DRUG ALLERGY: - USAFP



DRUG ALLERGY:

PCN/ASA/NSAID/RCM/Local Anesthetics

OVERVIEW

Background

Epidemiology

Classification

Clinical manifestations of drug reactions

Specific drugs:

Penicillin

ASA/NSAID’s

Radio contrast media

Local anesthetics

Summary

Background

Adverse reactions to drugs are not uncommon

“Allergy” or hypersensitivity to a drug is defined as “any immunologic response to a drug or its metabolites that results in an adverse reaction”

True allergic reactions require previous sensitization

Caused by a variety of drug classes

Present in a wide array of clinical syndromes

Able to affect any tissue or organ

Epidemiology

Adverse reactions to drugs are not uncommon

15% inpatients with ADE

Outpatient data lacking (17-25% ADE)

Immune-mediated rxns comprise up to 6-10% of observed ADE’s

Up to 33% of all Rx ADE’s are possibly allergic

Individual risk of an allergic reaction to a drug is 1-3%

Drug associated fatalities are reported in 0.1% of inpatients and 0.01% of surgical patient

Classification

Predictable (Type A)- Reactions that occur in most normal patients given sufficient dose and duration of therapy

Account for 80% of adverse drug reactions

Usually dose dependent

Due to the pharmacologic properties of the drug

Examples:

Overdosage – “exaggerated but characteristic pharmacologic effect produced by administering a supratherapeutic dose” i.e. Tylenol OD hepatic necrosis

Side effects – “excessive expression of known pharmacologic effects of a drug that occur at recommended doses” i.e. albuterol induced tremor

Secondary effects – “indirect pharmacologic effects of the primary drug action that are not attributable to overdosage, idiosyncratic reactions, hypersensitivity or intolerance” i.e. clindamycin induced C. difficile

May involve disease factors

Drug interactions – “unusual effects due to the simultaneous activity of 2 or more drugs” i.e. Seldane + E-mycin induced torsades

Unpredictable (Type B)- Uncommon hypersensitivity reactions seen in susceptible patients

Minority of drug reactions

Most (except intolerance) are unrelated to the drug’s pharmacologic actions and are not dose dependent

Examples:

intolerance – “undesirable pharmacologic effect that occurs at a subtherapeutic drug dose” i.e. ASA induced tinnitus

Idiosyncratic reaction – “uncharacteristic response to administration of a drug, unrelated to the pharmacologic actions of the drug” i.e. Chloroquine hemolytic reaction in G6PD

Hypersensitivity/allergic reactions – “immune-mediated reactions” 5-10%

Allergic Drug Reactions

Allergic or hypersensitivity drug reactions are immune-mediated and share the following characteristics:

Occur in a small number of patients

Require previous sensitization

Develop rapidly after re-exposure

Produce clinical syndromes associated with immunologic reactions

* Rxn may occur at much lower dose than normal

Concepts of drug hypersensitivity

* Hapten- covalent binding to carrier protein

* Pro-Hapten- enzymatic or non-enzymatic conversion to reactive intermediate

* Danger- drug-related cytotoxicity resulting in enhanced immune response + co-stimulatory signal i.e. virus

* Pharmacological interaction (p-i) concepts- non-covalent binding to MHC peptides

* Immune response humoral (ab), cellular (T cell) or both

Allergic reactions are more likely to occur with:

High molecular weight drugs (insulin)

Proteins (carbohydrates are less immunogenic)

Presence of inflammation (enhances the immune response)

Prolonged or repeated enteral or parental treatment

Certain HLA phenotypes

Gell and Coombs Classification

Type I: IgE-mediated mast cell degranulation causing immediate hypersensitivity or anaphylaxis

IgE specific antibodies cross-link; cell activiation

Usually occurs within 30 min of administration

May occur immediately in prior sensitization

Wheezing, urticaria/angioedema

Diagnose via history, PE, PST/RAST

Treatment: avoidance vs. desensitization

Examples: PCN (immediate reaction), Blood products, Vaccines

Type II: Cytotoxic reactions mediated by binding of IgG or IgM to cell bound antigens, leading to activation of complement

Usually due to blood products or rapidly haptenating drugs (PCN, Quinidine, Sulfonamides, Methyldopa)

Coomb’s positive hemolytic anemia/thrombocytopenia, AIN, pneumonitis

Diagnose by clinical syndrome and in vitro demonstration of antibody

Treatment: removal of offending agent, steroids

Type III: Immune-complex mediated by binding of antigens to antibody (IgG and IgM), with subsequent tissue deposition and complement activation

Local or disseminated inflammatory reactions

Due to high-dose, prolonged use of drug

Example: serum sickness (fever, LAD, arthralgias, nephritis, hepatitis etc.)

