HYPERSENSITIVITY Flashcards
drug/ food/ etc allergies
• Immunologically mediated hypersensitive reaction to sub in sensitised person
Response of immune system to antigenic sub leads to host tissue damage (organ specific// generalised systemic reaction)
6-10%
what is present in allergy
○ IgE released
○ Type 1 Immediate hypersensitivity
§ TH2 cells, IgE Ab, mast cells, eosinophils
§ Mast cell-derived mediators
§ Cytokine-mediated inflam
§ Eosino, neut
Immune response:
• Hives
• Rash
• Hypotension
• Bronchospasm
• Anaphylaxis
• Vasculitis
Drug hypersensitivity
• Adverse events that clinically resemble drug allergy
• Not proven to be associated with immune response
Drug hypersensitivity what is present
• Drug release mast cell
• Basophil derived mediators
• By pharmacologic or physical effect
•Not IgE
eg of drug hypersensitivity
• Vancomycin
• Red man syndrome
• Direct release of histamine when infused too quickly
• ACE/ sacubitril
• Angioedema
• Inhibit breakdown of bradykinin
• Inflammation, vasodilation, permeation
• NSAID
• Induced asthma
• Alter metabolism of prostaglandins
•Vasoconstriction
effector of allergic / DH reactions
○ Involve major components of INNATE/ ADAPTIVE immune
§ Cellular elements: macro, T, B lymph, mast cells
§ Ig E
§ Complements
§ Cytokines
○ Release of pharmacologically active chemical mediators
§ histamine
§ Platelet-activating factor – platelet aggregation
§ Prostaglandin
§ Thromboxane
§ Leukotrienes – bronchodilators
Clinical manifestation of drug allergies/ hypersensitive rxn
anaphylaxis
serum sickness (drug fever)
drug-induced autoimmunity
vasculitis
respiratory
hematologic
Serious cutaneous ADR
Anaphylaxis
Acute, life threatening reaction
Multiple organ systems involved
• Risk of fatality within first few hrs (acute)
○ Skin: hives, itch, flushed skin, swelling of lips, tongue, throat, face
○ Airway: bronchospasm, trouble breathing, chest tightness
○ CNS
○ CVS: low BP, fast HR
○ GIT
• Most reported: penicillin, NSAID, insulin
Serum sickness/ drug fever
• Circulating immune complexes (antigen in body, drug/ transplant)
• Systemic symptoms
• Fever, malaise, rash
Antibiotics
Drug induced autoimmunity
• Systemic lupus erythematosus (SLE)
• Hemolytic anemia: Methyldopa
•Hepatitis: phenytoin
vasculitis
• Inflammation and necrosis of blood vessel walls
• Limited to skin, or may involve multiple organs
• Kidney, liver etc
Allopurinol, thiazide (diuretic)
respiratory
• Asthma: NSAID
• acute infiltrative and chronic fibrotic pulmonary reactions: bleomycin (chemo)
• nitrofurantoin
Hematologic
• Eosinophilia common manifestation of DH
• Hemolytic anemia(RBC)
• Thrombocytopenia(PLT)
• Agranulocytosis
○ Low neut count
○ Low granulocytes
Serious cutaneous AD
• Drug rash with eosinophilia and systemic symptoms (DRESS)
•mucocutaneous disorders
•steven-Johnson syndrome
•toxic epidermal necrolysis
• Drug rash with eosinophilia and systemic symptoms (DRESS)
• Triad:
1) Rash
2) Eosinophilia
3) Internal organ involved
i. Hepatitis, carditis, interstitial nephritis, odynophagia
• Allopurinol, anticonvulsants
• 10% mortality
Stevens-Johnson syndrome (SJS)
• Bullous or blistering disorders. Dermatologic emergencies
• Can progress to:
○ Mucous mem erosion
○ Epidermal detachment
○ <10% detachment of BSA
• Antibiotics (sulfonamides) • 1-5% mortality
Toxic epidermal necrolysis (TEN)
• Bullous or blistering disorders. Dermatologic emergencies
• Can progress to:
○ Mucous mem erosion
○ Epidermal detachment
○ >30% detachment of BSA
• Antibiotics (sulfonamides) • 10-70% mortality
Genetic disposition for drug A/ HS
1) HLA (human leukocyte antigen) alleles incr susceptibility to several DHS syndrome
2) Metabolic deactivation of drugs affected by genetics
§ Phase 1,2 metabolism
Genetic disposition for drug A/ HS
1) HLA (human leukocyte antigen) alleles incr susceptibility to several DHS syndrome
2) Metabolic deactivation of drugs affected by genetics
§ Phase 1,2 metabolism
Therapeutic agents for A/ HS rxn: anaphylaxis
• Restore resp and CVS function
1) Epinephrine (adrenaline)
• Hosp
• IV fluids – restore vol, BP
• Intubation – save airway collapse
• Norepinephrine – SHOCK
• Steroids, glucagon
• diphenhydramine, ranitidine
•Antihistamines
Therapeutic agents for A/ HS rxn: Serious cutaneous ADR
• Less defined, standardized
• Manage like burn pts
1) Supportive care
a. Wound care
b. Nutritional support
c. Fluids
d. Temp regulation (ice bathe)
e. Pain management
f. Prevent infections
2) Steroids use ?
