Allergies and Angioedema

Drug Hypersensitivity Reactions ~15%
Immune-Mediated Reactions ~6-10%

Heterogenous reactions clinically resemble an allergy
May or may not be mediated via immune response
up to 15% of ADRs
E.g. urticaria from radiocontrast, aspirin induced asthma, opiate-related pruritis
flushing after vanco infusion

Drug Allergies
Definition per World Health Organization: “immunologically mediated
hypersensitivity reaction to a drug in a sensitized person”
Reserved for drug reactions in which a definite immune mechanism has
been proven
Account for 6-10% of all adverse drug reactions

Examples
Anaphylaxis from beta-lactam antibiotics
Halothane hepatitis
Steven-Johnson Syndrome from carbamazepine
Heparin-inducted thrombocytopenia

”Immediate” Allergy
IgE Mediated
Requires sensitization
Symptoms occur within minutes
Binding of allergen to IgE causes release of vasoactive amines (histamine) and leukotrienes from mast cells
Anaphylaxis, acute asthma, urticaria

Stored in basophil and mast cell granules

4 Types of histamine receptors (H1-H4)

Histamine receptors in vascular smooth muscle (mostly H1 and some H2) most important for allergy

Effects on smooth muscle
• Increased capillary permeability
• Bronchial and vascular smooth
muscle contraction
• Mucus gland hypersecretion

1. Penicillins (45.9/10,000 pts)
2. Sulfonamides (15.1/10,000 pts)
3. NSAIDs (13.0/10,000 pts)
4. Opiates (9.8/10,000 pts)
5. Cephalosporins (6.1/10,000 pts)
6. Macrolides (3.8/10,000 pts)
7. Fluoroquinolones (3.7/10,000 pts)

Autoimmune allergy
IgG or IgM Mediated
Drug binds to cell (typically a blood cell) as a hapten causing antibodies (IgG or IgM) to be
produced. Binding of antibodies to drug-cell complex initiates cytolytic reaction.
End result is cell destruction by either activation of complement system or phagocytic cells

Hemolytic Anemia
• Cephalosporins
• Methyldopa
• Penicillin
• Phenazopyridine

Thrombocytopenia
• Heparin
• Quinidine

Agranulocytosis

Immune Complex Allergies
IgG or IgM Mediated
Drug binds to antibodies, drug-antibody complexes deposit in tissues resulting in local or disseminated inflammatory reactions

Tissue Damage

Serum sickness

Most commonly associated with use of antiserums containing donor antigens (antitoxins &
antivenins)
Typically occurs 7-14 days after antigen administration
Fever, malaise, lymphadenopathy most common
May also have arthralgias, urticaria, morbilliform skin eruption

Delayed-Type Hypersensitivity
T-Cell Mediated
Exposure to antigen causes T-cell mediated inflammatory response via secretion of cytokines
Occurs within 1-3 days after contact
Typically manifests as dermatologic events

Medication History
Allergy History
Subjective findings of the allergic reaction
Objective Data
• BP, HR, RR
• Labs
• Physical exam (observe rash/skin
involvement if applicable)

Timing of reaction relative to the initiation of each of the patient’s current medications
Likelihood of cross-reactivity relative to documented allergy history
Presence of risk factors
Severity of the reaction

Dermatologic Reactions (SJS/TEN
Hematologic
Serum sickness
Drug rash with eosinophilia and
systemic symptoms (DRESS)
Anaphylaxis

Must fulfill at least one of the following three criteria:
1. Acute onset with skin-mucosal involvement and at least one of the following:
• Respiratory compromise
• Decrease BP, syncope or collapse
2. Two or more after exposure to likely allergen
• Skin-mucosal involvement
• Respiratory compromise
• Decreased BP, syncope or collapse
• GI symptoms
3. Decreased blood pressure after exposure to known allergen

Rapid onset and potentially fatal
Evaluate airway, breathing, circulation!
~50% of anaphylaxis fatalities occur within the first hour
Lifetime risk ~1-3%