Immune complex reactions can cause drug induced lupus syndromes (Hydralazine, Procainamide, Isoniazid, Phenytoin)

Treatment: removal of offending agent, steroids

Future administration of the offending agent is a relative contraindication

Type IV: Delayed hypersensitivity reaction mediated by T-cells (cell-mediated immunity)

Requires memory T cells for drug allergen (7-20 days initially; 8-120 hrs subsequent)

Examples: contact dermatitis, drug fever, drug-induced vasculitis

Diagnosis: clinical syndrome, patch test, in vitro test for antibody

Treatment: removal of offending agent, steroids

Future administration of offending agent is a relative contraindication

Risk Factors for Drug Allergy

Parenteral medications are more likely than oral to cause IgE-mediated reactions

Prophylactic doses are less likely to sensitize than high doses

Frequent courses of an antibiotic are more likely to induce reactions than rare courses

Women have a 35% higher incidence of reaction than men

HLA type may influence drug allergy when associated with certain diseases (HLA-DR3 associated drug-induced nephropathy in RA patients taking gold or penicillamine; abacavir reactions are highly associated with the presence of the HLA-B*57 allele)

A positive history of immune-mediated drug reaction in a parent increases the child’s risk of drug allergy 15-fold

Patients with SLE or HIV- increased risk

Clinical Manifestations

Multiple Organ System Patterns

Erythema Multiforme, Stevens-Johnson syndrome

Toxic Epidermal Necrolysis (TEN)

Hypersensitivity syndrome

Drug fever

Cutaneous patterns (most common)

Multiple drug allergy syndrome

Multiple Organ System Patterns

Anaphylaxis: IgE-mediated “acute, life-threatening immunologic reaction that consists of diffuse erythema, pruritis, urticaria, angioedema, bronchospasm, laryngeal edema and hypotension, alone or in combination”

Anaphylactoid: direct mast cell release of histamine; clinical syndrome identical to anaphylaxis

Thiamine, opiates, RCM, muscle relaxants, vancomycin

Erythema Multiforme

Erythematous, polymorphic eruption caused by drugs in 50% of cases; Lymphocyte cell mediated rxn; 1-2 wks after Rx

Target lesions, maculopapular rash, urticaria, vesicles

Three zones:

Erythematous central papule that may blister

Edematous middle ring

Erythematous outer ring

Symmetric; predilection for extremities

Major and minor forms

Stop the offending drug immediately and avoid in the future

Stevens-Johnson Syndrome (SJS)

Severe form of EM with mucosal and conjunctival involvement; 5% mortality

Fever and flu-like symptoms precede rash by 1-3 days

Epidermal loss 30% of BSA

High mortality rate (30-40%)

May be difficult to differentiate from SJS, as many of the same drugs cause both

Re-administration of drug for SJS/TEN is an ABSOLUTE CONTRAINDICATION

Steroids are not helpful and contraindicated in TEN

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)

Formerly Hypersensitivity Syndromes (HSS)

Specific syndrome associated with anticonvulsants, sulfasalazine, allopurinol etc.

