Immunology Flashcards
(225 cards)
1
Q
What cells are associated with the innate immune system response?
A
Epithelial cells/barriers eg skin
Phagocytes
Dendritic cells
Mast cells
Complement
NK cells
2
Q
What cells are associated with the adaptive immune system response?
A
B lymphocytes/plasma cells
T lymphocytes and effector T cells
3
Q
What are some of the key differences between the innate and adaptive immune system?
A
Innate immune system is less specific, recognising molecules shared by groups of related microbes or molecules produced by damage host cells cf adaptive which can recognise specific microbial and non-microbial antigens
Innate system is only able to recognise a limited number of molecules encoded by inherited (germline) genes cf adaptive which has very large diversity as receptor genes are formed by somatic recombination of gene segments
Innate system has no/limited memory whereas adaptive can
4
Q
What are phagocytes?
A
Cells that ingest and destroy microbes/damaged tissue
Neutrophils
Macrophages
5
Q
What are antigen-presenting cells?
A
Strictly speaking any nucleated cell that captures antigens and presents them to activated T helper lymphocytes
Normally implies (professional APCs):
Dendritic cells
Macrophages
B lymphocytes
6
Q
What are effector cells?
A
Any activated cell that performs a function to eliminate microbes eg phagocytes, antigen presenting cells, lymphocytes
7
Q
What are some of the key features of the innate immune response?
A
Early (within mins to hours)
Activated by recognition of limited subset of molecules (eg DAMPS and PAMPs, limited specificity and diversity)
No change in response with prior exposure to pathogen (ie no memory)
End result =
- inflammation
- antiviral response (type 1 interferons)
- activation of adaptive immunity
8
Q
How does the innate immune system interact with the adaptive immune system?
A
Antigen presentation via APCs
Enhanced activation of lymphocytes via co-stimulatory molecules (two signal hypothesis)
Augmentation of adaptive immune response via cytokines and chemokines eg IL-12 (stimulates T lymphocyte differentiation), IL-6 (stimulates B cell differentiation and activation)
9
Q
What receptors are found in the innate immune system?
A
Pattern recognition receptors
- series of primordial receptors found on multiple cell lines in the innate immune system with limited specificity
- recognise PAMPs (pathogen assoc molecular patterns) or DAMPs (danger assoc molecular patterns)
- examples incl Toll-like receptors
10
Q
Mutation of which toll-like receptor (1-9) predisposes people to HSV/HSV encephalitis?
A
Toll-like receptor 3
11
Q
What is the inflammasome?
A
A multiprotein complex that forms when certain pattern recognition receptors are activated, especially NOD-like receptors
These then activate caspase 1 which activates IL-1 and IL-18 - key inflammatory cytokines
12
Q
What are some examples of the inflammasome in action?
A
Gout - monosodium urate activates NLPR3 inflammasome in joints - IL-1ra eg anakinra is an effective tx option
Various inherited disorders caused by mutations in inflammasome components resulting in uncontrolled inflammation e.g. Familial Mediterranean Fever (FMF) - mutation in MEFV gene which encodes pyrin a protein that regulates inflammasome formation results in periodic fever, skin rashes, joint pain, serositis
13
Q
What is the complement pathway?
A
A cascade of plasma proteins
Classical pathway (C1q)
- activated by immunoglobulins, CRP or bacterial components
Alternative pathway (C3)
- spontaneous activation enhanced by microbial contact
Both converge on common pathway - C3b which then leads to C5 and then Membrane Attack Complex formation (C5b-9)
Zymogens = cleavage of each component causes its activation
Produces 2 fragments:
“a” components = anaphylatoxins (pro-inflammatory), smaller
“b” components = activate next protein, larger
14
Q
What is the main role of the complement system?
A
Direct microbial lysis and killing via the membrane attack complex
Opsonisation - coating of target to enhance uptake by phagocytes
Clearance of immune complexes
Activation and enhancement of inflammatory response via anaphylatoxins (e.g. C3a and C5a)
15
Q
Why is understanding the complement pathway relevant?
A
Because excessive complement pathway activation is implicated in ANCA vasculitis (eg C5a-mediated neutrophil activation and migration)
Now have therapeutics eg Avacopan a C5a receptor antagonist
Paroxysmal Nocturnal Haemoglobinuria (PNH) due to PIGa gene mutation resulting in absence of CD55 and CD59 on RBC surface
- C5i eculizumab effective treatment
Atypical haemolytic uraemic syndrome (aHUS) - due to mutations in regulatory complement proteins (factor H, factor I, MCP) resulting in uncontrolled complement activation, rapidly progressive TMA, renal failure, stroke
- treatment with C5i eculizumab
16
Q
Why are T cells called T cells?
A
Because they develop in the thymus
17
Q
How do T cells work?
A
They recognise protein antigens displayed on MHC molecules on antigen presenting cells via the T cell receptor
They do not see or respond directly to antigens in the circulation
18
Q
What are the two major subsets of T cells?
A
CD4 T helper cells
- note Treg cells are subset of CD4 cells important in maintaining peripheral tolerance
CD8 T killer cells
- directly kill infected/tumour cells
19
Q
What is the desired outcome of T cell development in the thymus?
A
To produce T cells with functional T cell receptors that recognise MHC but not self antigen
Does this via;
Positive selection - T cells that recognise MHC survive
Negative selection - T cells that recognise self-antigen are either deleted or differentiate into Treg cells, mechanism of central tolerance
20
Q
What is the AIRE gene and what happens if there is a mutation in it?
A
AIRE gene is expressed in thymic cells and encodes a range of tissue-restricted self-antigens to allow negative selection in the thymus
Mutations in AIRE leads to APECED (Autoimmune Polyendocrinopathy with Candidiasis and Ectodermal Dystrophy)
- multiple autoimmune complications and polyendocrinopathies (adrenal and parathyroid) with chronic candidiasis (due to autoantibodies against IL-17 and IL-22)
21
Q
What are the differences between DC4 and CD8 T cells in terms of recognition and function?
A
CD4
- recognise = MHC class II
- respond = to extracellular organisms
- function = activate other immune effector cells incl B cells and macrophages
CD8
- recognise = MHC class I
- respond = to intracellular organisms (eg viruses)
- function - direct killing of infected cells
22
Q
What are the different subsets of CD4 T helper cells?
A
Thelper 1 = produce IFN-y
- activates macrophage, IgG production
- helps with intracellular microbes eg TB
- targetable in autoimmune disease, tissue destruction assoc with chronic infections
Thelper 2 = produce IL-4, IL-5, Il-13
- activate mast cells, eosinophil activation, IgE production, alternative macrophage activation
- helps with helminths, parasites
- targetable in allergic disease
Thelper 17 = produce IL-17a, IL-17F, IL-22
- activates neutrophils, monocytes,
- helps with extracellular bacteria, fungi
- targetable in autoimmune inflammatory disorders
23
Q
How are MHC class I and II different?
A
MHC class I
- expressed on all nucleated cells
- processes internal antigens from viruses and intracellular bacteria
- interact with/activate CD8 T cells
MHC class II
- only expressed on professional APCs (eg macrophages, dendritic cells, B cells)
- process external antigens from phagocytosed organisms
- interact with CD4 cells
24
Q
What is the two signal hypothesis re T cell activation?
