informed of purpose and consequences and whom
- may refuse
- if in patient’s best interest = young patient abuse tell guardians
- in society’s best interest = dangerous drivers, harm to individuals
- professional has dual responsibility = member of armed forces, prison worker
- in case of serious crime/assault = disclose to police
- court of law
- tax inspectors for financial info
What is not a notifiable disease?
AIDS
Notifiable to PH Act
Statutory Duties
Abortions Drug Addicts Births Deaths Certain infections
Fitness to drive
- depends on vehicle
- up to age of 70 years then renews every 3 years, automatically done unless driver reports problem
- must inform DVLA of potential medical disability
Doctor concerns with patient informing DVLA
- inform patient they have legal duty to
- if refuse = suggest second opinion of diagnosis and risks and advice not to drive until obtained
- if continue to drive = persuade not to, involve next of kin
- if still drives = tell them that DVLA will be informed
- discuss matter with patient’s defence organisation
- give medical info to medical adviser at DVLA
- write to patient informing you have done
Prescribed drugs affecting fitness to drive
Transquillisers Antiepileptics Antidepressants Antipyschotics Antihistamines Analgesics Anaesthetics Opoiates, cannabis, LSD, alcohol
When is it justified to withhold truth from patient?
- if will cause real predictable harm =make them suicidal
- if patient states informed preference not to be told the truth
Helsinki Principles
1 - must conform to accepeted scientific principles and based on adequate lab and animal experiments
2 - Independent committee which conform with local laws should be able to guide/comment
3 - conducted by scientifically qualified people and under supervision of clinically competent medical people
4 - importance of research objective must be in proportion to inherent subject risk
5 - Assessment of risk and benefits must be done & concern for interests of subject must outweight interest of science and society
6 - respect subject’s autonomy and privacy, minimise harm
7 - docotrs cease investigation if hazards outweight risks
8 - physician obliged to preserve accuracy, reports should concord with principles laid down otherwise not published
9 - subject correctly informed and can withdraw at any time, consent needed in writing
10 - consent to be free from coercion
11 - informed consent obtained from legal guardian in case of incompetence
Who should patient sue in what scenario?
If GP = direct claim
If hospital doctor = against health authority and doctor
Define negligence
- duty of care
- breach of that duty
- person claiming suffered harm/damage
- damage caused by breach
Duty of care
Good Samaritans - ethical duty not a legal one
breach of duty of care
Failure to reach level of proficiency of peers
Bolitho Modification
- ignorance is not a defence
- genuine errors of clinical judgement not negligence if based on reasonable skill
- breach done (commission) or not done (ommission - failure to attend to a patient)
- misdiagnosis if history taking was poor, investigation poor, compared to reasonable doctor, not referred to specialist if doubt
Actionable Harm or Damage
Disability
Injury
Loss of earnings
Reduced quality of life
Legal Process
Letter of claim - must be acknowledged within 14 days and copies of requested notes within 40d
- letter of response within 3m
- claim form by civil court
- denial by defendant
- proofing
- assessment of quantum, settlement reached by trust leaving doctors to feel that justice was not done
- 5% go to court, decision based on expert opinion
Examples of neonatal single gene disorders
Sickle Cell Cystic fibrosis Hypothyroidism Phenylketonuria Medium chain Acyl CoA dehydrogenase deficiency Maple Syrup Urine Diseasse Isovaleric Acidaemia Glutaric aciduria type 1 Homocystinuria
Define single gene disease
Genetic disorder caused by a change affecting only 1 gene
Inheritance pattern of single gene diseases
Simple Mendelian patterns Auto dominant, recessive etc. X linked recessive X linked dominant Y linked dominant Imprinting Mitochondrial
Define epigenetics
Study of changes in organisms caused by modification of gene expression rather than alteration of genetic code itself
Type of DNA mutations
Missense
Nonsense (stop codons)
Fram Shift
Transcriptional control
Mutations in regulatory elements
Epigenetics = DNA methylation/chromatin modification, deletions, insertions, inversions, translocations
X linked recessive disorders
Haemophilia A
X linked severe combined immune disorder
Duchenne muscular dystrophy
Becker muscular dystrophy
X linked recessive inheritance mechanism
Males born to carrier mothers
1/2 sons affected
Daughters of affected fathers are carriers
Never father to son
Duchenne muscular dystrophy
Dystrophin mutation
Dystrophin - stabilises sarcolemma, protects muscle fibres from LT damage, links microfilament network of actin to proteins
Stem cells regenerate muscle to some extent but eventually die and get replaced by fat and CT
DMD vs Backer Muscular Dystrophy
DMD = dystrophin gene absent or non functional vs. partially functional in Becker
DMD greater incidence
Becker later onset 12 yrs vs. 3-5 yrs in DMD
Longer LE in Becker = 40s vs. 20s in DMD
Cardiomyopathy may present before skeletal symptoms in Becker vs. after in DMD
X linked dominant disorders
Some forms of retinitis pigmentosa
Chorndrodysplasia Punctata (cartilage and bone dev.)
Hypophosphatemic rickets
Mechanism of X linked dominant inheritance
Both sexes
More females
Affected sons have affeted mother
All daughters from affected father are affected
Autosomal recessive diseases
Pheylketonuria
Tay-Sachs
Hemochromatosis
Cystic Fibrosis
Autosomal Dominant Diseases
Huntingtons
Achondroplasia
Polycystic Kidney Disease
Werner mesomelic syndrome
Werner mesomelic syndrome
- hypo or aplasia of the tibiae
- preaxial polydactyly of hands and feet
- five fingered hand with absence of thumbs
- overexpression of SHH
Y linked dominant diseases
Retinitis pigmentosa
Y linked dominant inheritance mechanism
Only males
From father to all sons
Examples of imprinting conditions
Beckwith-Wiedemann syndrome
Prader-Willi
Angelman syndrome
Imprinting inheritance mechanism
Certain genes expressed in a parent of origin specific manner
If allele inherited from father is imprinted it is silenced and only the allele from the mother is expressed
Angelman syndrome
Neuro-genetic
Severe intellectual and developmental disability
Sleep disturbance
Seizures
Both sexes - only when mutated chromosome is maternally inherited
If mother is carrier = chance is 50%
Examples of mitochondrial conditions
Mitochondral myopathy
DM and deafness
Leber’s hereditary optic neuropathy
Leigh syndrome, subacute sclerosing encephalopathy
What can gene therapy help with?
Recessive disorders
Loss of function mutations
Small gene
Tissue is accessible = skin/blood
Treatment options
Gene therapy
Genome Engineering = CRISPR-Cas9 technique
Gene repair of double strand breaks
Complex disease = multi gene diseases
- common
- polygenic
- high frequencies of variants in pop
- variants have small affects on gene function
- unclear modes of inheritance
How to determine if genes are important?
Familial aggregation
Twin studies
Adoption studies
Examples of complex diseases
Essential HTN
CHD
Diabetes
Asthma, epilepsy, cancer
Genetic causes of HTN
- rare inherited syndromes of HTN
- majority of cases = polygenic complex
- 30-50% genes, 50-70% lifestyle factors
miR-425
Present in atria and ventricles
- expressed at levels similar to miR-208a which is known to have significant biological functions in the heart
- inhibiting it could enhance atrial ANP release in response to salt excess and HF