S/Sx’s- fever, papular rash, LAD (75%), hepatitis (50%), nephritis, eosinophilia 2-6 wks after starting new Rx

Morbilliform rash, often indurated/infiltrated, facial swelling, exfoliative dermatitis, bullae and purpura

Acute liver failure is most common cause of mortality, which is 18-40% in those with hepatitis

Alveolar or interstitial Pneumonitis

Felt to be immune-mediated, but cause unknown

Treat by stopping the drug, supportive care and steroids

Re-exposure to drug is contraindicated

* In some, is due to an inherited deficiency of epoxide hydrolase needed to metabolize toxic arene oxide made by cytochrome P-450 from parent drug (anticonvulsants)

* Slow acetylators may be at increased risk

Drug Fever

Idiosyncratic reaction

Variable pattern: Low grade/continuous; Spiking/intermittent

Eosinophilia, leukocytosis, rash

Elevated ESR

Almost always resolves within 48-72 hours of discontinuing the offending drug

Cutaneous Patterns

Urticaria/angioedema – common manifestation

Rapid onset after drug is given, resolves when drug is discontinued

Skin testing may confirm Dx

IgE-mediated, direct mast cell release, or bradykinin-mediated (ACEI)

Does not involve other organs, afebrile

Treatment: antihistamines, epinephrine if laryngeal involvement suspected

Morbilliform, maculopapular exanthems

Most common drug-induced skin reaction

Usually symmetric, confluent macules/papules- spare palms and soles

Predilection for dependent areas in hospitalized patients

Onset 4-10 days after Rx; up to 14 days after Rx completion

Common drugs: PCN, NSAIDs, (-lactams, sulfonamides, anticonvulsants, allopurinol

Maculopapular reactions occur more often (10%) with amoxicillin than other PCN’s and in 50-80% of patients with EBV, CMV, CML, hyperuricemia or allopurinol

Treatment: removal of offending drug with future avoidance

If necessary, can continue drug if no evidence of mucosal involvement, vasculitis (‘treating through’)

Allergic contact dermatitis

Most common example of delayed hypersensitivity

Caused by topical medications

Pruritic, erythematous, vesicular or maculopapular rash

Sensitization occurs in 5-7 days, with repeat topical or systemic exposure producing rash within 24 hours

Causes: neomycin, local anesthetics, parabens, ethylenediamine, PABA-containing sunscreen, corticosteroids (frequency of 3-5%)

* Fixed drug eruptions

* Consist of single or multiple round sharply demarcated plaques that appear soon after drug exposure and recur in exactly the same site with subsequent drug exposure

* Pruritus and burning are common

Multiple Drug Allergy Syndrome

Occurs primarily with antibiotics

General tendency to respond to haptens rather than specific classes of drugs

No treatment/difficult to diagnose

Prevention of reactions via prevention of infection and avoidance of unnecessary use of antibiotics

Diagnosis of Drug Allergy

Index of Suspicion!

History, including timing of drug administration/onset of rxn

Name of Rx

Timing?

Systems involved?

Why Rx given?

Other Rx?

Tx required for rxn?

Rx exposure before/since rxn?

S/Sx’s w/o Rx?

PMHx?

Caveats of PST to invalidated drugs (most drugs except PCN and some cephalosporins):

Not indicated for non-IgE-mediated reactions

Uninformative if negative

Must rule-out an irritant reaction if positive

Delay skin testing 2-4 weeks after anaphylactic episode to avoid refractory period

RAST testing often not available and not sensitive/specific

Serum tryptase and/or histamine in acute reaction

IgG, IgA and IgM to specific drugs are not useful

+ PST suggests Dx/may predict greater risk for future rxn

[pic]

Management of Drug Allergy

Identify and withdraw the offending drug

Treat anaphylactic reactions appropriately

Supportive care – most reactions resolve without treatment once the drug is removed

Can consider steroids if extensive dermal or systemic involvement

Educate patient on avoidance of drug and cross-reacting drugs (provide letter)

Recommend Medic Alert for severe reactions

Alternatives for Drug Allergic Patients

Recommend an unrelated alternative medication

Most common approach

Educate patient on avoidance of drug and cross-reacting drugs (provide letter, document in chart!)

