皮膚科學(xué)英語課件：Drug eruptions

1、Drug Eruptions Adverse Drug Reaction (ADR) References 1. Dermatology, 2nd some are not (Type B) Some adverse effects occur after a delay or after stopping BAD GOOD The skin is one of the most common targets for adverse drug reactions. Eruptions are observed in 0.1% to 1% of patients enrolled in pre-

2、marketing trials of most systemic drugs. In the case of medications such as antibiotics (e.g. aminopenicillins, sulfonamides) and anticonvulsants, at least 1%, and sometimes more than 5%, of patients receiving these drugs may develop a skin eruption. Approximately 2% of all drug-induced skin reactio

3、ns are considered serious Introduction Key features The skin is one of the most common targets for adverse drug reactions To determine the cause of the eruption, a logical approach based on clinical characteristics, chronologic factors and a literature search is required Exanthematous eruptions and

4、urticaria are the two most common forms of cutaneous drug reactions When an exanthematous eruption is associated with fever, lymphadenopathy and/or edema of the face, the possibility of DRESS must be considered and an evaluation for systemic involvement conducted Less common drug reactions include f

5、ixed, lichenoid, pustular, photo-, bullous and vasculitic reactions, as well as StevensJohnson syndrome and toxic epidermal necrolysis Early withdrawal of all potentially responsible drugs is essential, particularly in the case of severe drug reactions Key features Case secondary to phenobarbital Ex

6、anthematous drug eruptions q Lesions begin as erythematous macules that sometimes become slightly palpable; q The distribution is usually symmetric q The eruption begins on the trunk and upper extremities and progressively becomes confluent q It is typically polymorphous with morbilliform or sometim

7、es urticarial lesions on the limbs, confluent areas on the thorax, and purpuric lesions on the ankles and feet q Mucous membranes are usually spared q Pruritus and low-grade fever are often present q The eruption may be scarlatiniform on the trunk q Annular plaques or atypical target lesions that ar

8、e irregularly shaped are sometimes encountered, q The eruption disappears spontaneously after one to two weeks without complications and/or sequelae. Exanthematous drug eruption: ampicillin Symmetrically arranged, brightly erythematous macules and papules, discrete in some areas and confluent in oth

9、ers, on the trunk and the extremities. Exanthematous drug eruption: ampicillin in a patient with EBV mononucleosis Confluent maculopapular lesions, generalized. Maculopapular erythema caused by ampicillin Viral exanthems (e.g. Epstein-Barr virus, enteroviruses, adenovirus, early HIV, human herpesvir

10、us type 6 HHV-6, parvovirus B19 q The polymorphic nature of the cutaneous eruption as well as the presence of peripheral blood eosinophilia favor a drug reaction q In the absence of definite evidence, a drug etiology is favored in adults, whereas a viral cause is favored in the pediatric population.

11、 q Moreover, viral infections may enhance the risk of a drug eruption. Differential diagnosis Discontinuing the offending agent is the first therapeutic measure Largely supportive Topical corticosteroids Treatment Urticaria, Angioedema and Anaphylaxis Secondary to penicillin Erythematous and edemato

12、us papules and plaques, usually associated with pruritus The lesions vary in size and number and may assume a figurate or polycyclic configuration They can appear anywhere on the body, including the palms, soles or scalp Lesions can last longer than 24 hours Drug-induced urticaria: penicillin Large,

13、 urticarial wheals on the abdomen, thigh, and other areas such as the back and the face. Urticaria induced by acetylsalicylic acid Drug-induced angioedema: penicillin A. Angioedema has led to closure of right eye. B. Sublingual angioedema in another patient interfered with breathing, talking, and ea

14、ting and caused great concern. The most important step in the treatment of drug-induced urticaria is withdrawal of the causative agent. Treatment consists primarily of H1 antihistamines. Treatment Photosensitivity The combination of light plus drug Two major types: phototoxic and photoallergic Photo

