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Wrong concepts in drug
hypersensitivity and its impact on
clinical management
Werner J Pichler, MD
[email protected]
ADR-AC GmbH, Bern
Switzerland
NO CONFLICT OF INTEREST TO DECLARE
Common statements on drug allergy
• Drug allergy is dose independent
• Drug allergy requires a sensitization
phase to the drug itself
• Small molecules are not recognized
by the immune system
• Drug allergy is not predictable
correct
yes
no
① ②
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□
□
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□
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Amoxicillin Allergy
Immediate, IgE
Delayed, T cell
a patient with recurrent, febrile sinusitis and bronchitis
is treated with amoxicillin 3x750mg/d for 10d. She
tolerates it well. After 2 yrs she has again a sinusitis and
bronchitis with fever.
She takes a 750mg dose of
amoxicillin: after 10 min she
complains about malaise, palmoplantar itch, redness all over,
difficulty to breath, collaps. At skin
testing (i.d.) after 4wk she
develops a generalized urticaria in
min.
Immediate reaction to
very low doses of
amoxicillin (skin tests)
She takes 3x750mg for 7d, but
then develops generalized
pruritus and a measles like rash.
She stops treatment, and gets
anti-H1 and topical
corticosteroids.
LTT positive with SI of 8;
Delayed reaction to «normal»
doses of amoxicillin
Amoxicillin Allergy
Immediate, IgE
Delayed, T cell
a patient with recurrent, febrile sinusitis and bronchits is treated
with amoxicillin 3x750mg/d for 10d. She tolerates it well.
After 2 yrs she has again a sinusitis and bronchitis with fever.
She takes a 750mg dose of
amoxicillin: after 10 min she
complains about malaise,
palmo-plantar itch, redness all
over, difficulty to breath,
collaps. At skin testing (i.d.)
after 4wk she develops a
generalized urticaria in min.
Immediate reaction to
very low doses of
amoxicillin (skin tests)
She takes 3x750mg for 7d,
but then develops generalized
pruritis and a measles like
rash. She stops treatment, and
gets anti-H1 and topical
corticosteroids.
LTT positive with SI of 8;
Delayed reaction to «normal»
doses of amoxicillin
Amoxicillin Allergy:
Role of drug concentration depends on
initiation/effector phase and on mechanism (T, IgE)
1) Concentration differs: Sensitization ≠ effector
phase
Sensitization requires often normal doses (>100mg
to mg)
effector phase (IgE): ng or less
2) Concentration differs: IgE ≠ T cell reaction
IgE reactions can occur to very small amounts of
drug.
T cell reactions often require normal (therapeutic)
doses of drug
D
O
S
E
D
I
F
F
E
R
S
Drug concentration and immune
mechanism
No effect
S
Y
M
P
T
O
M
S
Dose
for
Anaphylaxis
Start of
desensitization
femtomolar
Dose for
IgE
picomolar
Therapeutic efficacy
Induction of T and B
cells,
T cell mediated
exanthems
nanomolar
micromolar
concentration differ for induction and elicitation
Is dose reduction more effective in
T-cell or IgE mediated reactions ?
S
Y
M
P
T
O
M
No
pharmacological
effect
Insufficient for
T cell dependent
DHR
No effect
of drug
Still IgE mediated
DHR
8mg
pharmacological
effect
DHR: T-cell
mediated
DHR: IgE mediated
80mg
100x
800mg
10x
YES: Lowering the dose by 10x may suffice to eliminate T cell
related symptoms , but is still causing IgE mediated reactions
Drug dose & drug allergy
• Immune reactions are (of course) dose
dependent: the higher the dose, the faster, the
severer the symptoms (IgE, T cell) !!!
• IgE mediated reactions occur already at very
low doses: it occurs below the concentrations
needed for pharmacological effects (but it is
nevertheless dose dependent)
• Further reducing the dose results in less
symptoms and may allow desensitization.
cross-reactivity:
Amoxicillin
role of affinity &
drug concentration
picomolar
IgE induced by amoxicillin
high
piperacillin
low
nanomolar
A cross-reactive compound binds
with lower affinity to IgE/TCR:
It requires a higher concentration
to elicit the same level of symptoms
cefadroxil
micromolar
Clinical impact
dose dependence:
Reducing the dose is always a good advise to
minimize or avoid potential symptoms of DHR
crossreactivity:
cross-reactive drugs bind (mostly) less affine to
IgE/TCR. Higher doses needed to elicit the same
symptoms.
