Drug Eruption: Li Xiao-hong

Drug Eruption

Li Xiao-hong Dept. of Dermatology The first affiliated hospital of zhengzhou university

Drug Eruption  An inflammatory process that results from the effects of a

drug administered systemically, e.g. by ingestion, inhalation, injection, or application rectally, and manifested usually by lesions distributed widely and symmetrically.  Internal organs could be involved in severe cases  The commonest adverse reaction caused by medications

Epidemiology Most medications: 0.1% Certain commonly used medications

(semisynthetic penicillins and sulfamethoxazole/trimethoprim): 3-5% The presence of HIV disease or EBV infection may increase the rate of drug Eruptions

Epidemiology Frequency •In the US: Incidence of cutaneous drug reactions is approximately 2-5% in hospitalized patients and more than 1% in the outpatient setting. •Internationally: Inpatient incidence of cutaneous drug reactions in Europe is approximately 2-3%.

Etiology Antibiotics Sulphanilamides NSAIDs Tranquilizers and hypnagogues Heterologous serum/vaccine Traditional Chinese medicine

Pathogenesis Nonimmunologic: are more common than immunologic eruptions  Adverse effects are normal and expected but unwanted effects of the drug. For

example, antimetabolite chemotherapeutic agents, such as cyclophosphamide, are associated with hair loss  Overdosage is the development of an exaggerated response from taking an increased amount of medication. For example, increased dosages of anticoagulants may result in purpura.  Intolerance to a medication may occur in persons with altered metabolism. For example, individuals who are slow acetylators of the enzyme Nacetyltransferase(NAT) are more likely to develop drug-induced lupus in response to procainamide

Pathogenesis  Accumulation of a drug: An example is the argyria (blue-gray

discoloration of skin and nails) observed with use of silver nitrate nasal sprays.  Phototoxic dermatitis is an exaggerated sunburn response caused by the formation of toxic photoproducts of systemic medications such as free radicals or reactive oxygen species.  Imbalance of endogenous flora may occur when antimicrobial agents preferentially suppress the growth of one species of microbe, allowing other species to grow more vigorously. For example, candidiasis frequently occurs with antibiotic therapy.  Direct release of mast cell mediators is a dose-dependent phenomenon especially problematic in individuals with mastocytosis. For example, aspirin and other NSAIDs cause a shift in leukotriene production that triggers the release of histamine and other mast cell mediators without involvement of antibodies to the drug.

Pathogenesis  Jarisch-Herxheimer phenomenon is an indirect drug-

induced effect caused by a reaction to bacterial endotoxins or microbial antigens liberated by the destruction of microorganisms. The reaction is characterized by fever, tender lymphadenopathy, arthralgias, transient macular or urticarial eruptions, and exacerbation of preexisting cutaneous lesions. The symptoms disappear with continued therapy, and medications should not be discontinued. The JarischHerxheimer reaction often is seen with penicillin therapy for syphilis.

Pathogenesis  Idiosyncratic causes include the following: • • •

•

• •

Individuals with infectious mononucleosis are likely to develop rash when given ampicillin. Persons who are immunocompromised have a 10-fold higher risk of developing a drug eruption than the general population. Sulfonamides are more likely to cause a reaction in patients with HIV infection, and a greater incidence of toxic epidermal necrolysis (TEN) from sulfonamides is seen in these in individuals This may reflect disordered cytokine release and immune dysregulation. Antigens on keratinocyte membranes may be altered and result in abnormal immunologic responses. A defect of TH1 helper cells may develop, resulting in a switch from TH1 to TH2 cell-type predominance, which is involved in allergic response. Subclinical infection with Epstein-Barr virus or cytomegalovirus can play a causative role in the immune dysregulation as well.

Pathogenesis Immunologic:  Type I (IgE-dependent): urticaria, angioedema, anaphylaxis;  Type II (cytotoxic): hemolysis, purpura;  Type III (immune complex): vasculitis, serum sickness,

urticaria, angioedema  Type IV (cell mediated): contact dermatitis, exanthematous reactions, photoallergic reactions

Classification of Drug Eruptions

Simple drug Eruptions: without systemic

symptoms or internal organ involvement. Complex drug Eruptions: with systemic symptoms or internal organ involvement.

Category of Drug Eruptions    

Simple drug Eruptions Exanthems (morbilliform/scarlatiniform) Urticaria/angioedema Fixed drug Eruption Erythema multiforme minor

Complex drug Eruptions Erythema multiforme major Exfoliate dermatitis Toxic epidermal necrolysis

46% 26% 10% 5%

4% 4% 1.3%

Other uncommon forms of drug Eruption 3.7%

Scarlatinform or Morbilliform Exanthems

Common causative drugs Semisynthetic penicillins Sulfamethoxazole Trimetheprim

Scarlatinform or Morbilliform Exanthems

Clinical features Occurs usually within the firth 2 weeks of treatment Appears first proximally characterized by erythema, often with small papules throughout Prominent pruritus Complex exanthems may present with systemic symptoms and internal organ involvement

