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Allergy and Immunology > First Aid, Chapter 7 Hypersensitivity Disorders, Drug Reactions > Flashcards

First Aid, Chapter 7 Hypersensitivity Disorders, Drug Reactions Flashcards

1
Q

What reactions does the term “adverse drug reaction” cover? What percentage of adverse drug reactions are allergic?

A

Expected side effects (e.g., sedation with antihistamines), intolerances (AERD), allergic reactions (PCN-induced anaphylaxis), or pseudoallergic reactions (radiocontrast media). Only about 10% of adverse drug reactions are allergic.

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2
Q

What are the Gell-Combs classification of drug reactions?

A
  • Type I: Immediate IgE-mediated hypersensitivity (e.g., PCN-induced anaphylaxis).
  • Type II: Antibody-dependent cytotoxic reactions.
  • Type III: Immune complex reactions (i.e., secondary to an antibiotic)
  • Type IV: Cell-mediated or delayed hypersensitivity reactions (e.g., to purified protein derivative [PPD]).
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3
Q

What are the subclassifications of type 4 drug reactions? What are the cytokines and cells involved? What are the clinical manifestations?

A
  • Type IVa, Th1 (IFNγ), Monocyte, Eczema
  • Type IVb, Th2 (IL-4 and IL-5), Eosinophil, Maculopapular or bullous
  • Type IVc, CTL (perforin and granzyme), CD4 and CD8, Maculopapular or bullous to pustular and increased CD8 T lymphocytes in skin
  • Type IVd, T lymphocytes and IL-8, PMNs, Pustular
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4
Q

What is the hapten hypothesis?

A

The hapten hypothesis states that small drugs, which are not by themselves immunogenic (haptens), become immunogenic or allergenic after binding to a self-carrier protein.

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5
Q

Why might some patients have a hypersensitivity reaction the first time they have a drug?

A

The drug binds to the TCR with sufficient affinity in the context of the TCR interacting with MHC and becoming immunogenic.

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6
Q

Describe how the interaction of drugs with immune receptors causes immuogenicity?

A

The pharmacologic interaction of drugs with immune receptors (p-i concept of drug allergy) states that once a drug binds to a T-cell receptor (TCR) with sufficient affinity, especially in context of the TCR interacting with major histocompatibility complex (MHC), then it may become immunogenic.

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7
Q

What is the prohapten hypothesis?

A

Most drugs by themselves are not immunogenic until they are metabolized to a reactive metabolite

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8
Q

What are risk factors for drug allergy?

A
  • Higher dose
  • IV route
  • Large-molecular-weight agents
  • Frequent or repetitive courses
  • Duration of previous courses
  • Female gender
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9
Q

What drug reactions is HLA-DR3 associated with?

A

Increased reactions to insulin, gold, and penicillamine.

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10
Q

What HLA marker is associated with reactions to abacavir?

A

HLA-B*5701 is strongly associated with reactions to abacavir and should be checked for prior to starting this drug.

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11
Q

What is HLA-B*5701 associated with?

A

HLA-B*5701 is strongly associated with reactions to abacavir and should be checked for prior to starting this drug.

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12
Q

Is atopy a risk factor for drug allergies?

A

Atopy is not a risk factor for most drug allergy, but is for reactions to latex or radiocontrast reactions.

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13
Q

What are the major and minor determinants of penicillin?

A
  • Major determinants = Benzylpenicilloyl polylysine (Pre-Pen)
  • Minor determinants = Penicillin G; penicilloate and penilloate if available
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14
Q

What component is most penicillin allergy related to?

A

The major determinants.

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15
Q

What is the prevalence of penicillin allergy? How many patients who report a history of allergy will tolerate it?

A

10% of patients report it. Of those, 90% will tolerate penicillin.

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16
Q

What percentage of patients lose their penicillin allergy?

A

PCN-specific IgE antibodies decrease over time (~10% per year). Therefore, ~50% of patients who had immediate reactions to PCN will have a negative skin test after 5 years, and ~80% will be negative at 10 years.

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17
Q

What is the predictive value of negative penicillin skin testing? Of positive penicillin skin testing?