A
T cell activation requires two signals
- should not get co-stimulation in cases of self-antigen - this leads to (peripheral) tolerance
Step 1 TCR and MHC-ag interact
Step 2 = costimulation
- CD28 on T cells
- CD80 (B7.1) and CD86 (B7.2) on APCs
25
What other molecules are expressed at the immunological synapse to control T cell activation?
CTLA-4
PD-1
These prevent unopposed T cell activation (ie put the brakes on / are inhibitory)
eg CTLA4 is upregulated when T cells activated, binds to CD80/86 and effectively displaces CD28 which inhibits T cell activation
26
What is the mechanism of action of Abatacept?
Abatacept is a fusion protein consisting of Fc region of IgG1 fused to the extracellular domain of CTLA-4
Abatacept binds to B7.1 and B7.2 to prevent T cell co-stimulation thereby reducing T cell activation
(ie stimulates action of CTLA-4)
Uses - RA, other autoimmune conditions
27
How do checkpoint inhibitors work?
Ipilimumab = CTLA-4 blocker
Pembrolizumab = PD-1 blocker
Atezolizumab = PD-L1 blocker
By blocking actions of CTLA-4 or PD-1 they "release" the brake on T cell activation leading to greater T cell activation and enhanced anti-tumour response
28
What are the conditions assoc with genetic mutations in T cell activation that appear as though people are on checkpoint inhibitors?
CHAI = CTLA-4 haploinsufficiency autoimmune infiltration
- inherited mutation in CTLA4 (loss of function)
- p/w excessive immune activation, lymphoproliferation
LATAIE
- mutation in LBRA a trafficking molecular for CTLA-4
- similar presentation to CTLA-4
Can treat both with abatacept
- tra
29
Why are B cells called B cells?
Because they are produced in bone marrow
30
What is the main role of B cells?
Antibody production (immunoglobulins)
- surface Ig which can act as B cell receptor, IgM and IgD
- secreted Igs - any isotype
Also have secondary roles incl antigen presenting cells, regulate immune response
REQUIRE T cell help for activation and function
31
Why is it rare to have isolated T cell immunodeficiencies?
Because B cells require T cells for activation and enhance their function so if T cell immunodeficiency, invariably get combined T and B cell immunodeficiency
32
What is the structure of immunoglobulins?
2x Heavy and Ligh chains
1x Fc region
2x Fv regions
Fc region = constant
- same for all antibodies of an isotype, responsible for effector function, activates complement and binds to Fc receptors to promote phagocytosis
Fv region = variable
- antigen binding site, highly variable/diverse due to VDJ recombination, contains complementarity determining regions (CDRs) which are loops at the end of the Fv region with highly variable amino acid sequences
33
What are the functions of immunoglobulins?
Provide primary defence against extracellular pathogens by
- neutralising microbes and toxins
- opsonisation and phagocytosis
- antibody-dependent cellular toxicity
- complement activation
34
What are the 5 different immunoglobulin isotypes?
IgG = major antibody isotype in the blood, does everything, multiple subclasses
IgM = expressed on B cell surface, acts as a B cell receptor, low antigen affinity
- also secreted in serum as pentamer with high avidity, very effective at activating complement
- important for early antibody responses (prior to class switching)
IgA - secreted on mucosal surfaces, important for mucosal immunity
IgE - activates eosinophils and mast cells, important for parasitic infection and allergy
IgD - expressed on B cell surface as B cell receptor, very low levels in the blood
35
Where does B cell development occur?
Initially in the bone marrow
Activation/differentiation and proliferation occurs in secondary lymphoid organs eg lymph nodes
36
What are the key events in B cell activation
B cells circulate in the peripheral blood and secondary lymphoid organs
If they encounter an antigen they migrate from follicle to germinal centre
They then undergo differentiation and proliferation with T cell help
Key events include:
- T and B cell interaction
- somatic hypermutation (affinity mutation)
- class switch recombination
They differentiate into antigen specific antibody secreting cells (either plasmablasts or long-lived plasma cells) or memory B cells
(small subset differentiate into short-liver plasma cells for early IgM response)
37
What is a plasmablast and how does it differ from a long-lived plasma cell?
Plasmablast is a short-lived differentiated B cells that secretes high levels of antibodies
Long-lived plasma cells produce low levels of antibodies and migrate to bone marrow and live for >20yrs and are important for memory response
38
Why don't most people treated with Rituximab become hypogammaglobulinaemia?
Because of persistence of long-lived plasma cells
39
What Ig subtypes are found in naive B cells?
IgD and IgM
therefore to produce other isotypes, need to undergo class switching in germinal centres
40
What are T follicular helper cells?
Specific subset of T helper cells that reside in lymph nodes important for B cell differentiation and activation
Interacts via immunological synapse through co-stimulatory molecules CD40L on T cell - CD40 on B cell
41
What are the general guides about organisms that patients with various immunodeficiencies will be suceptible to?
T cell def = intracellular bacteria (eg TB), fungi, protozoa, viruses
B cells = extracellular bacteria
Complement = encapsulated organisms eg neisseria
Phagocytes = intracellular bacteria and fungi
42
What are the key inborn errors of immunity?
Humoral (ie B cell) immunodeficiency
Combined (ie B and T cell) immunodeficiency
Complement disorders
Phagocyte defects
43
What are the key humoral immunodeficiency conditions and the resulting phenotypes?
X-linked agammaglobulinaemia
Common variable immunodeficiency (CVID)
HyperIgM syndrome
Typically manifest with recurrent sinopulmonary infections
Strep pneumoniae + H influenza
Hypogammaglobulinaemia
44
What are the key combined immunodeficiency conditions and their phenotype?
Severe combined immunodeficiency (SCID)
HyperIgE syndrome
Di George syndrome
Ataxia telangiectasia
(advanced HIV is essentially a combined immunodeficiency)
Susceptibility to intracellular bacteria (eg TB, mycobacteria, listeria, salmonella)
Fungi - pneumocystis, cryptococcus, histo
Viruses - CMV, HSV, VZV
Protozoa - toxoplasma, cryptosporidium
45
What are the main phagocyte defects and their phenotype?
Chronic granulomatous disease
Leukocyte adhesion deficiency
Susceptible to deep seated infections or recurrent abscesses
S aureus, serratia, burkholderia, nocardia
Fungi - aspergillus, candida
46
What are the main complement disorders and their phenotype?
C5 to C9 deficiency
Susceptible to disseminated severe neisseria infection
47
What is common variable immunodeficiency?
The most common antibody deficiency (besides selective IgA deficiency)
Affects 1:30,000, both genders equally
Typically only humoral immunodeficiency that presents in adulthood (rest usually in childhood), typically age 20-40
Highly heterogenous condition characterised by impaired terminal differentiation of B cells into memory cells and plasma cells
Less than 20% have identified genetic mutation
Produces:
- low levels of total IgG
- variable reductions in IgA and IgM
- low numbers of switched memory B cells and plasmablasts/plasma cells
- impaired specific antibody response eg to infections and vaccines
70% get non-infectious complications incl:
- autoimmunity
- enteropathy
- lymphoproliferation
- increased malignancy risk esp lymphoid (NHL) and gastric ca (H pylori-assoc)
- asthma and allergic disease
48
49
What are the 3 main types of chronic lung disease in px with CVID?
Bronchiectasis - older px
ILD - younger px esp with hx of autoimmune cytopenias, increased serum IgM and low CD3 T cell counts
Granulomatous-lymphocytic ILD - hx of autoimmune cytopenias, hypersplenism, polyarthritis etc
50
Autoimmune conditions are diagnosed in 30% of px with CVID - these patients are less likely to have recurrent infections and more likely to have enteropathy; what are the most common autoimmune conditions diagnosed in CVID?