15、toxic reaction in a patient receiving methotrexate. The erythema and bullae are obviously limited to sun-exposed sites and resemble an exaggerated sunburn. Clinically, a phototoxic drug reaction usually has the appearance of an exaggerated sunburn, but after a shorter-than-expected exposure time; It

16、 is limited to sun-exposed areas and is followed by hyperpigmentation. Photolichenoid drug eruption due to hydrochlorothiazide. The lesions favored the extensor surfaces of the forearms. Photoallergic eruptions are more chronic in nature than phototoxic reactions. Clinically, the lesions are pruriti

17、c and resemble dermatitis or lichen planus, but are primarily in sun-exposed sites. Over time, lesions may spread to non-sun-exposed areas. Note sparing of skin creases and area shielded by spectacle frames in this patient with photorelated hyperpigmentation from a phenothiazine drug Neutrophilic Dr

18、ug Eruptions Acute generalized exanthematous pustulosis (AGEP) Acute generalized exanthematous pustulosis (AGEP) An acute febrile drug eruption characterized by numerous small, primarily non-follicular, sterile pustules, arising within large areas of edematous erythema. Due to cephalosporinDue to me

19、tronidazole AGEP. Multiple tiny nonfollicular pustules against the background of diffuse erythema that first appeared in the large folds and then covered the entire trunk and the face. AGEP. Multiple sterile pustules surrounded by fiery-red erythema in a 58-year-old female who had fever and leukocyt

20、osis. AGEP. Multiple sterile pustules surrounded by fiery-red erythema in a 58- year-old female who had fever and leukocytosis. Clinically, AGEP is characterized by a high fever, which generally begins on the same day as the pustular rash, or, less often, a few days before or after the onset of the

21、eruption. Frequently, the lesions begin either on the face or in the major intertriginous zones (i.e. axillae and groin) and then disseminate over a few hours. Numerous small (5 mm), primarily non-follicular, sterile pustules arise within large areas of edematous erythema. There may be associated bu

22、rning, pruritus or both. The time between the drug administration and the skin eruption is relatively short, usually less than 2 days. The lesions last 1 to 2 weeks and are followed by a superficial desquamation. Drug Reaction with Eosinophilia and Systemic Symptoms: Hypersensitivity Syndrome (DRESS

23、) Hypersensitivity syndrome refers to a specific severe skin reaction with systemic manifestations. The acronym DRESS, for drug reaction with eosinophilia and systemic symptoms, has been proposed as a more specific term than hypersensitivity which would be appropriate for most types of drug reaction

24、s v DRESS develops 2 to 6 weeks after the responsible drug is begun, later than most other immunologically mediated skin reactions. v Fever and a cutaneous eruption are the most common symptoms of DRESS, seen in 85% and 75% of patients, respectively. v Cutaneous involvement usually begins as a morbi

25、lliform eruption, which later becomes edematous, often with a follicular accentuation. v Additional manifestations include vesicles, tense bullae induced by dermal edema, follicular as well as non-follicular pustules, erythroderma and purpuric lesions. v The face, upper trunk and extremities are usu

26、ally the initial sites of involvement v Edema of the face is a frequent finding and is a hallmark of DRESS. Clinical features DRESS q Lymph nodes are often enlarged q Arthralgias or even arthritis may be seen q The most common (and usually the most severe) site of visceral involvement is the liver.

27、The hepatitis is sometimes fulminant and is responsible for the majority of deaths associated with this syndrome (10% of cases). q Myocarditis, interstitial pneumonitis, interstitial nephritis, thyroiditis and even infiltration of the brain by eosinophils may be observed. q Prominent eosinophilia is

28、 common and is a very characteristic feature of this syndrome. q It is often accompanied by mononucleosis-like atypical lymphocytosis. q Elevation of hepatic enzymes can be a worrisome finding and requires serial evaluation. q Histologic examination of the skin demonstrates a dense lymphocytic infil

