allergies and hypersensitivities Flashcards
what is an allergy
immunological mediated hypersensitivity response to a substance in a sensitised person
what does an allergy cause
response of immune response to an antigenic substance leads to host tissue damage, manifesting as a organ specific or generalised systemic reaction
what are drug hypersensitivity reactions
includes adverse events that clinically resemble drug allergy but have yet proven to be associated with an immune response
drugs that can cause the release of mast cells and basophil derived mediators by a pharmacological/ physical effect rather than IgE
what are the effectors of allergic/ drug hypersensitivity reactions
major components of innate and adaptive immunity, pharmacologically active chemical mediators
what are the components of innate and adaptive immunity
cellular components, complements, cytokines, Ig
what are examples of pharmacologically active chemical mediators
histamine, platelet aggravating factors, thromboxanes, prostaglandins, leukotrienes
what are granulocytes
type of WBC that degranulates and release whole bunch of toxic substances that can damage both invading and nearby host cells
what is type 1 hypersensitivity
IgE mediated, occurs within minutes, genetic predisposition that makes T cells mores sensitive to allergen
what is the process of type 1 hypersensitivity
sensitisation phase: T cells bind to specific molecule on allergen and present it to APC which mounts an immune response if allergic, after this the naive T cells become primed and are now Th2 cells, when excited, it releases IL4 which causes B cells to undergo class switching and produce IgE Ab instead of IgM and will also release IL5 which stimulate production and activation of eosinophils. since IgE are highly specific they bind to Fce receptor on mast cells
early phase response: mast cells now have Fce receptor and IgE which will bind to allergen during reexposure causing degranulation of mast cell and thus release of mediators and cause effects of allergic reaction
late phase response: recruitment of more immune cells to site of allergen due to cytokines and mediators released
what are the mechanisms of injury in a type 1 hypersensitivity reaction
mast cell derived mediators and cytokine derived inflammation
what are examples of mast cell derived mediators
vasoactive amines, lipid mediators, cytokines
what are examples of cytokines that cause inflammation
eosinophils and neutrophils
what are the components involved in type 1 hypersensitivity
Th2 cells, eosinophils, IgE, mast cells
what is type 2 hypersensitivity
antibody mediated hypersensitivity, cytotoxic hypersensitivity, occurs due to escaped self reactive T and B cells which causes autoimmune disease if target healthy cells
what is the process of type 2 hypersensitivity
Ag bind to RBC which causes IgG specific to Ag to bind to Ag and form Ab-Ag complex which activates the complement system to kill off RBC
mechanism 1: C1 binds to Fc of Ab -> activate C2-C9 -> some get cleaved into chemotactic factors which attracts neutrophils -> degranulate and release oxygen radicals that are highly cytotoxic -> cell death and tissue damage
mechanism 2: C5b, C6-9 come together to attack complex, MAC inserts within cell membrane, causing channels to form which allows fluid and molecules to flow into and out -> osmotic difference causes fluid to rush in -> bursting of cell (lysis)
mechanism 3: IgG bind to C3b -> cell opsonised and targeted by phagocytosis by macrophages and neutrophils by targeting Fc domain of Ab of C3b bounded to IgG -> engulf and destroy
mechanism 4: Ab-Ag complex recognised by NK cells by Fc domain of Ab -> release of toxic granules -> causes perforation -> allows not only fluid but also enzymes which causes apoptosis of cells
mechanism 5: cellular dysfunction
what are the mechanisms of injury in type 2 hypersensitivity
complement and Fc receptor mediated recruitment and activation of leukocytes, opsonisation and phagocytosis of cells, abnormalities in cellular dysfunction
what are the components involved in type 2 hypersensitivity
IgG, IgM, extracellular matrix Ag
what is type 3 hypersensitivity
immune complex mediated hypersensitivity
what is the process of type 3 hypersensitivity
Ab are produced by plasma cells, IgM attaches to Ag which is presented to T cell -> T cell releases cytokines -> B cell activation and class switching from IgM to IgG -> smaller Ab-Ag complexes get deposited on vessel walls and not engulfed by macrophages -> activate complement system -> C1 binds to complement -> C2-C9 activated -> cleaved into fragments -> attract neutrophils -> try to phagocytose but cannot so degranulate -> release lysosomal enzymes and reactive oxygen species -> inflammation
what are plasma cells
fully matured and differentiated B cells
what are the components involved in type 3 hypersensitivity
IgM/IgG -Ag complexes deposited in vascular basement membrane
what is type 4 hypersensitivity
T cell mediated diseases
what is the process of type 4 hypersensitivity
Ag presented by APC to T cell via MHC II molecule -> release cytokine