ITP
AIHA
RA
Pernicious anaemia
Autoimmune thyroiditis
Vitiligo
51
What is the most common liver pathology in patients with CVID?
Nodular regenerative hyperplasia
52
What are the most common malignancies in CVID?
Non-Hodgkin Lymphomas - 2-8% lifetime risk
Gastric ca esp H-pylori related
53
How do you diagnose CVID?
1) Low serum IgG, IgA +/- IgM
- test twice to confirm
2) Poor or absent response to protein-based (tetanus/diptheria) and polysacchride--based (eg pneumococcal) vaccination
3) Absence of other defined immunodeficiency state
54
What is the differential diagnosis of hypogammaglobulinaemia?
Primary hypogammaglobulinaemia
- IgG deficiency
- Hyperimmunoglobulin M syndrome
Secondary hypogammaglobulinaemia
- Drugs eg rituximab, CART, BITE, long-term steroids, cytotoxic meds, select antiseizure meds
- malignancy/pre-malignant conditions esp CLL, MM, Waldenstrom's
- thymoma with hypogammaG (Good syndrome)
- protein losing enteropathy or nephrotic syndrome
- burns
- malnutrition
55
What is HyperIgM syndrome?
An X-linked disease due to defects of CD40L (or rarely UNG, AICDA enzyme def) in which isotype switch from IgM to IgA or IgG does not occur
Diagnosis should be suspected if appropriate clinical features (eg male, opportunistic infections) + low levels IgG and IgA with normal/increased serum IgM
Definitive diagnosis requires genetic testing
56
What clues may indicate Ataxia-Telangiectasia rather than HyperIgM syndrome?
Both can have high IgM levels
Elevated AFP + typical neurologic features and telangiectasias = ataxia-telangiectasia
57
What is ataxia-telangiectasia?
A multisystem, autosomal recessive disease caused by pathogenic variants in ataxia-telangiectasia mutated (ATM) gene resulting in loss of function / absent or defective ATM kinase function
Classic AT presents at birth/early childhood with progressive cerebellar ataxia, abnormal eye movements, extrapyramidal motor dysfunction (eg tremor, dystonia) and oculocutnaeous telangiectasias
Variant form = presents later but usually by age 10, milder cerebellar and extrapyramidal dysfunction
Investigations typically show:
Elevated AFP
T cell lymphopenia
Hypogammaglobulinaemia
Diagnosis often made based on abnormal newborn screen
Otherwise AFP + IgA levels may give clues then perform genetic testing to confirm
Progressive pulmonary disease and haematological malignancy cause premature morbidity and mortality
Life expectancy ~25 yrs
58
What are the key features of X-linked agammaglobulinaemia?
Humoral immunodeficiency characterised by recurrent sinopulmonary infections and susceptibility to enteroviral infections
X-linked (ie affects males) due to defects in Bruton tyrosine kinase (BTK) moleculre
Typically diagnosed between 6-24 mths
Characteristic finding = absence of tonsils and adenoids
Suspect in males with agammaglobulinaemia/hypogammaglobulinaemia, very low/absent CD19+ B cells, consistent clinical and family hx
Diagnosis confirmed with molecular study identifying defect in BTK gene
Treatment = Immunoglobulin therapy (IVIG or SCIG)
59
What are the key features of Severe Combined Immunodeficiency (SCID)?
Results from severe disturbances in development and function of T cells leading to defects in both cellular and humoral immunity and may also involve NK cells
Typically diagnosed soon after birth by newborn screening or family history
M with recurrent, severe, opportunistic infections, chronic diarrhoea, failure to thrive
Typical SCID defined by T cell count <50microL + low TRECS or a pathologic variant in an X-linked or autosomal gene known to cause SCID
Alternatively, presence of maternal T cells in circulation = strong evidence for SCID
Treatment = only definitive therapy = allogenic HSCT
- otherwise enzyme replacement therapy available for ADA deficiency
- otherwise supportive with IVIG + avoidance of infections
Prognosis
SCID is fatal usually within first year or life unless corrected ie via allogenic HSCT)
60
What are the 4 types of hypersensitivity conditions/reactions?
Immediate / Type 1
Antibody-mediated / Type 2
Immune-complex mediated / Type 3
T-cell mediated / Type 4
61
What is the primary immune mechanism and mechanisms of tissue injury/disease in Type 1 hypersensitivity reactions?
IgE antibodies + Thelper2 cells
Mast cells, eosinophils and their mediators eg vasorecctive amines,
62
What is the primary immune mechanism and mechanisms of tissue injury/disease in Type 2 hypersensitivity reactions?
Antibody-mediated
IgM and IgG antibodies against cell surface or extracellular matrix antigens
Involves opsonisation, phagocytosis, complement activation, abnormalities in cellular functions
63
What is the primary immune mechanism and mechanisms of tissue injury/disease in Type 3 hypersensitivity reactions?
Immune-complex mediated
Immune complexes of circulating antigens and IgM or IgG abs
Lead to complement and Fc-receptor mediated leukocyte activation
64
What is the primary immune mechanism and mechanisms of tissue injury/disease in Type 4 hypersensitivity reactions?
T cell mediated
CD4 T cells (esp T helper 1 + T helper 17)
CD8 cells
Lead to direct cell killing & cytokine mediated inflammation
65
How does type 1 / IgE mediated / allergic hypersensitivity develop?
IgE antibody production in response to a trigger antigen (usually innocuous environmental antigen)
The allergen-specific IgE then binds to mast cells
Then on re-exposure get cross-linking and activation of IgE-bound mast cells leading to mast cell degranulation and resulting clinical manifestations
66
What are mast cells and how do they play a role in allergic hypersensitivity?
Resident cells that reside in vascularised connective tissue beneath epithelial surfaces eg GI, resp, skin
They contain preformed mediators eg histamine, tryptase, TNG
Activation leads to release of these mediators as well as synthesis of lipid mediators (eg prostaglandins, leukotrienes - responsible for delayed response 2-4hrs)
67
What are the typical clinical responses to IgE-mediated hypersensitivity?
Food/venom/medications:
Cutaneous reactions
Anaphylaxis
Airborne allergens:
Allergic rhinosinusitis / conjunctivitis / asthma
68
What are the advantages and disadvantages of skin prick testing?
Quick to perform, rapid results
Operator dependent
Cannot be performed in all px (eg diffuse derm disease, severe dermatographism, px unable to cease antihistamines/other interfering medications)
Involves both positive (histamine) and negative (saline) controls
Judge wheal and flare response (indicator of local histamine release)
69
How is specific IgE testing helpful and what are the pros/cons?
Previously performed via RAST, now by enzyme or fluorescent immunoassays
Results reported as low-, high-, very-high levels of sensitisation
Generally less sensitive and less specific than skin testing
- not diagnostic, only indicative of them being capable of forming IgE in relation to antigen ie sensitisation, does not necessarily equate to clinically significant reaction
Cross-reactivity can occur
False +ve in px with high total IgE
False -ve if perform too soon after anaphylaxis, too long after exposure or due to degradation of allergens
70
What is provocation testing?
Gold standard for identifying allergic responses
Needs to be performed in controlled environment - time and resource demanding
Can be performed either single step or graded
Often used for historical medication allergies
71
What is the difference between desensitisation and drug challenge testing?