A

The predictive value of negative skin tests to PCN’s major determinants (i.e., PrePen) and minor determinants is ~97% for ruling out anaphylactic potential. The predictive value of positive skin test to PCN is about 60%. Ten percent to 20% of PCN allergic patients only react to minor determinants, therefore they should be included in any PCN skin test to have adequate predictive value.

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18
Q

What is the resensitization rate of penicillin after losing the allergy?

A

After losing PCN allergy, resensitization is rare with oral medications, but more common with subsequent exposure to high-dose IV PCN (e.g., ~16%).

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19
Q

What percentage of skin test negative patients will have a reaction to amp/amox? What percentage of EBV patients will develop such a rash to Amp/amox?

A

Approximately 10% of patients have a delayed maculopapular rash with AMP/AMOX, which is not IgE-mediated. 80% of EBV patients will develop such a rash.

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20
Q

Do carbepenams cross-react with penicillins?

A

PCN has moderate cross-reactivity with carbapenems (e.g., imipenem or meropenem) based on skin testing, but clinically important cross-reactivity is much rarer (0–11%), and there are no reactions in patients with negative PCN skin tests to imipenem or meropenem.

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21
Q

Does aztreonam cross-react with other b-lactams?

A

No, except for ceftazidime.

Mnemonic
AZtreonam cross-reacts with ceftaZidime.

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22
Q

What is the cross-reactivity between cephalosporins and penicillins? Why is the cross-reactivity low? Which cephalosporins cause more reactions and which cause less?

A

Cross-reactivity with PCN is rare (~2%), but some reactions can be fatal. The low cross-reactivity may be because some cephalosporin allergy can occur due to the R-group side chain and not the β-lactam ring. In general, first- and secondgeneration cephalosporins cause more allergic reactions than do third- and fourthgenerations cephalosporins.

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23
Q

How do you determine if it is safe for a penicillin allergic patient to safely receive a cephalosporin?

A

To determine if a patient with a history of PCN allergy may safely receive a cephalosporin, you should perform PCN skin testing. Patient who are negative on the PCN skin test may safely receive cephalosporins. Cephalosporin skin testing does not have sufficient negative predictive value to rule out anaphylactic risk in a patient with a convincing history.

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24
Q

If penicillin skin testing is unavailable, how do you determine if it is safe for a PCN allergic patient to receive a cephalosporin?

A

If PCN skin testing is unavailable, risk stratify the reaction and then either directly administer the drug, perform a graded challenge, or desensitize the patient.

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25
Q

What is the moiety contained on sulfonamide antibioitics?

A

Contains SO2NH2 moiety which is a aromatic amine at the N4 position.

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26
Q

What is the typical allergic reaction to a sulfonamide antibiotic?

A

The typical reaction is a delayed maculopapular rash, likely T-lymphocyte-mediated.

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27
Q

What percentage of HIV patients reat to TMP/SMX?

A

40-70% have a delayed rash.

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28
Q

Are type 1 reactions to sulfonamides as common as delayed reactions? What are type 1 reactions to sulfonamides reacting to?

A

Type I reactions are much rarer than delayed reactions. They are due to the N4 sulfonamidoyl hapten acting as the major determinant.

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29
Q

Why is there little cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics?

A

There is little clinically relevant cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics (e.g., furosemide), because nonantibiotic sulfonamides lack the aromatic amine at the N4 position.

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30
Q

What is the mechanism of pseudoallergic reactions?

A

These reactions are typically mediated by basophil and mast cell activation.

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31
Q

What are the risk factors for radiocontrast adverse reactions?

A

Radiocontrast adverse reactions are increased in women, asthma and/or atopy, cardiovascular disease, and prior history of reaction.

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32
Q

What type of contrast media can prevent reactions?

A

lower ionic contrast media or nonionic.

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33
Q

Describe symptoms of SJS. How do you differentiate SJS from TEN?

A

Stevens-Johnson syndrome (SJS) is defined by less than 10% epidermal detachment. In SJS, patients present with confluent, purpuric macules on face and/or trunk, mucosal involvement, and often systemic symptoms and fever. Other organ involvement may include ocular, liver, kidney, and lung. By contrast, toxic epidermal necrolysis (TEN) is more severe (>30% involvement).