what are the mechanisms of injury in type 4 hypersensitivity
macrophage activation, cytokine mediated inflammation for CD4+
direct target cell lysis, cytokine mediated inflammation for CD8+
what are the components involved in type 4 hypersensitivity
CD4+, MHC II, CD8+, MHC I
what are immune complexes
only if Ab bind to soluble Ag flowing freely in blood, not considered if Ab bind to Ag on cell surface
what are the clinical manifestations of hypersensitivity reactions
anaphylaxis, drug fever, drug induced autoimmunity, vasculitis, respiratory, hematologic
what is anaphylaxis
acute life threatening reaction that involves multiple organ symptoms
what are drugs commonly associated with anaphylaxis
NSAIDs, penicillin, insulin
what is drug fever caused by
systemic reactions caused by circulating immune complexes
what are drugs commonly associated with drug fever
abx
what are drugs commonly associated with vasculitis
allopurinol, thiazide
what are drugs commonly associated with respiratory manifestations
asthma - NSAIDs
acute infiltrative and chronic fibrotic pulmonary reactions - bleomycin, nitrofurantoin
what are examples of a hematologic manifestation
eosinophilia, hemolytic anemia, thrombocytopenia, agranulocytosis
what is are the examples of SCAR
drug rash with eosinophilia and systemic symptoms (DRESS), mucocutaneous disorders (SJS, TEN)
what is DRESS
triad of rash, eosinophilia and internal organ involvement
what are common drugs that can cause DRESS
allopurinol and anticonvulant
what is SJS/TEN
progressive bullous/ blistering disorders that constitute as dermatological emergencies, progress to include mucus membrane erosion and epidermal detachment
how to differentiate between SJS and TEN
<10% SJS, >30% TEN
what are common drugs that can cause SJS/TEN
abx especially sulfonamides
what is the treatment for SCAR
mostly supportive care (wound care, temperature regulation, nutritional support, pain management, fluids, prevention of infection)
what are the drugs that are susceptible to genetic predisposition for drug hypersensitivity
allopurinol. abacavir, carbamazepine, phenytoin
what are autoimmune diseases
when body is attacked by own immune system
what are examples of autoimmune diseases
rheumatoid arthritis, type 1 DM, grave’s disease, systemic lupus erythematous, systemic vasculitis, scleroderma, psoriasis, sjogren’s syndrome, multiple sclerosis
what is systemic lupus erythematosus
autoimmune disease associated with autoantibody production, is a multisystem disease
what are the characteristics of SLE
more prevalent in females, strong genetic predisposition and environmental factors
what is the pathophysiology of SLE
characterised by disorders of the innate and adaptive immune system, T and B cell signalling altered in SLE which causes abnormal clearance of apoptosis debris containing nuclear material which can stimulate immune responses, number of plasma cells increased in active SLE which increases number of Ab produced which causes tissue damage
what are the git clinical presentation of SLE
mouth and nose ulcers
what are the skin clinical presentation of SLE
butterfly rash, red patches
what are the respiratory clinical presentation of SLE
pleuritis, pneumonitis, pulmonary emboli, pulmonary hemorrhage
what are the cardio clinical presentation of SLE
endocarditis, atherosclerosis, inflamm of fibrous sac
what are the blood clinical presentation of SLE
high BP, anemia
what are the kidney clinical presentation of SLE
blood in urine
what are the muscle and joints clinical presentation of SLE
pain, arthritis aches, swollen joints
what are the other clinical presentation of SLE
hair loss, abnormal headache, high fever
what is lupus nephritis
lupus Ab affect structures in kidneys which help filter out waste, kidneys affected to different extents (class I to VI)
what is neuropsychiatric lupus
lupus affect brain, spinal cord and other nerves
what are the full blood count biomarkers and should it be low or high in SLE
decr RBC due to hemolytic anemia, decr WBC and lymphocytes, decr PLT
what are the immunological biomarkers and should it be low or high in SLE
positive antinuclear Ab (ANA), positive anti ds-DNA (dsDNA), positive antinuclear ribonuclearprotein (antiRNP), antismith Ab (anti-Sm), low complement (C3, C4, CH50)
what does positive ANA mean
immune system launch a misdirected attack on own tissue
what does positive anti-RNP suggests
connective tissue disease
why would there be low complement in SLE
due to activation of complement system in SLE (type III hypersensitivity)
what is the general treatment goals for SLE
goal to achieve remission but realistically to aim for low disease activity, to prevent flares, reduce use of steroids, improve QoL, minimise adverse effects, evaluate and treat comorbs, lifestyle and support groups
what are the approved FDA drugs for pharmacological treatment of SLE
aspirin, prednisolone, hydroxychloroquine, belimumab
what are the drug classes and its uses (and caution if any) for pharmacological treatment of SLE
NSAIDs - first line agent for acute symptoms, caution in lupus nephritis, increased cardiac risk and GI bleed