Desensitisation = giving gradually increasing doses of an allergen to alter the allergic response and ideally achieve tolerance (temporary or sustained)
Drugs tend to give small doses in quick succession until target dose achieved - temporary tolerance; once px stops taking medication regularly, can react to medication
A graded drug challenge is NOT the same as desensitisation
- drug challenge = diagnostic, desensitisation = therapeutic
- drug challenge attempting to evaluate if elicit reaction; desensitisation = seeking to bypass reaction
- use higher doses with drug challenge
72
What is anaphylaxis and how is it diagnosed?
It is an IgE-mediated hypersensitivity reaction that is SEVERE, SYSTEMIC, LIFE-THREATENING
It is a clinical diagnosis
- acute onset (minutes to hours)
- skin/mucosal involvement
+
- respiratory compromise (eg bronchospasm)
- hypotension or hypoperfusuion
- severe GI symptoms
Can occur in absence of skin manifestations
73
What are the common triggers for anaphylaxis?
Food = most common
- peanut
- tree nuts
- shellfish (crustaceans = most common cause of fatal anaphylaxis in adults)
- insect stings
- medications eg beta-lactam
- latex
- tick bites
- physical triggers eg cold, exercise
74
What are the causes of Non-IgE anaphylaxis?
IgE-independent immunologic mechanisms:
Contrast media
NSAIDs
Dextrans
Biologic agents
Non-immunological (direct mast cell activation)
Physical factors such as cold, exercise
Alcohol
Opioids
Idiopathic (without apparent trigger)
Mastocytosis
Previously unrecognised allergen
75
What is the management of anaphylaxis?
1) Remove allergen
2) Call for help
3) Lie patient flat (or allow them to sit if breathing difficult)
4) IM adrenaline without delay
(500mcg/0.5mg ie 0.5ml of 1:1000)
76
What are some of the adjuncts you can use in anaphylaxis management?
Adrenaline infusion (if requiring >2-3x IM doses)
Oxygen +/- intubation
IV fluids
Nebulised adrenaline for upper airway obstruction
Glucagon +/- vasopressors for persistent hypotension
Salbutamol or corticosteroids for persistent wheeze
Note steroids, antihistamines, bronchodilators do not treat other manifestations / have clear benefit so are NOT first line agents
77
What is the role of tryptase in diagnosing anaphylaxis?
Raised levels can be useful to support diagnosis but normal levels (occur in 50% of cases) do not exclude diagnosis
If elevated, need to check baseline to ensure return to normal range
Levels peak 1-2 hrs after onset of anaphylaxis
Acute mast cell degranulation = > 1.2x baseline tryptase + 2
78
How long do you have to observe a patient with anaphylaxis?
At least 4hrs after last dose of adrenaline (in case of biphasic reactions which often occur in first 4 hrs)
Observe overnight if severe reaction, required repeated doses of adrenaline, hx of asthma or protracted anaphylaxis, concomitant illness, lives alone/remote from medical care
79
What is the long-term management of anaphylaxis?
Referral to immunologist to:
- determine/confirm allergen
- education
- epi-pen prescription
- anaphylaxis action plan
- medic-alert bracelet
- consider desensitisation
80
What are the typical features of a food allergy?
Rapid onset
Spectrum of manifestations from cutaneous features -> anaphylaxis
Complete resolution after breakdown/digestion of allergen (usually hours)
Symptoms with each exposure
81
What is Food-dependent, exercise-induced anaphylaxis (FDEIA)?
Combination of food (allergen) and exercise (co-factor) precipitates reaction (ie symptoms occur if px exercises within hours of ingesting allergen)
Other co-factors may also trigger reaction incl alcohol, NSAIDs
82
What is the most common food allergen in Food-dependent, exercise-induced anaphylaxis (FDEIA)?
Omega-5-gliadin found in wheat
83
What are the features of Mammalian meat allergy?
Allergen = alpha-gal (galactose-alpga-1,3-galactose) found in mammalian meat
Found in saliva of ticks (requires sensitisation with tick bite, cannot happen without hx of preceding tick bite)
Usually results in delayed reaction (3-10hrs post meat exposure) with GI symptoms +/- anaphylaxis
Note px can have tick allergy without developing MMA
84
How do you treat mammalian meat allergy?
Epipen, anaphylaxis action plan
Tick avoidance/safe removal
Avoidance of all red meat + gelatine products +/- mammalian milk products
Medic alert bracelet
Avoid therapeutics incl gelatine or bovine substances (certain vaccines, cetuximab)
85
What did the LEAP study establish re food allergies?
Early introduction of peanuts resulted in reduced incidence of peanut allergies
86
What is the role of Omalizumab in patients with food allergies?
Omalizumab increases reaction threshold for peanut and other common food allergens
Not yet approved for this indication in Aus
87
What are the different types of drug allergy?
Immediate allergy (usually within 1hr) = IgE-mediated - typically cause urticaria, angioedema, anaphylaxis
Non-immediate (delayed) drug allergy = T-cell mediated - typically cause exanthema, organ involvement, fevers
88
How do you evaluate drug allergy?
Clinical history
IgE mediated - skin prick and/or intradermal
T cell mediated - intradermal and/or patch
Gold standard = drug provocation test
89
What components of the penicillin structure can penicillin allergy relate to?
Beta-lactam ring OR Side/chain
Cf cephalosporin allergy
Usually side chain
90
If allergic to beta-lactam ring, what medications are you allergic to?
All penicillins
Theoretical cross-reactivity with cephalosporins but in reality low risk
91
If you are allergic to side chain, what medications are you allergic to?
All penicillins and cephalosporins with same side chain
92
Patients with allergies to ampicillin/amoxicillin R1 side chain should avoid which cephalosporins?
Cefaclor, cephalexin
93
Patients with allergy to aztreonam side chain should avoid which cephalosporin and vice versa?
Ceftazidime
94
Is it possible to be allergic to cephalosporins as a class?
No, rare as they are generally side chain allergies and side chains differ between the different subgroups of cephalosporins
95
What does adult-type atopic dermatitis typically affect?
Upper arms
Back
Wrists
Hands
Fingers
Feet
Torso
96
What T-cell mediated response do all atopic dermatitis subtypes share?
T helper 2 response
97
How does Dupilumab work?
Inhibits IL-4 and IL-13 signalling
Significantly improves atopic dermatitis severity and can reverse atopic dermatitis barrier defects
Well tolerated
98
What are the most common side effects of dupilumab?
Ocular
Others:
Injection site reactions
Nasopharyngitis
99
What are the key cytokines implicated in atopic dermatitis and what signalling pathway do they use?
IL-4, IL-13, IL-22, IL-31, IFN-Y, TSLP
Signal via JAK pathway
100
What is the role of Upadacitinib in atopic dermatitis?
JAKi
Significant improvement in atopic dermatitis disease severity and high rates of clear skin
101
What are the main side effects of Updacitinib?
Acne
Cough/nasopharyngitis
Headaches
Herpes infections
UTI
Elevated CK
Theoretically increases risk of CV disease and thromboses and should be avoided in px with:
- established CVD or risk factors for CVD
- known malignancy
- age >65
102
In addition to topical corticosteroids and/or calcineurin inhibitors, what other newer topical agents are available for management of atopic dermatitis?
Topical PDE4i crisaborole
Topical JAKi ruxolitinib
103
What are the main treatment strategies for atopic dermatitis?