34
Q

What is the treatment of SJS and TEN?

A

Although steroids may be helpful in early SJS, they are contraindicated in TEN. Treatment is supportive, although intravenous immunoglobulin (IVIG) can be helpful due to the presence of Fas-blocking antibodies.

35
Q

What is the mechanism of SJS and TEN?

A

Mechanisms of action include reactive metabolites causing Fas/FasLmediated apoptosis of epidermal cells as well as cytotoxic T-lymphocyte activation and perforin release.

36
Q

What are high risk agents for causing SJS and TEN?

A

High-risk agents include PCN and sulfonamides, anticonvulsants, NSAIDs, and allopurinol.

37
Q

What is the mechanism of red man syndrome? How can the reaction be prevented or stopped?

A

“Red man syndrome” is a rate-related infusion reaction characterized by flushing, erythema, and pruritus caused by direct activation of mast cells. May respond to decreased rate, premedication with antihistamine, and stopping concurrent narcotic medications.

38
Q

Other than red man syndrome, what other reaction can vancomycin cause? What other medications can also cause this same reaction?

A

Vancomycin may also cause linear IgA bullous dermatitis with tense blisters. Less commonly, this reaction may occur due to captopril, furosemide, lithium, or TMP-SMX (Bactrim).

39
Q

What is the prevalence of cough in ACE I?

A

20% of patients.

40
Q

When does ACE I angioedema usually occur? What is the mechanism? Does it respond to treatment? How long after discontinuation can it continue to occur?

A

ACE I-induced angioedema is usually observed in the first week after starting the medication; however, up to 30% of patients present months or even years afterward. Interferes with degradation of bradykinin and therefore rarely responds to antihistamines or steroids. May occur in up to 0.7% of the population and is increased in African Americans. Intermittent angioedema can develop for up to a month after the patient is off the medication, and around 2% of patients continue to have episodes when switched to another antihypertensive.

41
Q

What are common medications that cause DRESS?

A

Common offending agents are anticonvulsants, sulfonamides, allopurinol, and minocycline.

42
Q

What are symptoms of DRESS? What is the natural course of DRESS? When does it resolve after discontinuation? What is the treatment?

A

fever, lymphadenopathy, and hepatitis. Facial edema is characteristic. This reaction occurs weeks after therapy, develops over days, and, unlike most drug reactions, symptoms may worsen even after drug discontinuation and last for weeks afterwards. Initial treatment is with systemic corticosteroids. IVIG has been reported to be helpful in patients who did not respond to systemic steroids.

43
Q

Describe fixed drug eruptions. What are common offending agents?

A

Typically, fixed drug eruption appears as a purple-blue macule that occurs at same location upon each subsequent exposure to the drug but may take any dermatologic manifestation. Due classically to Bactrim or phenolphthalein.

44
Q

What reactions do local anesthetic agents cause? How do you differentiate from a hypersensitivity reaction? How do you diagnose it?

A

Although lidocaine and other “-caine” medications are commonly blamed for “allergic reactions,” these rarely cause any actual hypersensitivity; rather, these are associated most commonly with vagal reactions (e.g., a clinical clue is bradycardia as opposed to the usual tachycardia that would accompany anaphylaxis). Positive skin tests do not necessarily indicate actual allergy; therefore, graded challenges are more predictive of allergic reactions.

45
Q

What is the most common cause of perioperative drug reactions?

A

Quaternary ammonium muscle relaxants such as succinylcholine.

46
Q

Do quaternary ammonium muscle relaxants require haptenation?

A

These agents do not require haptenation since they act as bivalent antigens able to directly bind adjacent IgE antibodies on cell surfaces.

47
Q

Is skin testing useful with quanternary ammonium muscle relaxants?

A

Skin testing has been shown to be helpful in such cases if positive; if negative, the predictive value is uncertain.

48
Q

What are common causes of perioperative drug reactions?

A

Most commonly quaternary ammonium muscle relaxants, can also be due to latex, antibiotics, barbiturates, or propofol (contains sulfites).