steroids - mono/ adjunct therapy to prevent flares and maintain low disease activity, has rapid onset, caution with long term use
biologics - target and disrupts functioning of B cells
immunosuppressants
what is the chosen drug for treatment of SLE (moa and duration of use)
all patients with SLE to take hydroxychloroquine due to its anti inflamm, anti thrombotic and immunomodulatory effects, has minimal adverse effects and to be used for 4-8w
what are examples of immunosuppressants used for treatment of SLE
IV/PO cyclophosphamide, mycophenolate, azathioprine
what is cyclophosphamide used for in SLE
severe organ involvement as induction therapy
what is mycophenolate used for in SLE
induction and maintenance therapy
what is azathioprine used for in SLE
alternative to mycophenolate for maintenance
how do you evaluate the therapeutic outcome for SLE
ADR, comorbs, biomarkers, disease progression based on questionaires
what are the questionaires used to measure disease activity
SELENA-SLEDAI, BILAG
how often are lab tests conducted for SLE
q1-3m if active, q6m if stable
what are the biomarkers in the lab tests for SLE
anti-dsDNA, CRP, FBC, complement, urinalysis/ renal func, LFTs
what are the biomarkers that do not need to be repeated every session for SLE
anti-RNP, ANA, antiSm
what is antiphospholipid syndrome
antiphospholipid antibodies are present, which act as inhibitors and bind to phospholipid in clotting factors thus increasing the risk of clotting and thrombosis
what are the three primary antiphospholipid Ab
lupus anticoagulant, anticardiolipin, anti-beta glycoprotein 1
what is the treatment for APS
primary thromboprophylaxis using hydrochloroquine, aspirin
secondary thromboprophylaxis using warfarin
what are the drugs of high risk that can cause drug induced lupus
procainamide, hydralazine, quinidine
what are the other drugs that can cause drug induced lopus
methyldopa, carbamazepine, isoniazid, minocycline
what is the potential moa of drugs that causes drug induced lopus
small molecules that induce an immune response by binding to larger molecules like proteins
what is the treatment for drug induced lupus
stop use and consider symptomatic treatment
what is the goal for induction treatment to achieve immunosuppression
high potency and short course treatment asap to reduce existing damage and prevent worsening of autoimmune condition
what are the drugs used in induction therapy and how does it achieve immunosuppression
prevent acute rejection with lymphocyte depleting therapy using basiliximab and alemtuzumab
what are the drug classes used in maintenance therapy to achieve immunosuppression
corticosteroids, calcineurin inhibitors, mTOR inhibitors, antimetabolites, biologics
what are examples of drugs that are calcineurin inhibitors
cyclosporin, tacrolimus
what are examples of drugs that are mTOR inhibitors
sirolimus, everolimus
what are examples of drugs that are antimetabolites
mycophenolate, azathioprine
what are examples of drugs that are biologics
adalimumab
what are the complications of immunosuppression
opportunistic infections, cancer, renal toxicity, hepatotoxicity, blood disorders, cardio complications (htn, hyperlipidemia, hyperglycemia)
what are the types of opportunistic infections that can result from immunosuppression
bacterial, viral, fungal, parasites
what are the drugs that can cause renal toxicity
calcineurin inhibitors (tacrcolimus, cyclosporin)
what are the drugs that can cause hepatotoxicity
antimetabolites (mycophenolate, azathioprine)
what are the blood disorders as a result of immunosuppression
thrombocytopenia, leukopenia, pancytopenia
what are the drugs that can cause hyperglycemia
mTOR inhibitors (sirolimus, everolimus), calcineurin inhibitors (tacrolimus, cyclosporin)
what is thrombocytopenia
low PLT
what is leukopenia
low WBC
what is pancytopenia
low WBC, RBC, PLT
what are the therapeutic effects of steroids
DMARD effect in RA, anti inflamm and immunosuppression (decr pain, swelling, physical disability, stiffness), anti allergic, decr endothelial permeability and dysfunction
what are the adverse effects of steroids
incr cvs risk, cataract glaucoma, hirsutism and skin thinning, gastric ulcer if concomitant NSAIDs, weight gain, fluid retention, cushing syndrome, impaired glucose metabolism, insulin resistance, beta cell dysfunction, neuropsychiatric symptoms, HPA insufficiency, osteonecrosis, osteoperosis, myopathy, infections
what does HPA stand for
hypothalamus-pituitary-adrenal
who is most susceptible to HPA axis suppression
patients on chronic corticosteroid therapy
what is the process of HPA axis suppression
exogenous glucocorticosteroids causes decr secretion of CRH and ACTH due to negative feedback -> over time leads to atrophy of HPA axis due to inactivity -> results in adrenal suppression
what is CRH and where is it secreted from
corticotropin-releasing hormone from hypothalamus
what is ACTH and where is it secreted from
adrenocorticotropic hormone from pituitary
what is the approximate cut off of steroid use to prevent adrenal suppression
> 5mg prednisolone equivalents daily for more than 3w