Common statements on drug allergy
• Drug allergy is dose independent
• Drug allergy requires a sensitization
phase to the drug itself
• Small molecules are not recognized
by the immune system
• Drug allergy is not predictable
correct
yes
no
□
□
①
□
□
②
□
□
IgE-mediated anaphylaxis w/o prior exposure
Examples
radio-contrast media
cephalosporins
NMBA (e.g. rocuronium)
dyes (patent blue)
chlorhexidine
…………..
chlorhexidine
iodihexanol
perioperative
anaphylaxis
«Anaphylaxis at first sight»
the acute symptoms appear in patients
without prior exposure
• Mostly i.v. applied drugs
• Mostly high concentrations
• Often relative large molecules, often bi- or
polyvalent
• Severe reactions like cardiac arrest, asystoly
Anaphylaxis at first sight
Three possibilities:
1. Sensitization to the drug in environment:
e.g. chlorhexidine in cosmetics, dental
hygiene products, etc…..
Some sensitizations are often hidden !
• Patent blue anaphylaxis:
• Do you ask your patient whether she was
wearing blue shoes???
Anaphylaxis at first sight
Three possibilities:
1. Sensitization to the drug in environment:
e.g. chlorhexidine in cosmetics
2. Sensitization to a small, common epitope in
environment and drug
Pholcodin
Baldo et al. CEA, 2007
NMBA, tubocurarine
Quarternary
ammonium
Anaphylaxis at first sight
Three possibilities:
1. Sensitization to the drug in environment:
e.g. chlorhexidine in cosmetics
2. Sensitization to a small, common epitope in
environment and drug
3. Very high drug concentrations may
compensate for low affinity
[P]
Affinity/
dissociation constant
P
Clinical impact:
Sensitization to the drug itself is not an absolute
requirement for IgE mediated anaphylaxis
Anaphylaxis at first sight may occur with high
concentrations, iv application, large drugs
Common statements on drug allergy
• Drug allergy is dose independent
• Drug allergy requires a sensitization
phase to the drug itself
• Drug allergy is not predictable
• Small molecules are not recognized
by the immune system
correct
yes
no
□
□
□
□
①
□
②
□
Drug allergy is not predictable ?
P-i concept: binding of drug to certain HLA
molecules changes the HLA-peptide
conformation and elicit immune reactions;
If the drug binds with high affinity to only a
certain HLA-protein (e.g. HLA-B*57:01), this
reaction is predictable by typing for HLA.
TCR
p-i concept (p-i HLA)
a drug fits into a particular HLA
molecule
the drug binds to a unique region
in the HLA by van der Waals
forces (only B*57:01).
The {peptide-drug-HLA} complex
is then recognized by the TCR
like an allo-allele
HLA
HLA-peptide-TCR complex
HLA-B*5701:
binding groove
for abacavir
Illing et al, Nature 2012
Ostrov D et al, PNAS 2012
Drug allergy is not predictable ?
Certain T cell mediated drug allergies can be
avoided by excluding patients with a certain
HLA from drug treatment
Abacavir (HLA-B*57:01)
Carbamazepine (HLA-B*15:02)
Allopurinol (HLA-B*58:01)
Common statements on drug allergy
• Drug allergy is dose independent
• Drug allergy requires a sensitization
phase to the drug itself
• Drug allergy is not predictable
• Small molecules are not recognized
by the immune system
correct
yes
no
□
□
□
□
□
①
□
②
Small molecules and the immune
system
• Riboflavin story: Riboflavin is Vitamin B2
• It is synthesized by bacteria and mushrooms,
like e.g. mycobacterium tuberculosis, E. coli
• direct recognition of small molecules by
specialized T cells !
«Riboflavin story»
• precursor compounds (e.g. 5-A-RU)
of riboflavin is presented as small molecule
on special, MHC1-like molecules (MR1).
• The reactive T cells are CD4- CD8- αβ+ TCR
(invariant, mucosa associated invariant T
cells, MAIT): These recognize riboflavin
precursor and act by cytotoxicity, IFNg+
Kjer-Nielsen L, et al. MR1 presents microbial vitamin B , metabolites to MAIT cells. Nature. 2012 29;491:717-23
MHC 1 vs MR1
MHC 1
MR1
MHC related1
MHC-1 vs MR1 binding cleft
«Small molecules are not recognized by
the immune system»
Small molecules can interact with the specific
immune system:
• Via p-i: CDR2/Vb20-TCR (Sulfamethoxazole):
«sulfa-allergy (?)»