49
Q

What percentage of insulin patietns develop anti-insulin antibodies? Does this translate into reactions? What HLA class confers increased risk to insulin allergy?

A

Up to 50% of patients receiving insulin may develop anti-insulin antibodies, but these patients often tolerate insulin without clinical reactions. HLA-DR3.

50
Q

What is the allergenicity of insulin preparations?

A

Bovine > porcine > human

51
Q

How can local reactions to insulin be improved?

A

Most patients can tolerate continuing insulin treatment despite local reactions; however, if needed, antihistamines or splitting doses may help.

52
Q

What is NPH insulin allergy sometimes related to? What should you do in this situation?

A

NPH insulin may have allergy to the protamine component rather than the insulin, and switching to nonprotamine-containing insulin can be helpful.

53
Q

Can anaphylaxis to insulin occur? Can desensitization be done?

A

Anaphylactic reactions are rare but may occur; insulin desensitization has been successfully performed.

54
Q

What is cytokine release syndrome? What are the abnormal lab tests that accompany it? What are common inciting agents?

A

Many are prone to cytokine release syndrome with resultant fever, rash, bronchospasm, capillary leak syndrome, GI symptoms, meningoencephalopathy with abnormal liver functions tests (LFTs), uric acid, lactate dehydrogenase (LDH), IL-6, and TNFα. Inciting agents may include rituximab (anti-CD20) or muromonab (anti-CD3).

55
Q

What is a common reaction caused by sirolimus? What else can cause this reaction? What is it used to treat?

A

Sirolimus (rapamycin), which antagonizes IL-2 signaling in particular, is known to cause capillary leak syndrome with resultant hypotension. Interestingly, highdose monoclonal antibody therapy with IL-2, used in the treatment of metastatic melanoma, is also known to cause this syndrome (cytokine storm).

56
Q

What are common adverse reactions of interferon therapy?

A
  • Flu-like symptoms
  • Urticaria
  • Dermatitis
  • Vasculitis
  • Idiopathic thrombocytopenic purpura (ITP)
  • Autoimmunity
  • Depression
57
Q

What reaction is common in TNF inhbitors (infliximab, etanercept)? What test should be checked prior to therapy?

A
  • serum sickness

- disseminated mycobacterial infection and/or TB, so check a PPD prior to therapy and annually thereafter

58
Q

What reactions does etanercept cause?

A

Injection-site and local reaction (in addition to serum sickness and disseminated mycobacterial infection and /or TB).

59
Q

What reaction does epoetin cause?

A

Pure red cell aplasia

60
Q

What reactions do alteplase and tPA cause?

A

Anaphylactoid reactions

61
Q

What is cetuximab? What is it used in?

A

Cetuximab is a monoclonal antibody against the epidermal growth factor receptor and is used in certain colorectal and head and neck cancers.

62
Q

What is the mechanism of hypersensitivity to cetuximab? Does it vary by geographic region?

A

The rate of hypersensitivity reactions to cetuximab varies by geographic region. Caused by presence of IgE antibodies against naturally occurring galactose-α-1,3-galactose (i.e., oligosaccharides related to the ABO blood group) even prior to exposure to cetuximab. These pre-existing IgE antibodies appear to put such patients at risk for anaphylaxis to cetuximab, which also contains galactose-α-1,3-galactose.

63
Q

What are common causes of immune-induced hemolytic anemia?

A

Quinidine, methyldopa, or PCN.

64
Q

What are common causes of immune-induced thrombocytopenia?

A
  • Quinidine
  • Propylthiouracil
  • Gold
  • Sulfonamides
  • Vancomycin
  • Heparin (i.e., specific IgG to heparin-platelet factor 4 forms immune complexes)
65
Q

What is the presentation of pulmonary drug hypersensitivities? What medications cause it?

A

Pulmonary drug hypersensitivity presents with:

  • Cough
  • Migratory infiltrates
  • Peripheral eosinophilia
  • Pulmonary fibrosis

May be seen with bleomycin, methotrexate, and nitrofurantoin. Nitrofurantoin may also be associated with pleural effusion or interstitial pneumonitis and/or fibrosis. NSAIDs may be associated with eosinophilic pneumonia.