Recommend Medic Alert for severe reactions

Recommend a medication not identical to, but potentially cross-reactive with, the drug in question

10 years, frequently in 3rd to 4th decade

Scripps Clinic reviewed 300 AERD patients between 1995-2001 and found 57% were female and nasal polyps and asthma first presented at an average age of 34 years

European study of AERD:

Rhinitis appeared at an average of 30 years of age

Asthma followed the onset of rhinitis

ASA/NSAID-induced respiratory symptoms followed the onset of asthma

Nasal polyps developed last

Female:male was 2.3:1

Females had earlier onset and more severe disease

Atopy present in 1/3 with family history of AERD in 6%

Prevalence in asthmatic adult population is 9-20%

Prevalence in adult asthmatics with nasal polyps is 34%

Adult asthmatics with history of respiratory symptoms to ASA/NSAID’s will have a positive oral challenge to ASA/NSAID’s 66-97% of the time

Clinical presentation: ingestion of ASA or cross-reacting NSAID in setting of an asthmatic with rhinitis and nasal polyps induces:

Intense rhinorrhea

Nasal congestion

Conjunctival injection

Periorbital edema

Laryngospasm

Bronchospasm (wheeze, SOB, chest tightness)

Reactions can be slow in onset, occurring 30-120 minutes after ingestion

Patient may experience only lower respiratory tract symptoms, upper respiratory tract symptoms, or both

Most experience symptoms of both

The dose of ASA or NSAID that provoked the symptoms is the most important indicator of severity

Pathogenesis

Although the history may suggest a type I reaction, thus far IgE mediated mechanisms have NOT been clearly demonstrated

skin test responses with ASA are typically negative (only 1 case report)

Usually no serum Ab against ASA or its derivatives in affected patients

ASA and most NSAID’s, as non-specific COX-inhibitors, inhibit COX-1 more potently than COX-2

All NSAID’s that inhibit COX-1 cross-react with ASA, even on first exposure to the new NSAID

Degree of cross-reactivity is proportional to the amount of NSAID required to inhibit COX-1

Selective COX-2 inhibitors (rofecoxib and celecoxib) do not cross-react in AERD

Partially selective COX-2 inhibitors (nimesulide, meloxicam) don’t cross-react at small doses where inhibition of COX-2 is felt to be predominant, but do cross-react with ASA at higher doses, where inhibition of COX-1 is predominant

COX-1 is expressed in all mammalian cells, whereas COX-2 is inducible by inflammatory mediators

With inhibition of COX-1 and COX-2, excess arachidonic acid is shunted via the 5-lipooxygenase pathway to produce leukotrienes, specifically LTC4, LTD4, and LTE4

Evidence supporting LO “shunt” theory

BAL fluid shows ( LTC4 in patients with AERD compared to non-AERD asthmatics

LTE4 is elevated in urine of AERD patients even before ingestion of ASA/NSAID, as compared to non-AERD asthmatics

AERD patients have decreased levels of anti-inflammatory lipoxins (also generated by LO from arachidonic acid)

Therapy with LT-antagonists can inhibit AERD bronchoconstriction

On exposure to ASA/NSAID’s, COX-1 is inhibited, causing a decrease in production of PGE2

PGE2 inhibits 5-LO, so in its absence, with ongoing production of arachidonic acid, excess leukotrienes are produced

Leukotrienes result in bronchoconstriction, vasodilation, mucous secretion and eosinophil chemotaxis

[pic]

Diagnosis

Based primarily on history of respiratory symptoms in an asthmatic after ingestion of ASA/NSAID’s

If the diagnosis is unclear, confirm with an Aspirin Challenge

Must be done in hospital setting

Prefer asthma be under good control

May continue current medications, although leukotriene modifiers may decrease the lower respiratory response (not upper respiratory)

Up to 25% of patients with convincing history may have a negative oral challenge

Lysine-ASA, a soluble form of aspirin, has been used for nebulized bronchoprovocation challenge in outpatient setting, but is not available in the United States

Treatment:

The usual guidelines for asthma therapy also apply to the ASA/NSAID-intolerant asthmatic

Avoid all routes of ASA/NSAID administration

Tylenol is generally a safe substitute

Case reports: patients who are very sensitive to ASA have also reacted to tylenol (which has very low but detectable COX activity)

Magnesium salicylate and Salicylic acid also have very low COX activity and are alternatives

COX-2 inhibitors:

Theoretically should not cross-react because of preservation of PGE2

Experience is limited but small reports show that although safer than COX-1, they may not be completely specific for COX-2, especially at higher doses

Should be used with caution

Leukotriene-inhibitors

5-lipoxygenase inhibitors

zileuton

Cysteinyl LT receptor antagonists (LTD4)