Autoimmune diseases
condition where body attacked by own immune system
Autoimmune diseases caused by:
○ Genetic background
○ Environmental stimuli: smoke, infections, drug use
= incr autoimmune disorder developed
Autoimmune diseases difficult to treat
§ Do not respond to treatment/ lose response/ do not tolerate/ ADR
§ Drugs are poorly indicated, off-label
□ Not researched sufficiently on
□ Greater variability of treatment among centers and specialists
§ Costly drugs
§ Stigma, weakness, less likely to seek help/ diagnosis
SLE Clinical manifestation
• Disease fluctuates with periods of remission, flares, progression
• BUTTERFLY Rash on face
• Muscle and joints
○ Joints swollen, tender
○ Arthritisaches
○ Swollen joints
• Heart
○ Endocarditis
○ Atheroclerosis
• Lung
○ Pneumonitis
○ Pul emboli
○ Pul hemorrhage
• Kidney
○ Blood in urine
• Blood
○ Anemia
○ High BP
○ Low blood counts: WBC, RBC, PLATELETS
SLE assiociations
• Auto-Ab production (multi-system disease)
• More prevalent in females
• Genetic disposition + environ factors
• Smoke, infections, drugs
• Mortality 2.6-3x > general pop
• CVS, renal, infections
Pathophysiology
• Disorder of innate & adaptive
• T, B lymph activation and signaling altered • Abnormal CL of apoptotic debris ○ (containing nuclear material) ○ Not cleared fast enough etc • Stimulate immune response ○ Incr n.o. plasma cells inactive SLE ○ Produce autoAb --> tissue damage § Target nucleic acid § Nuclear proteins
Clinical presentation
(organs)
1) lupus nephritis
2) neuropsychiatric lupus
3) cardiovascular CVS
1) lupus nephritis
• Class I - minimal mesangial
• Class II - mesangial proliferative
• Class III - focal
• Class IV - diffuse
•Class VI - advanced sclerosing (cancer)
2) Neuropsychiatric lupus
• Cerebrovascular disease -stroke
• Anxiety+
• Seizure
• Cognitive dysfunction
• Confusion
• Peripheral neuropathy
• Psychosis
Clinical presentation
(LABS)
- Full blood count
a. Hemolytic anemia
b. WBC, LYMPH, RBC, PLT - Immunologic
a. Anti(nuclear) Ab — ANA
b. Anti(double stranded DNA) Ab — dsDNA
c. Anti(smith)Ab —- Anti-Sm
d. Anti(nuclear ribonucleoprotein) Ab – anti-RNP
e. Low complement (C3,4, CH50)
i. Used to monitor if pt responding to treatment
ii. Try to incr back to normal lvls
Clinical presentation
(LABS)
- Full blood count
a. Hemolytic anemia
b. WBC, LYMPH, RBC, PLT - Immunologic
a. Anti(nuclear) Ab — ANA
b. Anti(double stranded DNA) Ab — dsDNA
c. Anti(smith)Ab —- Anti-Sm
d. Anti(nuclear ribonucleoprotein) Ab – anti-RNP
e. Low complement (C3,4, CH50)
i. Used to monitor if pt responding to treatment
ii. Try to incr back to normal lvls
SLE management OVERALL
• Remission is goal <– low disease activity
• Prevent flares, other organs
○ Slow disease activity
○ Reduce STEROIDS use
○ Improve QOL
○ Minimise ADR
• Treat other comorbidities
• Lifestyle, support grp
• No smoking
Pharmacological
(General)
• Aspirin (NSAID)
• Prednisolone (steroids)
• Hydroxychloroquine (1st line SLE)
○ Immunomodulatory
• Belimumab (biologics)
• Immunosuppressants
• Steroid sparing (less reliance)
○ Induction therapy
§ Mycophenolate: induce + maintain
§ Azathioprine: maintain
Aspirin
• 1st line for acute symptoms
Caution: lupus NEPHRITIS, incr cardiac risk, GI bleed
Prednisolone (steroids)
• Mono/ adjunct
• Control flares, maintain low disease activity
• Rapid onset
•Concern: high dose, LT effect
Hydroxychloroquine (1st line SLE)
antimalaria class of drugs
• Even preg
• Prevent flare
• LT survival
○ Anti-inflamm
○ Immunomodulatory
○ Anti-thrombotic effect
○ Minimal adverse effects
• 4-8wks to have effect
Belimumab (biologics)
• Target, disrupt function of B cells, plasma cells
○ Belimumab/ rituximab
Ongoing trials for other biologics
Immunosuppressants
• IV/PO cyclophosphamide
• Steroid sparing (less reliance)