Major causes
1. Drugs (highest fatality rate)
2. Venom
Hymenoptera (bee) stings
3. Food
Shellfish
Soybeans
Nuts
Wheat
Milk

Cutaneous
Urticaria and angioedema (85-90%)
Flushing (45-55%)
Pruritis without rash (2-5%)

Respiratory
Upper airway angioedema (50-60%)
Dyspnea, wheezing (45-50%)

Cardiovascular
Hypotension (30-35%)

Abdominal
N/V/D 25-30%

Activate emergency response system
Epinephrine
Recumbent position with lower extremity elevation
Oxygen, fluids
Antihistamines, H1 blocker, H2 blocker
Corticosteroids
Inhaled beta-agonists

Non-selective adrenergic agonist (𝛼 and 𝛽 activity)
Rapidly increases systemic vascular resistance, increases
cardiac output, reverses bronchoconstriction and mucosal
edema and stabilizes mast cells and basophils.
Dose for anaphylaxis is 0.01mg/kg, max 0.5 mg IM for adults,
0.3mg IM for children

IV administration is generally not recommended given increased
risk of medication errors
Continuous infusion may be considered for anaphylactic shock

Neither antihistamines nor glucocorticoids urgently treat life
threatening cardiovascular (hypotension) or respiratory
(bronchospasm) symptoms.

Limited evidence to support benefit, may be helpful in
addressing symptoms of anaphylaxis but take time to reach peak effect

Antihistamines
H1 – Diphenhydramine (IV)
H2 – Famotidine (IV)

Glucocorticoids
Methylprednisolone IV

Penicillin is the most common drug allergy (45.9/10,000 pts) however; true IgE mediated reactions are still rare (~0.459%).
10-20% of patients report penicillin allergies of patients who report
penicillin allergies, only ~10-20% have a positive skin test

Incidence of anaphylaxis amongst patients treated with penicillins is estimated at 0.01%

Patients with reported penicillin allergy had significantly:
• More exposure to fluoroquinolones, clindamycin, and vancomycin (P < .0001)
• Longer hospital stay (0.59 days, 9.9%; 95% CI, 0.47-0.71)
• Higher incidence of C. difficile by 23.4% (95% CI, 15.6% to 31.7%)
• Higher incidence of MRSA infections by 14.1% (95% CI, 7.1% to 21.6%)
• Higher incidence of VRE by 30.1% (95% CI, 12.5% to 50.4%) than expected compared
with control subjects

Penicillins covalently bind to plasma proteins to create hapten—carrier complexes

Various haptens are created depending on binding site
• Penicilloyl (Major)
• Penicillanyl (Minor)
• Penicillenate (Minor)

All four types of immune mediated reactions (I-IV) have been reported with penicillin
IgE mediated reactions directed at R-group side chain
Wide variety of idiopathic reactions also occur
Cutaneous reactions are common, up to 8% of patients taking aminopenicillins
Incidence of rash is ~100% in patients receiving ampicillin with viral infections

idence of anaphylaxis with cephalosporins ranges from 0.0001-0.1%
Early cephalosporins produced from Penicillium mold and then chemically modified.
• Cephalosporins produced between 1960-1980’s had minor contamination by penicillin.
• Early risk of cross-reactivity estimated at 10-15%
Rate of cross-reactivity (if penicillin allergic) is predicted by R1 chain similarity.

Carbapenems
• Incidence of cross-reactivity if penicillin allergic is low
• Estimated at 0.9-11%

Aztreonam
• No cross reactivity if penicillinallergy
• Significant antimicrobial resistance

Compounds containing sulfa (SO2NH2) moiety
• Antibiotics (e.g. TMP/SMX)
• Thiazide and loop diuretics
• Oral hypoglycemics (e.g. sulfonylureas)
• Carbonic anhydrase inhibitors (e.g.acetazolamide)
Incidence ~4.8% sulfonamide antibiotics, 2% sulfonamide nonantibiotics
IgE mediated reactions are uncommon
Limited/no evidence of cross-reactivity between sulfonamide antibiotics and nonantibiotics