66
Q

What antigen/antibody setting does serum sickness occur in?

A

Serum sickness occurs most readily or efficiently in the setting of slight antigen excess.

67
Q

What medications typically cause serum sickness? What is the mechanism?

A

It may occur with PCN, sulfonamides, and phenytoin. It is secondary to formation of immune complexes.

68
Q

What are symptoms of serum sickness?

A
  • Fever
  • Erythema multiforme or urticaria
  • Arthralgias
  • Lymphadenopathy (typically appearing 1–3 weeks after starting treatment)
69
Q

How long does serum sickness last? What is the treatment of serum sickness? Can patients be desensitized?

A

Best treatment is to stop the offending medication, steroids, and antihistamines. Patients cannot be desensitized to the offending agents.

70
Q

What antibody is drug-induced cutaneous lupus associated with? What is the typical skin findings in drug-induced cutaneous lupus?

A

Drug-induced cutaneous lupus is associated with anti-Ro (SSA) antibodies. Typically, physicians will see photodistributed erythema or scaly, annular plaques weeks after starting a drug.

71
Q

What are common causes of drug-induced cutaneous lupus?

A
  • Hydrochlorothiazide (HCTZ) -Calcium channel blockers
  • ACE inhibitors
  • Antifungals
72
Q

What antibodies are found in drug-induced lupus (systemic)? What medications cause this?

A

Antihistone antibodies. Commonly secondary to procainamide, hydralazine, phenytoin, and isoniazid.

73
Q

What is the mechanism of drug-induced thrombocytopenia in heparin?

A

Specific IgG to heparin-platelet factor 4 forms immune complexes.

74
Q

What chemotherapeutics cause anaphylactoid reactions? How should they be managed?

A

Taxanes (e.g., paclitaxel, docetaxel) cause anaphylactoid reactions, which may be treated or prevented with steroids and antihistamines. Asparaginase may cause either anaphylactoid or anaphylactic reactions.

75
Q

What chemotherapeutics cause IgE mediated classic reactions? What is the treatment?

A

Platinum compounds (e.g., cisplatin, carboplatin, and oxiplaten) can cause IgE-mediated, classic allergic reactions; thus, patients may be desensitized if necessary. Asparaginase may cause either anaphylactoid or anaphylactic reactions.

76
Q

What is the mechanism of asparaginase drug allergy? How should it be managed?

A

Asparaginase may cause either anaphylactoid or anaphylactic reactions; however, some patients only react to asparaginase produced from Escherichia coli, so substituting formulations from other sources may avoid future reactions. Skin testing to asparaginase may help identify some at-risk patients.

77
Q

Can skin testing to drugs other than penicillin be helpful?

A

For medications other than PCN, unstandardized skin testing to liquid or solution forms of the drug may be pursued, and the known irritant concentrations are published for several antibiotics. Positive skin tests to a nonirritating concentration of the drug, especially in the context of a convincing history, suggests that drug-specific IgE may be present.

78
Q

What are indications to do a drug desensitization rather than a challenge?

A

Higher-risk situations may warrant drug desensitization rather than graded challenge. Risk factors would include a concerning clinical history (i.e., initial reaction was anaphylactic or urticarial), recent rather than remote reactions, and certain comorbid conditions (e.g., heart disease).

79
Q

What is the protocol for drug desensitizations?

A

Patients receive progressively increasing doses of the drug every 15–20 minutes for IV medications or every 20– 30 minutes for oral dosing until a full therapeutic dose is tolerated.

80
Q

What can help determine the starting dose of a drug desensitization?

A

skin testing

81
Q

How do you manage mild-moderate reactions in drug desensitization?

A

Mild-to-moderate reactions do not necessarily preclude continuing desensitization but do warrant repeating the dose at which the reaction occurred or decreasing the dose after the reaction subsides.

82
Q

What are contraindications to drug desensitizaton?

A

Contraindications to desensitization include exfoliative or blistering skin reactions and immune complex-mediated reactions, which include:

  • TEN/SJS
  • DRESS
  • Serum sickness
  • Hepatitis
  • Hemolytic anemia
  • Nephritis

Allergy and Immunology (68 decks)

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