1. Drug Allergy, Diagnosis and Treatment
Seong H. Cho, MD
Division of Allergy and Immunology
University of South Florida Morsani College of Medicine
경희의대 류마티스내과 IS 교수

2. Allergy-Immunology Primary immunodeficiency (ex. CVID)
Angioedema and urticaria
Immunologic lung disease
(ex. ABPA, hypersensitivity
pneumonitis)
Eosinophilc GI disorders
(ex.EoE)
Hypereosinophilc syndrome
Mastocytosis

3. Classification of Drug Reactions
Type A reactions (Most common)
Predictable
Related to pharmacologic actions of the drug
No specific host factors

4. Type A Reactions Toxicity - Renal failure from aminoglycosides
Side effect - Sedation from antihistamines
Secondary effect - Diarrhea from antibiotics
Drug Interaction - Theophylline toxicity from concomitant erythromycin

5. Type B Reactions Unpredictable Less Common
Occur in susceptible individuals

6. Type B Reactions Intolerance - Tinnitus with aspirin
Idiosyncratic reaction - Hemolysis with dapsone in G6PD deficiency
Hypersensitivity (Specific immunologic) - Anaphylaxis after penicillin
Pseudoallergic (non-immunologic) - Anaphylactoid reaction to radiocontrast media

7. Gell & Coombs Classification
Type I - Immediate hypersensitivity (IgE-mediated)
Type II - Cytotoxic reactions
Type III - Immune complex (e.g. serum sickness, drug fever)
Type IV - Delayed hypersensitivity

8. Immunopathobiology of Other Drug Reactions
Pseudoallergic reactions
: Due to non-IgE-mediated mast cell activation
Examples - Opiates, vancomycin,
radiocontrast media
NSAID-urticaria
Innate Immune Reactions
: Complement activation
Bradykinin release

9. Clinical Manifestation: Exanthems
Most common cutaneous drug eruption
Usually develops days after new medicine
Typically described as morbilliform “maculopapular”
Immunopathogenesis
:Many T cell mediated

10. Fixed Drug Eruptions Mechanism unknown
Typically develops 1-2 weeks for initial reaction but sooner with later exposures
Occur in same location
with each subsequent
exposure to drug
Pleomorphic: Eczema,
erythematous papules,
hyperpigmented areas,
bullous, urticarial
Examples: Tetracycline, NSAIDs, carbamazepine

11. Serum Sickness
Mediated by immune complexes: Heterologous antisera, snake antivenom, Rabbit antithymocyte globulin (ATG) and rituximab
Clinical features: Fever, lymphadenopathy, arthralgias, rashes, gastrointestinal symptoms, proteinuria (some cases)
Typically occurs after 1-3 weeks: More rapidly in previously sensitized

12. Serum Sickness-Like Reactions
Small molecular weight agents: Penicillin, sulfonamides, thiouracils, phenytoin
May lack features of immune complexes, hypocomplementemia, vasculitis, renal disease
Cefaclor most common cause in children
- Altered metabolism leading to toxic reactive
intermediates

13. Drug Fever Caused by release of pyrogens from phagocytes :
- can be immune complex or T cell-mediated.
Typically 7-10 days after therapy
Fever pattern variable
Relieved within 48 hrs of stopping drug

14. Severe Cutaneous Adverse Reactions (SCAR)
AGEP
DRESS
SJS/TEN

15. Acute Generalized Eczematous Pustulosis (AGEP)
Characterized by fine
pustules, fever, and neutrophilia
Rash begins in intertriginous
areas or face as edema and
erythema
 Nonfollicular sterile pustules
develop afterwards
Atypical target lesions, blisters and oral mucosal involvement uncommon but may confuse with SJS or TEN
Lesional T cells secrete high amounts of IL-8 (CXCL8)

16. DRESS Drug Rash Eosinophilia Systemic Symptoms Causative Drugs
: Anticonvulsants, sulfonamides, allopurinol,
minocycline, dapsone, sulfasalazine,
abacavir, nevirapine, hydroxychloroquine,
vancomycin, etc.

17. Clinical Features of DRESS (I)
Rash
: Exanthem, erythroderma, erythema multiforme,
purpura
Facial edema is diffuse and may be mistaken for angioedema
- Genital & extremity edema
Fever
: Vast majority of cases
Hypotension
: Up to 40% cases

18. Clinical Features of DRESS (II)
Hematologic abnormalities
- Eosinophilia in > 50%
- Anemia, neutropenia, thrombo-
cytopenia/cytosis less common
Hypogammaglobulinemia in some cases

19. Organ Involvement in DRESS
Lymphadenopathy <30% cases
Liver involvement in >60% cases
Renal dysfunction < 30% cases
: 40-80% with allopurinol
Respiratory & Cardiac less common
: Eosinophilic pneumonitis, cough, dyspnea,
pharyngitis, Pericarditis, myocarditis

20. Unique Aspects of DRESS
Reaction occurs after 2-8 weeks of therapy
Symptoms may worsen after drug discontinued
Symptoms may last weeks to even months after drug discontinued

21. Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)
SJS/TEN thought to represent a spectrum of a single reaction
SJS: < 10% total body surface area
Overlap SJS/TEN: 10-30% body surface area
TEN: >30% surface area involvement