Emollients for all patients
Topical steroids
Addition of wet wrap therapy (if mod-severe eczema flare)
104
What are the adverse effects of topical corticosteroids in atopic dermatitis?
Overall incidence of adverse events is low
Principle - use lowest-potency formulation that effectively treats a patient's dermatitis
Side effects include:
- skin atrophy
- hypopigmentation
- striae
- purpura
- focal hypertrichosis
- acneiform eruptions
- telangiectasias
- rare to get systemic adverse effects eg cushing syndrome, diabetes, reduced bone density, reduction in linear growth rate (in pre-pubertal)
105
What are the risk factors for skin atrophy with topical steroid use in atopic dermatitis?
Higher-potency steroids
Occlusion
Use on thin/intertriginous skin
Older age
Long-term continuous use
106
How do topical steroids vary in their potency?
Low-potency: hydrocortisone, desonide
Mid-potency: fluticasone, triamcinolone, fluocinolone
High-potency: mometasone, betamethasone, desoximetasone
Very high-potency: clobetasol, ulobetasol, diflorasone.
107
When are topical calcineurin inhibitors (pimecrolimus, tacrolimus) used in atopic dermatitis?
When there is a need for daily topical steroids to maintain eczema, particularly if facial eczema with eyelid involvement
108
What are the adverse effects of topical calcineurin inhibitors?
Erythena
Pruritis
Skin irritation or burning
Theoretical risk of malignancy
109
When is UV phototherapy indicated for atopic dermatitis?
If moderate-to-severe generalised eczema
Has immunosuppressive, immunomodulatory and anti-inflammatory properties
110
When is systemic therapy indicated for atopic dermatitis?
Px with moderate-to-severe eczema that has not responded to topical therapy and phototherapy
Once adequate education has been provided and current infection has been excluded
111
What are the main systemic treatments for atopic dermatitis?
csDMARDs
- Methotrexate
- Ciclosporin
- Azathioprine
- Mycophenolate
Biologics
- Dupilumab
- JAKi upadacitinib
112
When is Dupilumab or Upadacitinib indicated in atopic dermatitis?
According to PBS criteria:
If despite treatment with medium-high potency steroid/calcineurin inhibitor for 28days patients have:
Eczema Area and Severity Index score >20
+
Physicians Global Assessment score >4
+
Dermatology Life Quality Index
+
Lesions >6mths
+
Sole-subsidised biologic
+
Treated by dermatologist or immunologist
+
Over 12 years of age
113
How do you treat low severity PJP pneumonia in AIDS?
3 week of PO TMP-SMX Q8H
+
Maintenance TMP-SMX afterwards
114
What constitutes high-severity PJP pneumonia?
Hypoxaemia <94% or PaO2 <70mmHg on room air
115
How do you treat high-severity PJP pneumonia?
Same as low-severity (Bactrim) but at higher doses (intravenous and Q6-8H rather than PO/Q8H) for 21d
+ adjunctive corticosteroids (pred 40mg BD for 5 days then wean)
+ then maintenance therapy with Bactrim 80/400mg daily
116
How do you treat PJP pneumonia if patient is hypersensitive to TMP-SMX?
Clindamycin + Primaquine
OR
Pentamidine
Other options in certain circumstances:
Dapsone + trimethoprim (unless hypersensitivity to SMX as risk of cross reactivity)
OR
atovaquone
117
Homozygosity for what CD4 coreceptor renders someone effectively immune from HIV?
CCR5 delta 32
118
Which class of ART requires pharmacokinetic boosting?
Protease inhibitors
119
What is the preferred treatment regimen for HIV?
2x NRTI + anchor drug from other class
120
Why would you test for HLA-B*5701 when starting someone on HIV treatment?
If positive - unable to prescribe abacavir as it is a risk factor for drug hypersensitivity
121
What are the contraindications to abacavir therapy?
HLA-B*5701+
Cardiovascular disease
122
What is the preferred form of Tenofovir in HIV?
TAF rather than TDF
TAF = Tenofovir alafenamide
123
What ART can cause an artificial elevation in eGFR?
Dolutegravir
124
What is the preferred two test method for diagnosing HIV?
Screen with HIV Ab-Ag test (tests for p24 Ag)
Then confirm with:
Western Blot
OR
HIV viral load PCR
125
What is one of the disadvantages of PrEP?
May delay the diagnosis of HIV infection
126
Who is daily PrEP recommended for?
Everyone at risk of HIV infection incl
MSM/trans:
- at least one episode of condomless anal intercourse with HIV+ partner (not on tx or has detectable viral load on tx)
- at least one episode of condomless anal intercourse with casual partner
- chemsex (eg using ice or GHB and having sex)
- rectal gonorrhoea/chlamydia or gonorrhoea
- plans to travel to high HIV prevalence area
- person entering/leaving institutional correctional facilities
Heterosexual
- 1+ episodes of condomless anal or vaginal intercourse with HIV+ partner or casual HIV+ partner or planning to conceive with HIV+ partner
IVDU
- shared injecting equipment with HIV+
127
What testing must be performed prior to prescribing PrEP?
HIV Ab/Ag (rationale: PrEP regimen is insufficient for tx of acute or chronic HIV)
- must repeat every 3mths
Renal function
STI testing eg gonorrhoea, chlamydia, syphilis
Hep A, HBV and HCV serology
(and recommend vax against HAV + HBV)
bHCG
No data on performing Vitamin D or BMD testing prior to starting PrEP but 10% have low BMD and tenofovir does reduce BMD
128
How do you manage px with recent high-risk exposure outside the 72hr window for the commencement of PrEP?
Closely monitor for seroconversion over next 2-8 weeks using HIV Ab-Ag testing before reverting to standard PrEP monitoring
129
What are the contraindications to PrEP?
eGFR <60
(Tenofovir assoc with risk of severe proteinuria and proximal renal tubular dysfunction/Fanconi syndrome and has not been studied in px with eGFR <60)
130
Can PrEP be safely used during pregnancy and breastfeeding?
Yes
No adverse pregnancy outcomes
(weak signal = low BMD and lower length/head circumference at 1yr)
131
What is the only PrEP regimen currently approved in Aus?
Daily tenofovir (TDF)and emtricitabine
132
How does on-demand PrEP work?
Also known as event-based PrEP
Administer 2 tabs 24hrs before potential sexual exposure to HIV followed by 3rd tablet 24hrs after and 4th tablet 48hrs
Can now be used in px with HBV
133
Which patient populations does ASHM recommend on-demand PrEP for?
cis-gender men
trans assigned male at birth who are not taken oestradiol-based hormone therapy or have a uterus or do not engage in receptive vaginal sex
all others - daily PrEP recommended
note TGA has not approved on-demand PrEP
134
When is long-acting injectable HIV PrEP indicated?
Injectable PrEP is with Cabotegravir
For people >12yo with HIV acquisition risk
- at risk if PrEP not prescribed + HIV neg +contraindications ot oral options
TGA and PBAC approved but not currently PBS listed / available in Aus
135
What are the contraindications to Cabotegravir (and therefore long-acting injectable PrEP)?
HIV infection/unknown HIV status
Non-adherence
Known hypersensitivity
Concurrent UGT1A enzyme inducers eg rifampicin, phenytoin, carbamazepine etc
136
What are the main side effects of PrEP therapy?
Headache, nausea and flatulence
Rare hepatotoxicity
137
How long is it until you achieve high HIV protection after commencing PrEP?
