Chapt. 9: Drug Allergy

Question 1

During the acute reaction phase of an allergic reaction, what laboratory test are advisable?

Answer 1

Serum tryptase (to prove mast cell involvement)

Question 2

During the acute reaction phase of an allergic reaction, what laboratory tests are advisable?

Answer 2

ESR
CRP
Liver enzymes to define organ involvement and severity

Question 3

What are the most common drug classes involved in hypersensitivity (immediate and delayed) reactions?

Answer 3

Antibiotics
NSAIDs
Anticonvulsants

Question 4

What are some drugs that induce severe systemic forms of delayed-type hypersensitivities?

Answer 4

HLA class 1 allele. Here, HLA testing is recommended before use.

Question 5

When is a patient’s risk for drug hypersensitivity increased?

Answer 5

During viral infections (EBV, HIV), during or shortly after a severe drug hypersensitivity reaction (‘flare up’) or if high doses, prolonged or repetitive treatment courses are needed (ex. cystic fibrosis)

Question 6

What is the incidence of ADR?

Answer 6

10-20% of hospitalized patients and up to 25% of outpatients.

Question 7

Typically, drug allergy affects what organ system?

Answer 7

Skin, but organ involvement (hepatitis) and blood eosinophilia are also common in systemic forms of drug hypersensitivity and may serve as ‘red flags’ for a more severe course.

Question 8

What are the 2 usual subtype classifications of ADRs?

Answer 8

Type A reactions: predictable from known pharmacologic properties

Type B reactions: unpredictable or unexpected and restricted to a vulnerable subpopulation.

Question 9

What are the majority of these unexpected type B reactions?

Answer 9

Hypersensitivity reactions. They are responsible for about 1 in 6 of all ADRS.

Question 10

What comprise the Hypersensitivity reactions?

Answer 10

1. Allergic (immune-mediated)
2. Pharmacologic (direct interaction with specific immune receptors (HLA, TCR)
3. Non-allergic intolerance (also called ‘pseudo-allergic’) reactions without a defined genetic defect

Question 11

Defines a non-allergic hypersensitivity reaction with a genetic background?

Answer 11

Idiosyncrasy

Question 12

What is otherwise known as favism?

Answer 12

G6PD deficiency

Question 13

What is a drug reaction seen with favism?

Answer 13

Hemolytic anemia upon intake of metimazole or one of the other G6PD-dependent drugs

Question 14

What is the definition of immediate type vs delayed type hypersensitivity?

Answer 14

Onset of symptoms before or after 1 hour

Question 15

Might help distinguishing whether the probable immunologic mechanism is anti-body mediated (mostly IgE), immediate-type or a T-cell-mediated, delayed-type reaction.

Answer 15

Timing of the reaction

Question 16

What is more common, immediate type or delayed type reactions?

Answer 16

Delayed-type reactions are much more frequent

Question 17

Is an atopic genetic background with IgE-mediated response to ingested or inhaled proteins (ex. hay fever) associated with an increased risk for drug hypersensitivity?

Answer 17

No.

Question 18

What is haptenization?

Answer 18

It is when drugs bind to an endogenous carrier protein. Thus, immunogenic complexes arise and can illicit a complex immune response with B and T cell reactions.

Question 19

What is the MOA of most drug hypersensitivity reactions?

Answer 19

Due to T-cell stimulations and are caused by direct binding of the drug to a HLA or a T-cell receptor (TCR) molecule.

Question 20

What does the term p-i concept refer to?

Answer 20

Pharmacological interaction with immune receptors

Question 21

What are the most common drug classes causing hypersensitivity reaction?

Answer 21

beta-lactam antibiotics and NSAIDs

Question 22

What are the most common clinical manifestation of drug allergy?

Answer 22

Cutaneous reactions such as maculopapular reactions and urticaria

Question 23

What are some more severe and potentially life-threatening reactions?

Answer 23

TEN - toxic epidermal necrolysis
SJS - Stevens-Johnson syndrome
DRESS - Drug rash with eosinophilia and systemic symptoms
Immune hepatitis

Question 24

In the US, how many patients die from ADR?

Answer 24

1 in 300 hospitalized patients, and 6-10% of these reactions are most probably allergic in origin.

Question 25

In what patients is HLA screening recommended?

Answer 25

Only for Abacavir with HLA B*57:01 (common in white european origin populations) and for

Carbamazepine HLA B*15:02, the risk allele for southeast asians

Question 26

Under the Gell and Coombs classification, what is type 1? Name 2 examples

Answer 26

Anaphylactic (IgE-mediated).
Acute anaphylaxis
Urticaria

Question 27

Under the Gell and Coombs classification, what is type 2? Name 2 examples

Answer 27

Complement-dependent cytolysis (IgG/IgM)
Hemolytic anemias
Thrombocytopenia

Question 28

Under the Gell and Coombs classification, what is type 3? Name 3 examples

Answer 28

Immune complex damage
Serum sickness
Drug fever
Some cutaneous reactions and vasculitis

Question 29

Under the Gell and Coombs classification, what is type 4? Name 4 examples

Answer 29

Delayer or cellular hypersensitivity
Contact dermatitis
Morbilliform eruptions
SJS/TEN
Hepatitis

Question 30

In an already sensitized individual and not on first contact, Ig-E mediated reactions tend to appear rapidly, within what time frame?

Answer 30

Within minutes for IV doses to 1 hour (after oral intake)

Question 31

For sensitization, what is needed by LMW compounds?

Answer 31

Haptenization

Question 32

What mediates delayed-type hypersensitivity?

Answer 32

T-cell

Question 33

Why is delayed type sensitivity delayed?

Answer 33

An exathema may only arise after expansion and the migration of the drug specific effector T cells into the tissue. This explains an amoxicillin-induced exanthema at day 7-10 of treatment.

Question 34

Upon re-exposure in delayed type hypersensitivity, what is the pattern of response?

Answer 34

Symptoms of these T cell reactions may appear much faster (within 2-48 hours), dependent on the amount of drug-reactive (primed) T cells and drug dosage.

Question 35

What is the cornerstone for both IgE and T-cell mediated reactions?

Answer 35

T cell recognition

Question 36

What is the process of T cell recognition?

Answer 36

Depends upon drug presentation by antigen-presenting cells (APC) on their HLA molecule and engagement of the corresponding TCR on CD4 or CD8 T lymphocytes.

Question 37

Can drugs directly bind to the immune receptors?

Answer 37

Yes

Question 38

In highly stimulatory circumstances such as DHS/DRESS, may even structurally unrelated drugs taken regularly illicit allergic reactions?

Answer 38

Yes

Question 39

What are some states of ‘organ predisposition’ with a lower local reaction threshold which may lead to clinical symptoms even without a compound-specific sensitization? (3)

Answer 39

Chronic urticaria
Asthma
Rhinosinusitis

Question 40

What class of medications might exacerbate chronic urticaria?

Answer 40

NSAIDs

Question 41

In the state of ‘organ predisposition’, what is the time frame for a reaction to occur?

Answer 41

Within 15 minutes, are highly dose dependent and do not require a sensitization phase

Question 42

Why do NSAIDs cause this urticaria?

Answer 42

Based on this mode of action of all NSAIDs interfering with the arachidonic acid metabolism and ultimately leading to a prostaglandin-leukotriene imbalance.

Question 43

What is the MOA of non-allergic intolerance to radio contrast media?

Answer 43

Rely on their capacity of direct mast cell activation, most probably due to their high (salt) concentration and rapid infusion rate that is needed for their optimal radiographic characteristics. No sensitization phase is needed.