Associated with eight types of drug
hypersensitivity reactions
• Rhinitis, sinusitis, asthma
• Urticaria
• Angioedema
• Anaphylaxis
• Pneumonitis
• Aseptic meningitis

Two most common aspirin sensitivity reactions are respiratory (asthma and rhinorrhea) and
urticaria/angioedema
Urticaria/angioedema may be IgE or non-IgE-mediated

Induction of temporary drug tolerance may be used for patients with a history
of immediate reaction to a drug for which no reasonable alternatives exist (e.g
penicillin G for neurosyphilis)
Involves a stepwise process of incremental dosing of the drug or related
compound
Incremental exposure allows gradual mast cell degranulation to prevent allergic
reactions.

Reactions amenable to desensitization
• Dermatologic (flushing, pruritis, urticaria, angioedema)
• Respiratory (sneezing, dyspnea, wheezing)
• Gastrointestinal (abdominal pain, nausea, vomiting)
• Cardiovascular (hypotension)

Localized subcutaneous or submucosal swelling resulting from dilation
of vascular structures and extravasation of fluid into interstitial tissues.
May occur in isolation, accompanied by urticaria or as a component of
anaphylaxis.
Urticaria & angioedema share the same pathophysiology but differ in
the level of skin involved
• Urticaria: dilation of vascular structures in superficial dermis
• Angioedema: dilation of vascular structures in deeper dermis and
subcutaneous tissues

Typically affects areas with loose connective tissue, such as face, lips, mouth, throat, larynx,
uvula, extremities, genitalia, bowel wall.
Symptoms include: urticaria, flushing, pruritis, bronchospasm, abdominal pain, vomiting

Lasts for hours to days

Swelling of airway may be life-threatening

Angioedema can occur for a variety of reasons but can be sorted into three categories: mast-cell mediated etiologies, bradykinin mediated etiologies and idiopathic.
Mast-cell mediated etiologies:
• Allergic/IgE mediated reactions
• Immunologic and other non-IgE mediated mast cell activation
Bradykinin mediated etiologies
• Hereditary angioedemas
• Inhibition of enzymes involved in bradykinin degradation

Occurs as a result of activation of mast cells which release inflammatory mediators which
cause venodilation, increased vascular permeability and resultant tissue edema.
Typically associated with urticaria and/or pruritis
Given similar etiology, treated similarly to anaphylaxis (epinephrine, antihistamines,
glucocorticoids)

Occurs as a result of either overproduction of bradykinin or inhibition of bradykinin degradation
Urticaria and pruritis are absent (no mast cell involved)
More commonly involves GI mucosa, presenting with bowel edema
Does not respond to epinephrine, antihistamines, and glucocorticoids

Accounts for ~30% of all angioedema cases presenting to the emergency department.
Overall incidence of 0.1-0.7% (more common than with ARB’s)
Risk factors: black race, history of angioedema, age > 65 years, aspirin or NSAID use, female sex, smoking, seasonal allergies
Risk is highest within one week of initiation but can occur at any time

DPP-IV Inhibitors: sitagliptin, saxagliptin, linagliptin, alogliptin
May occur independent of ACE inhibitors, risk greatly increased with concomitant therapy with ACE inhibitors
True incidence is unknown

Inherited alterations that cause bradykinin-mediated angioedema. Typically starts in childhood

Characterized by recurrent attacks
• Cutaneous angioedema without angioedema and severe abdominal symptoms are most common
features
• Genital, bladder, muscle and joint swelling are rarebut may occur.
• Laryngeal episodes are less common (0.9% of attacks) but >50% of patients with HAE will have a laryngeal attack during their lifetime

Before 2009 no FDA-approved therapies existed for HAE attacks
Fresh Frozen Plasma (FFP) was often used given it contained C1-INH however concerns existed that FFP may worsen HAE as it also contains other substrates such as bradykinin, substance P etc.
Specific agents are now available for prophylaxis and acute management of HAE attacks
Patients typically have two doses of on-demand therapy for acute attacks and receive prophylaxis as needed