7 days of daily dosing although single loading dose of two PrEP tablets considered to provide good protection
138
What are the 4 INSTI-based therapies recommended as first line for adults with HIV viral load <500,000?
Lamivudine+dolutegravir (Dovato)
TAF+emtricitabine+bictegravir (Biktarvy)
TAF+emtricitabine+elvitegravir+cobicistat (Genvoya)
Dolutegravir+abacavir+lamivudine (Triumeq)
139
Which of the 4 first-line INSTI-based therapies is NOT recommended for HIV viral load >500,000
Dovato
140
What do you give to a pregnant women with HIV and viral load >1000 or unknown viral load or detectable but <1000 during childbirth to prevent perinatal transmission of HIV?
Zidovudine IV in addition to their regular ART
141
Do you need to give intrapartum antiretroviral therapy to prevent perinatal transmission of HIV in pregnant women taking ART with an undetectable viral load near birth?
No
142
What are the most common HIV-related renal diseases seen?
HIVAN (HIV-associated nephropathy)
- almost exclusively in advanced HIV in african patients explained by genetic suspectibility (polymorphism in APOL-1 gene)
- manifests as heavy proteinuria without haeamturia, rapid worsening of renal function, increased echogenecity on USS, collapsing FSGS on biopsy
- tx with ART +/- pred and ACEi
HIVICK (HIV immune complex kidney disease)
- composed of variety of histological conditions incl IgA and lupus-like syndrome
- due to deposition of immune complexes within kidneys and assoc effects eg tubulointerstitial infalmmation
- p/w microhaematuria, variable proteinuria, impaired renal function
- more favourable prognosis than HIVAN
- tx with ART
143
Which ART are assoc with renal disease and should be avoided in px with CKD?
TDF
Ritonavir/lopinavir
Ritonavir/darrunavir
Ritonavir/atazanavir
144
Which ART may be assoc with increased serum Cr due to inhibition of tubular creatinine excretion without damage to kidneys?
Dolutegravir
Cobicistat
Rilpivirine
145
What is the clinical triad in patients with Fanconi syndrome, incl those caused by TDF ART?
Proteinuria
Hypophosphataemia
Renal glycosuria
146
How does HIV infection affect HBV disease?
HIV co-infection modifies natural hx of HBV infection
Persistent HBV infection more common in HIV infection
HBV DNA levels higher in HIV+ than HIV-
Rates of seroconversion from HBeAg to anti-HBe lower in HIV+
Seroconversion back to HBsAg+ may occur in advanced HIV
Lower levels of ALT despite high levels of HBV replication
More likely to progress to cirrhosis
HIV infection assoc with 17x inc in liver-related mortality
Higher rates of HCC
Severe hepatotoxicity occurs in 10% of px commencing combined ART and HIV-HBV coinfection is an independent risk factor for cART-related hepatotoxicity
Hepatitis flares (acute rises in LFTs due to immune restoration following cART)
147
Which ART drugs are especially implicated in severe hepatotoxicity and should be used cautiously in px with HIV-HBV coinfection?
Ritonavir
Nevirapine
Tipranavir
148
What are the preferred initial ART treatment regimens for px with HIV-HBV coinfection?
TAF+emtricitabine+bictegravir (Biktarvy)
OR
TAF+emtricitabine+elvitegravir+cobicistat (Genvoya)
149
When should Post-exposure prophylaxis (PEP) ideally be given?
Within 72hrs of exposure
Then continue to take daily for 28days
Note it is not PBS listed
2 drug regimen = TDF + emtricitabine
150
What exposures constitute an indication for PEP if HIV status is unknown?
Receptive or insertive anal intercourse
Receptive or insertive vaginal intercourse
Shared contaminated injecting equipment
Consider for needlestick/sharps exposure/mucus membrane and non-intact occupational exposure
151
When is a 3 drug post-exposure prophylaxis regimen indicated?
In cases of receptive/insertive anal or vaginal intercourse OR shared injecting equipment or occupational needlestick/sharps exposure in px with known HIV not on ART or VL >200 or VL unknown
152
What does 3 drug PEP consist of?
TDF-emtricitabine+ dolutegravir
153
Is PEP recommended for oral sex or semen splash to eye or human bite?
No - even if HIV+
154
Is PEP recommended in cases where source is HIV+ but VL is not detectable or they are taking PrEP?
No, except in occupational exposure
155
Is PEP indicated for needlestick injuries from discarded needles in the community?
No
156
What is mastocytosis?
A rare disorder due to chronic and episodic mast cell mediator release and excessive mast cell accumulation in one or more tissues
Pathogenesis - unclear, one part may be due to gain-of-function mutations in KIT a receptor on mast cells that when stimulated by stem cell factor leads to development and expansion of mast cells from haematopoetic progenitors
Despite genetic component, most cases not inherited ie somatic
Adults develop systemic forms in 95% of cases (in contrast children have cutaneous/skin-limited disease in >90%)
157
What are the characteristic presentations of mastocytosis?
Mastocytosis in Skin - gradual development of maculopapular cutaneous mastocytosis/urticaria pigmentosa which consists of multiple monomorphic, reddish brown macules
- may have assoc urticaria with rubbing of the skin or hot showers
- majority will note systemic mast-cell mediated symptoms such as flushing, cramping, hyperacidity and diarrhoea
Systemic mastocytosis
- recurrent severe anaphylactic episodes to hymenoptera (bee, wasp etc) stings, exercise, medications given in perioperative setting or unexplained should raise suspicion, esp if negative venom allergy testing
Less severe symptoms = flushing, tachycardia, regular GI symptoms (diarrhoea, cramping, hyperaciditiy), syncope etc
NOTE urticaria and angioedema are NOT typical
158
What is Darier's sign and what does it indicate?
Darier's sign = development of erythema or urticaria within 5mins of the examiner lightly rubbing/stroking/scratching an area of skin
- suggestive of presence of mast cells within the lesion
- may not be present in px taking antihistamines
159
What are some less common presentations of systemic mastocytosis?
Cytopenias (due to infiltration bone marrow by mast cells and interference with normal haematopoiesis)
Osteoporosis and pathologic bone fractures in a young male adult without risk factors for osteoporosis
Adult with sclerotic or lytic bone lesions on imaging who is found to have mast cell infiltrates on bone marrow biopsy
160
How do you diagnose mastocytosis?
Cutaneous mastocytosis
- typical skin lesions + typical histologic mast cell infiltrates on skin biopsy
Systemic mastocytosis - 1 major + 1 minor or 3+ minor
- major - multifocal dense mast cell infiltrates on bone marrow or extracutaneous biopsy
- minor
- mast cells that express CD25 in addition to normal mast cell markers
- persistently elevated serum total tryptase
- detection of relevant KIT mutations
- >25% spindle-shaped or immature/atypical mast cells on bone marrow or extracutaneous biopsy
161
How do you treat mastocytosis?
Anaphylaxis - adrenaline
Urticaria - antihistamines
GI symptoms - H2RA
Flushing/bronchospasm/abdo cramps unresponsive to antihistamines/H2RA - montelukast
Further treatment based on subtype of systemic mastocytosis ie indolent systemic mastocytosis vs smouldering SM vs SM with assoc haematologic neoplasm
162
How is mast cell activation syndrome different to mastocytosis?