• riboflavin precursor molecules presented by MR1
to MAIT cells: first line defense to
mycobacteria
The immune system has developed tools
to recogize specifically small molecules
Common statements on drug allergy
• Drug allergy is dose independent
• Drug allergy does not always require a
sensitization phase to the drug itself
• Drug allergy is not sometimes predictable
• Small molecules are not recognized by the
immune system: MR1/MAIT and p-istimulations
Clinical impact:
• Always consider dose! A dose reduction is
always worth a try (is not always sufficient)
• risk of anaphylaxis at first sight: i.v. injecton of
high concentrations of large molecules
• Certain DHR are avoidable, as they are
predictable
• The immune system has established a system
to directly interact with small molecules: DHR
is no more «exotic»
Thank you very much
Wrong concepts in drug hypersensitivity
5. Drug allergy is dependent on hapten mechanism:
→ ONLY A MINORITY OF DRUG REACTIONS ARE DUE
TO HAPTEN MECHANISM
6. Drug allergy is an allergy
→ NO, DRUG ALLERGY IS OFTEN NOT DIRECTED TO THE
DRUG ITSELF, IT IS AN ALLO-IMMUNE REACTION
7. Reactions appearing within hrs are not T cell
mediated:
→ SOME T CELL MEDIATED REACTIONS IN HIGHLY
SENSITZED PATIENTS CAN OCCUR WITHIN HOURS:
ABACAVIR, VEMURAFENIB, AMOXICILLIN;
CARBAMAZEPIN
Protein-ligand binding/affinity
The dissociation constant is commonly used to describe
the AFFINITY between a ligand (such as a DRUG) and a protein i.e. how tightly a
ligand binds to a particular protein.
AFFINITY is defined by
where L and P represent molar
complex, respectively
concentrations of the protein, ligand and
The smaller the dissociation constant, the more tightly bound the ligand is, or the higher the
affinity between ligand and protein: For example, a ligand with a nanomolar (nM)
dissociation constant binds more tightly to a particular protein than a ligand with a
micromolar (μM) dissociation constant.
nanomolar is more affine than micromolar
Adverse drug reactions
Type A reaction
Pharmacological action
Predictable
Dose dependent
Rational
Type B reaction
1 Not pharmacological action
2 Not predictable
3 Not dose dependent
4 Bizarre
“As more becomes known about the mechanisms of specific
adverse drug effects, this classification will be revised further
and classification of currently unclassifiable reactions will
become easier”
IR Edwards, JK Aronson: Adverse drug reactions: definitions, diagnosis, and management,
LANCET, 356: 9237; 1255-1259, 2000
Adverse drug reactions
Type A reaction
Pharmacological action
Predictable
Dose dependent
Rational
Type B reaction
immune mediated
1 Not pharmacological action
2 Not predictable
3 Not dose dependent
4 Bizarre (immune-mediated =
complex diseases !!)
Some immune mediated reactions are «off target»
(pharmacological) activities of the drug on immune receptors.
- In the time of personalized medicine, they are, are least partly
predictable and avoidable;
- dose dependence?
Origin of wrong statements
1. Classification of type A and B reactions
MD Rawlins, JW Thompson: Pathogenesis of
adverse drug reactions; Textbook of adverse drug
reactions, Oxford (1977 & 1981), DM Davies (Ed.),
Oxford Univ. Press, p. 10 & p. 11
2. Classification of drug allergy as immediate and
delayed forms (<1hr, >6hr);
Johansson SG, et al. A revised nomenclature for
allergy. An EAACI position statement from the
EAACI nomenclature task force. Allergy. 2001
Sep;56(9):813-24.
Alle Ding' sind Gift, und nichts ohn' Gift;
allein die Dosis macht, daß ein Ding kein
Gift ist.
- Paracelsus (1493-1541) -
“All things are poison, and
nothing is without poison;
only the dose permits
something not to be
poisonous.”
• (Some) Type B ADRs are
dose dependent.
Role of drug concentration
Pharmacology
Immunology
initiation > < elicitation
no effect
effect
toxic effect
Concentration
naive > < effector
of immune response
The IgE/Fc-IgE-RI system is geared to
react to extremely small doses
Affinity maturation for B-cells
Simple, one cell model
Complex, > 1 cell involved, naive>< memory, IgE
Riboflavin
synthesis
pathway in E.coli
Drug concentration and immune
mechanism
No
symptoms
S
Y
M
P
T
O
M
Dosis
for
Desensitization
IgE
Dose
for
Anaphylaxis
Dose for
anaph
femtomolar
picomolar
T-cell reactions
Induction
of T and B
cells
nanomolar
For
DRESS
mmolar
Lowering the dose eliminates symptoms even in IgE (desesitization)
amoxicillin
cross-reactivity:
role of affinity &
drug concentration
Higher drug concentration
needed to elicit symptoms
piperacillin
S
Y
M
P
T
O
M
S
cefadroxil
anaphylaxis
amoxicillin
No symptoms
high
affinity
piperacillin
low
urticaria
Low
high
Very low
cefadroxil
According to
a molecule (L) can bind to IgE (P), if
provided in sufficiently high concentrations (binding with low affinity)
If the molecule is large and can bind with various epitopes to IgE,
crosslinking and anaphylaxis may occur……
Kd=
L
[ ] [P]
L
[ P]
dose reduction: different effect on
T-cell or IgE mediated reactions
S
Y
M
P
T
O
M
No effect
of drug
No
pharmacological
effect
No T cell reaction
Only
IgE mediated DHR
8mg
pharmacological
effect
+
DHR: T-cell
mediated
+
DHR: IgE mediated
80mg
100x
800mg
10x