Zafirlukast, montelukast

ASA-desensitization:

all AERD patients can be desensitized

Eliminate the respiratory reaction by increasing exposure to oral ASA

Requires hospital admission ~ 2-3 days

May become resensitized if ASA stopped >2-5 days

Useful in patients requiring continuous ASA/NSAID treatment

Stroke or CAD prophylaxis, rheumaic dz, etc

Has also been shown to improve both upper and lower airway disease in patients with AERD

Asthma not well controlled on steroids/LT/B-agonists

Repeated nasal polypectomies and sinus operations

Type 2: NSAID-induced Urticaria/angioedema in patients with chronic urticaria

In patients with chronic idiopathic urticaria, ASA-induced urticaria reported in 21-30%

Usually occurs 2-4 hours following ingestion

Dose-dependent

Increased with high activity of underlying urticaria

Antihistamines and leukotriene receptor antagonists prevent or modify these reactions

Diagnosis:

Oral challenge is only diagnostic tool

Most people react to doses of 325-650mg

Reactions are later (6hrs) so challenge is modified to start with higher doses (100mg)

Treatment:

Avoidance of ASA/NSAIDS decreases acute flares but usually patient continues to have chronic urticaria

Desensitization to ASA is NOT effective

Type 3: ASA/NSAID-induced cross-reacting urticaria in normal individuals

Urticaria or angioedema with NSAID’s that inhibit COX-1

May develop chronic urticaria at a later date

Type 4: Blended reactions in normal individuals

Urticaria, angioedema, rhinitis, bronchospasm

May be due to one or more NSAID’s

Type 5: Single NSAID-induced urticaria/angioedema in normal individuals

Requires prior sensitization

No cross-reaction between ASA and other NSAIDs

Atopy may be a risk factor

More common if NSAID is taken intermittently than chronically

Type 6: Single NSAID-induced anaphylaxis

IgE-mediated reaction to a single NSAID

Patient may be challenged to a structurally different NSAID or ASA

Sulindac, tolmetin and zomepirac share a common acetic acid structure and may cross-react

Type 7: Aseptic Meningitis caused by a specific NSAID

Diagnosis of exclusion

Presentation involves a patient with recurrent bouts of meningitis within 12-24 hours of the same NSAID

Symptoms resolve when the NSAID is discontinued

Reported with ibuprofen, sulindac, tolmetin and naproxen

Cross-reactions do not occur

Type 8: Hypersensitivity Pneumonitis

Due to specific NSAIDS (not ASA)

Often seen in patients with chronic arthritis

Patients will often tolerate a different NSAID

Strict Avoidance of offending NSAID

Radiocontrast Material (RCM)

First used by Swick, an American urologist, in 1928

1950’s, ionic monomeric RCM was introduced and became the standard RCM

1980’s, ioxaglate became the first ionic low-osmolar RCM

1986, nonionic lower osmolar RCMs were introduced in the United States (iopamidol, iohexol)

1996, FDA approved iodixanol, a nonionic RCM (iso-osmolar to blood)

Over 10 million contrast studies annually in US

Adverse reaction rate 2-3% with low osmolar RCM, up to 12.66% with high osmolar RCM

Most reactions minor

Moderate reactions in 1.0%

Life-threatening reactions 0.01 -0.1%

10,000 patients annually

Mortality rate 1/75,000 - 1/170,000

130 patients annually

Classification of RCM

Ionic or nonionic

Monomeric or dimeric

Hyperosmolar or lower osmolar

Benzoic acid with iodine in 3 positions of the benzene ring

Ionic monomers have a tri-iodinated benzene ring – are also hyperosmolar (>1400 mOsm/kg)

Ionic dimer (ioxaglate) are lower osmolar

Nonionic monomers (iohexol, iopamidol, ioversol, iopromide and ioxilan) are lower osmolar

Nonionic dimer (iodixanol) – lowest rate of reactions

Iso-osmolar: iodixanol (visipaque)

Decrease of anaphylactoid reactions from 2.5% to 0.7% in study of 1411 patients

Decrease in adverse reaction from 20% to 6.7% in another study of 120 patients

Most RCM non-ionic

Lower rate of reaction with non-ionic RCM

Large Japanese study

Ionic RCM group (169,284 cases) vs nonionic RCM group (168,363 cases)