Mast cell activation syndrome (MCAS) as an umbrella term or category of conditions with primary MCAS referring to systemic mastocytosis and secondary MCAS being a severe IgE-dependent allergy with another idiopathic MCS category
There's also Monoclonal Mast cell activation syndrome (MMAS) - another form of primary MCAS - which describes px who experience episodes of mast cell activation symptoms (eg recurrent flushing, GI cramping, hypotension) and meet 1-2 minor criterion but not the fully diagnostic criteria for systemic mastocytosis
163
What is urticaria?
Hives
A skin condition characterised by red, blanching, oedematous, non-painful, pruritic lesions that typically resolve within 24hrs and leave no residual markings
164
What time frame defines acute (vs chronic) urticaria?
Acute urticaria = less than 6 weeks
Chronic = daily/near-daily episodes for >6 weeks
165
What is angio-oedema?
Sudden pronounced swelling of the subdermis or mucous membranes
- can occur with or without urticaria
- may be painful
- often affects the face/lips, mouth, upper airway, genitals and extremities
166
How common is urticaria?
Acute urticaria - lifetime prevalence ~20%
Chronic urticaria ~1-2%, women > men
167
How common is angio-oedema?
ACEi-related angio-oedema - 0.5%
Hereditary angio-oedema - 1 in 50,000
Acquired angio-oedema - 1 in 500,000
168
What is the cause of acute urticaria?
Most allergic / IgE-mediated reaction to drugs (beta-lactam) or foods (milk, eggs, peanuts, shellfish), insect bites/stings
Certain drugs (e.g. NSAIDs, aspirin, opioids) may cause urticaria through direct mast cell degranulation
Radiocontrast dye and viral infections may cause acute urticaria through non-IgE mediated mechanisms
169
What causes chronic urticaria?
Two main types - chronic inducible urticaria (<10%) triggered by heat, cold, pressure, sunlight etc
Chronic non-inducible - nil clear/predictable trigger
- uncertain aetiology, half are thought to be autoimmune (eg assoc with Hashimoto's thyroiditis or SLE
some autoantibody-mediated (IgG antibodies to IgE receptors or IgE)
Rest idiopathic
170
What are the causes of angio-oedema (without urticaria)?
Hereditary
ACEI
Autoimmune disorders
Drugs, inset bites, food
Idiopathic
Lymphoproliferative disorders eg NHL, MGUS
171
What is hereditary angio-oedema (HAE)?
An autosomal dominant condition caused by mutations in SERPING1 gene which codes for C1 inhibitor.
2 subtypes
- type 1HAE - deficiency of C1 esterase
- type 2 HAE - dysfunction of C1 esterase
172
What is the pathophysiology of angio-oedema?
Can be histamine-mediated or bradykinin-mediated
Histamine-mediated = same mast cell and basophil processes responsible for urticaria
- most px with idiopathic acquired angio-oedema have histamine-mediated
Bradykinin-mediated = due to aberrant activation of the contact-kinin system
- responsible for the hereditary angio-oedema and ACEi-induced angio-oedema (ACEi block ACE which normally breaks down bradykinin)
173
Why do patients with hereditary angio-oedema have bradykinin-mediated angio-oedema?
Because C1 esterase inhibitor (a component of the complement system) inhibits production of bradykinin
Therefore in HAE, deficiency or dysfunction of C1 esterase inhibitor leads to increased bradykinin product
174
Atypical urticarial lesions should raise suspicion for what conditions?
Cholinergic urticaria
Urticarial vasculitis
175
What tests should you perform for someone with acute urticaria?
Generally none
Diagnosis all in history + exam incl triggers
Consider serological allergy testing
176
What evaluation should you perform in someone with chronic urticaria?
Detailed hx
Physical exam incl
- dermatographism
- cold urticaria (place ice cube on skin for 5mins)
- delayed pressure urticaria (place sand bag over shoulder for 30mins)
- aquagenic urticaria (apply water compress)
Investigations
- FBC, inflammatory markers
Consider:
- TSH
- ANA
- serum tryptase (systemic mastocytosis)
- skin biopsy (if concern for urticarial vasculitis)
177
What investigations should you perform for the evaluation of angio-oedema without urticaria>
C4 (screening)
C1 esterase inhibitor level
C1 esterase inhibitor function
C1q level
178
When does ACEi-induced angio-oedema typically occur?
Within days of initiating therapy although some individuals experience it after years of treatment
179
What other drugs may cause drug-induced angio-oedema?
NSAIDs
Antibiotics
180
What are the clues that would point towards hereditary angio-oedema?
Positive family history (but 25% no fhx)
Decreased C4 levels
Decreased C1 esterase levels or function
Normal C1q levels
181
What test differentiates acquired angio-oedema from hereditary angio-oedema?
C1q
C1q = normal in hereditary
C1q = low in acquired
Both have low C4 level, C1 levels and function
Note if C1q normal but suspicion for acquired
- could test SERPING1 gene mutation (only present if HAE)
Note whilst anti-C1-INH antibodies are characteristic of acquired C1 esterase inhibitor deficiency, 30% of px with HAE have these antibodies, as well as 3% of normal controls
182
How do you treat acute urticaria?
Generally self-limiting
Avoid triggers
Non-sedating antihistamines
If severe, consider short-course corticosteroids
If assoc angio-oedema - adrenaline + hospitalisation + intubation (if stridor/resp arrest imminent)
183
How do you treat chronic urticaria?
If inducible - trigger avoidance
If not
- psychosocial stress reduction
- second generation antihistamines (eg loratadine, cetirizine, fexofenadine) taken prophylactically (ie daily) for years
- consider short courses of steroids for exacerbations
- 2nd line options =
add H2RA (eg famotidine) OR omalizumab
OR ciclosporin
184
How do you treat angio-oedema?
Hospitalisation + adrenaline + airway protection
Drug-induced (eg ACEi) - identify and avoid drug
Acquired angio-oedema - antihistamines +/- montelukast
- 2nd line = omalizumab, ciclosporin, etc
185
How do you treat hereditary angio-oedema?
Acute attacks
- C1esterase inhibitor concentrates OR
- Plasma kallikrein inhibitors (ecallantide) OR
- bradykinin B2 receptor antagonists (icatibant)
Note adrenaline, antihistamines and systemic steroids have no proven efficacy in hereditary angio-oedema
Chronic treatment
- Plasma-derived C1 esterase inhibitor = preferred prophylaxis treatment
2nd line = Danazol
3rd line = tranexamic acid (but less efficacious)
186
What are the associations and appropriate evaluation for someone with acquired angio-oedema due to deficiency of C1 esterase inhibitor?
# Lymphoproliferative malignancies eg NHL, indolent lymphomas such as splenic marginal zone lymphoma
Rare syndrome of recurrent episodes of angio-oedema without urticaria
Typically presents >40yo (cf hereditary angio-oedema which typically presents before age 20
Acquired C1 esterase inhibitor deficiency assoc with underlying lymphoproliferative, malignant or autoimmune disorder whereas HAE are otherwise healthy
Acquired - swelling affects face more; HAE = extremities
Acquired = low C1q; hereditary = normal C1q
Acquired is assoc with:
# MGUS
# Autoimmune disease incl SLE, AIHA, cyroglobulinaemia
# Infections eg H pylori
Evaluation should include:
- FBC
- blood film
- chem20
- SPEP
- serum FLC
- imaging for lymphadenopathy
- age-appropriate ca screening
- consider bone marrow biopsy
187
Is the absence of a family hx of angio-oedema diagnostic of acquired C1 esterase inhibitor deficiency?