22. SJS vs TEN
*Nikolsky’s sign

23. Clinical Features of SJS/TEN
Triad
1. Mucous membrane erosions: lip, oral cavity,
conjunctiva, nasal cavity, urethra, and vagina
2. Target lesions
3. Epidermal necrosis with detachment
Multi-organ involvement
- Gastrointestinal, hepatic, pulmonary, renal
Mortality: SJS: < 5%; TEN: 10-50% or higher
High risk patients: HIV, SLE, BM transplant

24. Penicillin Allergy (Antigens)
Major determinant (BPO)
: 95% PCN reacts with self-proteins via
beta-lactam ring to form benzylpenicilloyl
(BPO)
Minor determinants
- penicilloate
- penilloate
- penicillin G

25. Penicillin Allergy
90% patients with a Hx of PCN allergy will tolerate PCN
~ 80% PCN allergic patients lose PCN IgE after 10 years
1/3 patients with vague Hx of PCN allergy are PCN skin test positive

26. PCN Skin Tests
Negative predictive value for anaphylaxis is close to 100% if skin test negative to penicilloylpolylysine (Pre Pen) and minor determinants
10-20% of PCN-allergic patients show skin test reactivity only to penicilloate or penilloate
: Clinical significance is unknown

27. Penicillin and Cephalosporins
Share a common beta-lactam ring

28. Cephalosporin & PCN Allergy
Only 2% of penicillin skin test-positive patients react to treatment with cephalosporins: Some fatal
If penicillin skin testing is unavailable, and cephalosporin needed, it may be given via graded challenge
: Negative cephalosporin skin test appears to
predict tolerance (Romano 2004)
Patients with a history of non-severe reaction to penicillin rarely react to cephalosporins

29. Cephalosporin Allergy
Most hypersensitivity reactions to cephalosporins are directed at the R group side chains rather than the beta-lactam group
Cephalosporin allergic patients should avoid cephalosporins with similar R-group side chains

30. PCN Allergy and Monobactams
Aztreonam (monobactam) does not cross-react with other beta-lactams
: except for ceftazidime
shares an identical R-group side chain

31. PCN Allergy and Carbapenems
Moderate allergic cross-reactivity between penicillin and carbapenems based on skin tests
: 50% PCN-allergic patients skin test positive to
imipenem (Saxon 1988)
Clinical cross-reactivity variable but much lower
- Recent studies suggest 0-11% react
No reactions in patients with negative skin test to imipenem or meropenem
NEJM 2006;354:2835-7,
Ann Intern Med 2007;146:266-69,
JACI 2009;124:167-9.

32. Skin testing for Non-PCN Antibiotics
There are no validated diagnostic tests for evaluation of IgE-mediated allergy to nonpenicillin antibiotics
A negative skin test result does not rule out the possibility of an immediate-type allergy
Positive skin test results to a drug concentration known to be non-irritating suggests the presence of drug-specific IgE

33. Vancomycin: Red Man Syndrome
Constellation of symptoms
: Pruritus, flushing, erythroderma common
: Hypotension uncommon
Due to nonspecific histamine release that is
rate related (rare reports of IgE-anaphylaxis)
Severity correlates with amount of histamine
released into plasma
Severity reduced by reducing rate to < 500 mg/hr
and premedication with H1-antagonists

34. Radiocontrast Media Reactions
Mechanisms
- Anaphylactoid
: Direct mast cell activation
? IgE mediated (Allergy Feb;64(2): )
- Delayed reactions due to type IV hypersensitivity
Reaction rate from ionic contrast > non-ionic contrast
No evidence that sensitivity to seafood or iodine predisposes or is cross-reactive with RCM reactions

35. Radiocontrast Anaphylactoid Reactions
Risk Factors
- Female
- Asthma
- Cardiovascular disease
- Prior reaction to RCM
Management
- Non-ionic RCM
- *Pre-treatment
1. Prednisone 50 mg
: 13, 7, 1 hr prior
2. Diphenhydramine 50 mg
: 1 hr prior
3. Ephedrine/albuterol
4. H2-antagonists
: controversial
*Pre-treatment does not completely prevent RCM reactions

36. Aspirin-Exacerbated Respiratory Disease (AERD)
Associated with asthma, rhinitis, sinusitis, nasal polyposis
Symptoms with NSAIDs
: Rhinorrhea, conjunctivitis, bronchospasm
- Rarely flushing, urticaria, GI symptoms,
laryngospasm, hypotension
Dependent on COX-1 inhibition
COX-2 inhibitors generally safe

37. Angiotensin Converting Enzyme (ACE) Inhibitors
Cough
- Incidence up to 20%
- Mechanism unknown
- Angiotensin II receptor blockers (ARBs) tolerated
Angioedema
%, more common in African-Americans
- Usually delayed in onset: mean 1.8 yrs (Malde 2007)
- Likely des-Arg bradykinin induced
- Usually tolerate ARBs but case reports of AE with
ARBs too

38. Management of the Drug Allergic Patient
For most drugs no validated in vivo or in vitro diagnostic tests are available
If a patient requires a medication they are allergic to options include:
1) finding an alternative medication
2) performing a graded drug challenge
3) performing drug desensitization

39. Journey in the US NU
UCLA UT
USF

40. UCLA School of Medicine

41. University of Tennessee College of Medicine

42. Northwestern University School of Medicine

43. University of South Florida College of Medicine

44. University of South Florida, Tampa, FL

45. USF Health North Campus

46. USF-Affiliated Tampa VA Hospital

47. Tampa Bay Area

48. USF Health South Campus

49. Thank You!!!