Scarlatinform or Morbilliform Exanthems Differential diagnosis Morbilli High fever Koplik’s spot Upper respiratory symptoms Typical exanthem Lymphopenia with a decreased WBC count Skin biopsy: syncytial keratinocytic giant cell Serologic test:

Scarlatinform or Morbilliform Exanthems Differential diagnosis Scarlatina Occurs during the course of streptococcal pharyngitis Red, edematous tonsils covered with exudate Strawberry tougue Typical exanthem: Rough sand-paper appearance Pastia’s line: A linear petechial eruption over the skin folds

Urticaria/Angioedema

Common causative drugs NSAIDs, by nonimmunologic mechanism Penicillin and related beta-lactam antibiotics, by immnologic mechanism

Lesions Pruritic wheals and angioedema

Fixed Drug Eruption

Common causative drugs NSAIDs Sulfonamides Trimethoprim Barbiturates Tetracycline Phenolphthalein Erythromycin

The Evolution of the Lesions in Fixed Drug Eruption Target lesion Clearing within a week

Postinflammatory hyperpigmentation Repeating ingestion of the offending drugs

Recurrence at the same site

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Erythema Multiforme(EM)

Common causative drugs Trimethoprim Sulfamethoxazole Fansidar-R Sulfadexine Antibiotics NSAIDs

Erythema Multiforme(EM)

Types of EM EM minor EM Major (Stevens-Johnson Syndrome)

EM Minor Clinical Manifestations

No or only a mild prodrome Classical “target”or “iris” lesions with three zones: Central dusky purpura An elevated, pale ring Surrounding macular erythema

Symmetrical and acral distribution Mucosal involvement: 25%, limited to oral mucosa Lasting for 1 to 4 weeks

EM Major (Stevens-Johnson Syndrome) Clinical Manifestations

Usually having a febrile prodrome Incomplete “atypical targets” Distributed diffusely or on the trunk Prominent mucosal involvement: involving More than 2 mucosae in 70%. Lasting for more than 3 weeks

Toxic Epidermal Necrolysis(TEN) Common causative drugs: the same as those in EM. Proceeded by fever or influenza-like syndrome. Appearing on the face and trunk and spread rapidly. Beginning with skin pain and simple erythema, rapidly followed by skin loss, Nikolsky’s sign is positive. More than two mucosal surfaces are involved.

Exfoliate Dermatitis

Common causative drugs Sulfa drugs Allopurinol Gold Phonyoin Phenobarbital

Exfoliate Dermatitis Clinical features Obstinate scaling Itching erythroderma Prutitus Chilliness Involvement of mucous membrane and internal organs

Some Types of Uncommon Drug Eruption

Photosensitive drug Eruption Lichenoid drug Eruption Red man syndrome Drug-induced pseudolymphoma

Photosensative Drug Eruption Common causative drugs NSAIDs Sulfmethexazole/trimethoprim Thiazide diuretics and related sulfonylureas Quinine and quinidine Certain tetracycline

Photosensitive Drug Eruption

Types of photosensitive drug Eruption Phototoxic drug Eruption Photoallergic drug Eruption Lichenoid drug Eruption Pseudoporphyria

Phototoxic Drug Eruption

Could occur in anyone Related to the dose of both the medication and the ultraviolet Require no prior exposure and participation

Photoallergic Drug Eruption

Occur after some period of drug

exposure Not drug dose dependent The immune system is involved— positive photopatch testing

Lichenoid Drug Eruption Common causative drugs Gold Hydrochlorothlazide NSAIDs D-penicillamine Captopril Quinidine Antimalarials

Lichenoid Drug Eruption Clinical features Distribution Photodistribution or generalized

Lesions Plaques, small papules, or exfoliate erythema

Mucous membrane involvement Plaques or erosions

Red Man Syndrome Causative factor Infusion of vancomycin—elevated blood histamine

Clinical features Macular eruption Pruriatus Heat Pypotension

Red Man Syndrome

Prevention Reducing the rate of infusion of the antibiotics Pretreatment with H1antihistamines

Drug-induced Pseudolymphoma Common causative drugs Anticonvulsant Sulfa drugs Dapsone Antidepressants

Drug-induced Pseudolymphoma Clinical features Resembling lymphoma

Histopathologic features The overall histology must be consistent with the diagnosis of lymphoma Other features such as keratinocyte necrosis and dermal edema help to distinguish these Eruptions from true lymphoma

Lab Studies:  CBC with differential: Leukopenia, thrombocytopenia, and    

eosinophilia may be detected with serious drug eruptions. Serum chemistry: Amylase and lipase can be elevated in drug hypersensitivity syndromes. Special attention to electrolyte balance and renal/hepatic function indices is required in severe reactions such as SJS, TEN, and vasculitis. Cultures: Direct cultures according to clinical suggestion of primary infectious etiology or secondary infection. Rechallenge through skin prick or patch testing to confirm the causative agent is of limited value. Skin tests may not provide immediate answers and potentially are hazardous to patients who experience severe reactions.

Treatment of Drug Eruption

Cessation of the offending drug Antihistamines In severe examples, systemic

administration corticosteroid and IVIG