No - more than 25% of px with HAE carry de novo mutations and therefore lack positive fhx
On the other hand, presence of family member with HAE essentially excludes diagnosis of acquired C1 esterase inhibitor deficiency
188
189
Why is the cause and pathogenesis of sarcoidosis?
Unknown
190
What are the risk factors for sarcoidosis?
Female
Age 20-60
Black race
191
What is sarcoidosis?
A multisystem disorder of unknown etiology characterized by the accumulation of T lymphocytes, mononuclear phagocytes, and noncaseating granulomas in involved tissues;
Mostly involves lungs but also skin, eyes and lymph nodes
192
Which part of the lungs does sarcoidosis have a predilection for?
Upper lobes and bronchovascular bundles
193
How do patients with sarcoidosis usually present?
50% based on incidental findings on CXR
Specifically fairly symmetrical bilateral hilar adenopathy and variable parenchymal abnormalities
These px tend to have stage 1 or 2 disease
May in retrospect have systemic symptoms related to respiratory or extrapulmonary manifestations
194
Do patients with sarcoidosis often have an abnormal respiratory examination?
No - often normal
195
For patients with symptomatic pulmonary sarcoidosis, what are the common symptoms?
cough, dyspnea, fatigue, and chest pain
Often accompanied by systemic symptoms including
fatigue, malaise, fever, and weight loss, muscle weakness, exercise intolerance
196
What are the most common extrapulmonary manifestations of sarcoidosis?
Skin lesions (eg, erythema nodosum, facial rashes including lupus pernio and papular sarcoidosis, nodular sarcoidosis lesions, and sarcoidosis hypopigmentation)
peripheral lymph node enlargement
visual changes (especially uveitis and dry eyes)
Hypercalciuria and mild hypercalcemia
197
What is Lofgren syndrome?
An acute manifestation of sarcoidosis often in 20-40yo women who p/w acute-onset fever, hilar adenopathy, and variable proportions of erythema nodosum or bilateral ankle inflammation
Highly specific but not pathognomonic for sarcoidosis
198
Why should you not biopsy erythema nodosum in lofgren syndrome?
Because it will show panniculitis rather than granuloma
199
What is Heerfordt syndrome?
Rare manifestation of sarcoidosis
combination of anterior uveitis, bilateral parotid gland enlargement, facial nerve palsy, and fever
200
What is another rare but characteristic presentation of sarcoidosis?
Lupus pernio is characterized by violaceous or erythematous indurated, infiltrative plaques distributed on the central face, particularly the nose and cheeks
201
What is the characteristic HRCT feature of sarcoidosis?
presence of small nodules (2 to 5 mm) in a perilymphatic distribution
Micronodules surrounding a large nodule or conglomerate mass, also called the "galaxy sign," are a pattern highly suggestive of sarcoidosis
The finding of faint "icing" or "frosting" calcifications in lymph nodes is also suggestive
202
Does FDG-PET help differentiate sarcoidosis from infection or malignancy?
No, but it may help identify more occult lesions amenable to biopsy
203
What other conditions should be considered in the differential of someone with suspected sarcoidosis?
TB/ mycobacterial infection
Fungal infections
HIV
Eosinophilic granulomatosis with polyangitis
Lymphoma
Pulmonary Langerhans cell histiocytosis and Erdheim-Chester disease
204
What is the role of serum ACE in diagnosing sarcoidosis?
Limited
Altho elevated in 75%, neither sens nor specific
205
How do you diagnose sarcoidosis?
No gold standard, rather typical need 3 elements:
●Compatible clinical and radiographic manifestations
●Exclusion of other diseases that may present similarly
●In many cases, histopathologic detection of non-necrotizing granulomas
206
What tests should you perform in someone with confirmed sarcoidosis?
Respiratory function tests
Eye exam
Baseline bloods incl vit D testin
207
What is the characteristic finding on respiratory function testing in someone with sarcoidosis?
A restrictive pattern (reduced vital capacity and total lung capacity) and a reduction in DLCO
208
What prognostic factors are associated with need for treatment in sarcoidosis at 2 years?
Dyspnoea grade 2 or requirement for systemic tx within first 6mths
Other factors reduce risk of spontaneous remission or predict worse outcomes include:
Older age, Black race, lower socioeconomic status, female sex, and higher Scadding stage and number of organs involved
209
What is the prognosis of sarcoidosis?
Most px with mild pulmonary disease or asymptomatic radiological involvement will experience Spontaneous remission, including radiographic resolution,
- 60 to 80 percent of patients with radiographic stage I disease
- 50 to 60 percent with stage II disease
- in less than 30 percent with stage III
However px with more extensive resp involvement or reduced lung function are more likely to develop fibrocystic scarring (stage IV radiographic disease) over time
Fibrocystic scarring increases the risk of progressive fibrosis, pulmonary hypertension, chronic pulmonary aspergillosis (CPA), and respiratory failure.
210
When is treatment indicated in sarcoidosis?
In symptomatic disease, eg pulmonary stages 2-4
Usually it is not necessary to treat stage 1 pulmonary disease unless there is progressive adenopathy
211
What is the mainstay of treatment for symptomatic sarcoidosis stage 2-4 disease?
Oral steroids
- improve symptoms, CXR appearance and spirometry
- uncertain whether have any long-term disease modifying activity beyond 2 years
212
What are second line agents for sarcoidosis?
Steroid-sparing agents eg MTX, azathioprine, leflunomide, MMF, hydroxychloroquine
213
What are some important supportive measures in pulmonary sarcoidosis treatment?
Oxygen therapy if resting/exercise oxygen sats <88%
214
In patients with end-stage lung disease what treatment may be indicated?
Lung transplant
215
How do you treat cutaneous sarcoidosis?
Topical or intralesional corticosteroids
If severe/ refractory - oral corticosteroids
Lupus pernio may respond to infliximab
216
How do you treat ocular sarcoidosis?
Opthalmology care
Topical corticosteroids
Oral reserved for resistant disease or optic neuritis
217
How do you treat Cardiac sarcoidosis?
Multidisciplinary team approach
Higher dose corticosteroids + steroid-sparing agent
Refractory disease - infliximab
218
How do you treat neurosarcoidosis?
Corticosteroid therapy
219
What are the manifestations of neurosarcoidosis?
Cranial neuropathies incl optic neuritis
Meningeal disease
CNS parenchymal disease eg mass lesions, encephalopathy, seizures
Spinal canal disease (eg cauda equina)
Myopathies
Pituitary disease eg diabetes insipidus
220
What is the most important cause of renal failure in sarcoidosis?
Disordered calcium metabolism
221
What is the most typical histological finding in renal sarcoidosis?
Granulomatous interstitial nephritis
222
How do you treat renal sarcoidosis?
1st line = Glucocorticoids
2nd line = hydroxychloroquine + ketonazole (if hypercalcaemia/hypercalciuria) OR Aza/MMF if granulomatous interstitial nephritis
3rd line = infliximab
223
When does severe/life threatening haemoptysis occur in sarcoidosis and how do you treat it?
In people with aspergillomas or bronchiectasis
Treat with bronchial artery embolisation OR endobronchial balloon tamponade
224
What % of cases of cardiac sarcoidosis lack extra cardiac involvement?
25%
So absence of extra cardiac sarcoid involvement does not exclude cardiac sarcoid
225
How do you diagnose cardiac sarcoidosis?
Definitively require endomyocardial biopsy (if no extrcardiac sarcoidosis).
If extracardiac involvement or ‘probable’ diagnosis can be made using FDG-PET and cardiac MRI