Adverse reactions were 12.66% (severe 0.22%) with ionic RCM and 3.13% (severe 0.04%) with nonionic RCM

Types of reactions

Vasovagal reactions

Reactions due to physiochemical properties (i.e. osmolality) of the agent

Anaphylactoid reactions

Anaphylactoid reaction

Non-IgE mediated mechanism

Reactions may occur with first exposure

Otherwise identical to anaphylaxis

Can still be fatal

Hyperosmolality seems to play central role

Direct correlation between osmolality and adverse reactions

Actual mechanism uncertain

Possible etiologies:

Direct mast cell activation with release of histamine and other mediators

Activation of coagulation, kinin and complement cascades

Inhibition of platelet aggregation also occurs

Red cell aggregation and endothelial disruption

Shown in vitro

Clinical Presentation:

Onset of symptoms

Typically during or within a few minutes of IV administration

Rarely after 20 minutes

Most common symptoms

Likely due to vagal stimulation

Nausea, emesis, flushing, urticaria, pruritis, sneezing, cough, pain at site of infusion, palpitations, facial edema, rigor, hoarseness, chest pain and abdominal pain

Others: pallor, diaphoresis, lightheadedness, dyspnea, hypotension, cardiac arrest

Diagnosis made by history / exam alone

NO in vitro / in vivo tests are available

Skin testing is NOT helpful

“Test doses” NOT helpful

Severe / fatal reactions have occurred with a 1-2 ml IV test dose

Severe reactions have followed negative test doses

Identifying higher risk patients is the best way to prevent or minimize future reactions

|Factor |Risk |

|Previous anaphylactoid reaction to RCM |17-60% |

|Heart disease |2-5x |

|Atopy |3x |

|Asthma |10x |

|Beta-blockers | |

| |2.5x |

| |(may increase severity) |

Management of acute reactions:

STOP THE INFUSION

Treat identically to IgE-mediated anaphylaxis

EPINEPHRINE

Antihistamines

Steroids

Other supportive measures as indicated

Most reactions respond promptly

Do not ignore potential for fatal outcome!!!

Perform procedures with trained personnel and emergency equipment

Prevention of future reactions:

Premedication

Use of low osmolar contrast agents

Use of alternative contrast agents

RCM Premedication

[pic]

Treatment of patients needing RCM for emergency procedures:

Document need for particular study and that alternatives are unsatisfactory (i.e. MRI)

Document informed consent

Recommend nonionic, low osmolar RCM

Pre-treat: steroids, antihistamines, ephedrine

Successful emergency regimen used in past

Hydrocortisone 200mg IV Q4 hrs until study done

AND benadryl 50mg IM 1 hour before RCM

+/- ephedrine

Document

There has not been time for conventional pretreatment

There is limited experience w/ rapid schedules

Emergency equipment available

Study of 657 procedures in 563 patients

Rate of anaphylactoid reactions on repeat exposure in patient with previous reaction to RCM:

Low-osmolar Nonionic RCM:

Evaluated 800 studies with high osmolar vs. 200 studies with low osmolar RCM

Other Agents - Gadolinium

Gadolinium (GAD)- based media are the primary contrast agents used in MRI

Incidence of reactions is MUCH lower than RCM, on the order of 0.0003% - 0.01%

Non-IgE mechanism, again NO testing available

Do NOT need to pre-treat when giving GAD in patients with prior RCM reaction

In rare patient with actual anaphylactoid reaction to GAD, may consider pretreatment as with RCM

Final thoughts:

Anaphylactoid reactions may occur when RCM administered by nonvascular routes

Retrograde pyelograms, hysterosalpingograms, myelograms, arthrograms

Pretreatment doesn’t work for:

ARDS, noncardiogenic pulmonary edema, renal protection

Reaction to RCM does not mean:

Allergy to topical iodine cleansers or other iodides

Immediate hypersensitivity to shellfish

Shellfish allergy is a reaction to the shellfish protein, not to iodine

Local Anesthetic Reactions

Drugs anesthetize the area to which they are applied by blocking nerve conduction and preventing depolarization of cell membranes

Incidence:

2-3% of local anesthesias

True allergies are exceedingly rare

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