○ Several organ involved
○ Induction therapy
§ Mycophenolate: induce + maintain
§Azathioprine: maintain
Complications/ types of SLE
1) Antiphospholipid syndrome (SLE-APS)
2) drug-induced SLE
1)Antiphospholipid syndrome (SLE-APS)
• Antiphospholipid Ab
○ Lupus anticoagulant, anticardiolipin, anti-b2 glycoprotein (+ve)
• High risk of clotting, preg morbidity
• Treatment: ○ 1* thromboprophylaxis § Hydroxychloroquine + aspirin ○ 2* thromboprophylaxis (repeated clots) Warfarin
- Drug-induced SLE
10-15% of SLE from drug use
• IDIOSYNCRATIC reactions: due to genetic, environment
• MOA:
○ Small mole induce immune resp
When bind to larger mole (albumin, proteins)
Drug-induced SLE (high risk drugs)
○ Procainamide (anti arrhythmia)
○ Hydralazine
○ Quinidine
○ Minocycline, isoniazid, methyldopa, carbamazepine, others
Drug-induced SLE 1st treatment
1* treatment:
○ STOP risk drug
○ SYMPTOMATIC TREATMENT
Maybe reversible, but SLE condition may also just start
Evaluation and monitoring of SLE
• ADR
• Development of comorbidities
• Measure disease acitvity
• SELENA-SLEDAI
• BILAG
• Regular labs: (look at trend)
• ACTIVE = (1-3mnths)
• STABLE = 6-12mnths
labs to monitor
○ Don’t need ANA, anti Sm, anti-RNP Ab to repeat at each visit
§ Do not fluctuate with disease activity
1) Urinalysis/ renal function
2) Anti-dsDNA Ab
a. More uncontrolled condition = higher
b. Aim for near 0 (normal)
3) Complement C3, 4 levels
a. Responding to treatment? Try icnr lvls
4) C-reactive protein
a. Inflammatory market
5) Full blood count (WBC, RBC, PLT)
6) Liver function test
Immunosuppression in practice
○ Rest of life
§ Autoimmune conditions
§ Solid organ transplant
§ Stem cell/ bone marrow transplants
§ Blood disorders/ cancer
INDUCTION of immunosuppression
§ High potency, short course therapy
§ Initiate asap to:
□ Reduce existing damage
□ Prevent worsening of autoimmune condition
§ Initiate to prevent:
□ Acute rejection with lymph depleting therapy
- Basiliximab, alemtuzumab
MAINTENANCE of imunosuppression
§ Calcineurin inhibitors
□ Cyclosporin, tacrolimus
§ Antimetabolites
□ Mycophenolate, azathioprine
§ Corticosteroids
§ mtor inhibitors – transplants
□ Sirolimus, everolimus
§ Biologics
□ Adalimumab
Complications with immunosuppression
§ Risk opportunistic infections
§ Risk cancers
§ Blood disorders
□ Leukopenia, thrombocytopenia, pancytopenia
§ Hepatotoxicity
□ Mycophenolate, aza (Antimetabolites)
§ Renal toxicity
□ Cyclo, tacro (Calcineurin inhibitors)
§ Hypertension, hyperlipemia, hyperglycemia
□ (Calcineurin inhibitors & mTOR inhibitors)
opportunistic infections
□ Bacterial: Mycobacterium TB, listeria (meningitis), legionella
□ Viral: Cytomegalovirus, Epstein Barr, HV □ Fungal: Cryptococcus (soil), Aspergillus, pneumocystis jiroveci □ Parasites: Toxoplasma gondii (cat)
Corticosteroids
○ Long term use: anti-inflammatory, immunosuppressive effects
○ Conditions:
§ Asthma, COPD, autoimmune disease, transplant, IBD - CD/ UC, eczema, cancer, pain
ADR with steroids
1) CVS risk
2) cataract, glaucoma
3) skin thinning, hirsutism (hair)
4) gastric ulcer
5) weight gain, fluid retention, CUSHING, b-cell dysfunciton/ insulin resistance
6) neuro-psychiatric symptoms, HPA insuff
7) osteoporosis
8) myopathy
9) infections
HPA Axis suppression (reliant on corticosteroids)
§ Hypothalamic pituitary adrenal axis suppression
□ Common in pt on chronic CS therapy
1) Excess exogenous CS/ glucocorticoids
2) Decr secretion of CR, ACTH
3) HPA axis less active
a) Unable to recover function to produce endogenous steroids
b) Adrenal cortex atrophy (smaller)
how to reduce Adrenal suppression
□ Supraphysiologic dose > 5mg pred daily (>3wks)
-May occur at lower dose/ lower duration too
□ Tapered withdrawal
□ Maintain suspicion of adrenal suppression when pt take CS