29、trate in the superficial dermis associated with eosinophils and dermal edema. DRESS Syndrome Common causes: aromatic anticonvulsants (oxcarbazepine, carbamazepine, phenytoin, phenobarbital, etc.) and sulfonamides. Other drugs implicated: lamotrigine allopurinol NSAIDs captopril CCBs mexiletine fluox

30、etine dapsone metronidazole minocycline antiretrovirals. DRESS Syndrome Overall risk for phenytoin is between 0.1-0.01%. Usually occurs 2-6 weeks after initiation of the medication, which is later than most drug eruptions. May be difficult to distinguish from serum sickness and vasculitis. Median on

31、set of DRESS syndrome after initiation of therapy with Trileptal is 13 days (range 4-60). No definite evidence of cross-reactivity with other agents, but it is a possibility. Treatment is supportive. Medication should be stopped as soon as the diagnosis is suspected. Severity is dependent upon the a

32、mount of time the drug is continued after hypersensitivity occurs. Corticosteroids have been required in some cases, but their use is controversial. Day of Admit Day 2 Day 4 Bullous Eruptions Fixed drug eruption StevensJohnson Syndrome (SJS) Toxic Epidermal Necrolysis (TEN) Bullous Eruptions Fixed d

33、rug eruption Fixed drug eruption unusually severe bullous reaction. Fixed drug eruption Fixed drug eruption A. Tetracycline. Two well-defined periorbital plaques with edema. This was the second such episode following ingestion of a tetracycline. No other lesions were present. B. Tylenol. A large ova

34、l violaceous lesion with blistering in the center. Erosive mouth lesions were also present. Fixed drug eruption A. Phenolphthalein. A large area of dusky, violaceous erythema covering the entire groin and suprapubic region and extending to the upper thighs. It followed the ingestion of a phenolphtha

35、lein-containing laxative. B. Doxycycline. Multiple lesions. Similar violaceous plaques were also on the anterior and posterior trunk. Generalized fixed drug eruption: tetracycline. Prostrated, 59-year-old woman with fever. Multiple confluent violaceous red erythematous areas, some of which later bec

36、ame bullous q Clinically, one or a few, round, sharply demarcated erythematous and edematous plaques are seen, sometimes with a dusky, violaceous hue, central blister or detached epidermis q The lesions can be found anywhere on the body, but favor the lips, face, hands, feet and genitalia q An erosi

37、on may develop centrally and the lesions progressively fade over several days, often leaving a residual postinflammatory brown pigmentation q Upon readministration of the causative drug, the lesions recur at exactly the same sites. q With each recurrence, additional sites of involvement may appear o

38、r the number of lesions may remain constant. q The presence of numerous lesions is referred to as generalized FDE Heparin-induced thrombocytopenia with thrombosis syndrome. A Ischemia and necrosis of the foot. B Petechiae due to thrombocytopenia and an irregular area of cutaneous necrosis due to thr

39、ombosis. Bullous Eruptions StevensJohnson Syndrome and Toxic Epidermal Necrolysis (TEN) Clinical features that can alert the clinician to the possibility of a more severe drug-induced eruption include edema of the face a marked peripheral blood hypereosinophilia (suggestive of a systemic hypersensit

40、ivity syndrome/DRESS) mucous membrane lesions painful or dusky skin which may announce TEN or SJS. StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are considered rare, life-threatening, drug-induced skin reactions within a clinical spectrum and early detection is essential. 57 Ste

41、vens Johnsons syndrome Flaccid bullae leading to epidermal detachment (10% body surface area, the patient was classified as having SJSTEN overlap. B Close-up of epidermal detachment, whose appearance has been likened to wet cigarette paper. Clinical features of toxic epidermal necrolysis (TEN). A. D

42、etachment of large sheets of necrolytic epidermis (30% body surface area), leading to extensive areas of denuded skin. A few intact bullae are still present. B. Hemorrhagic crusts with mucosal involvement. C. Epidermal detachment of palmar skin. Treatment of toxic epidermal necrolysis (TEN). Facial

43、involvement of a patient with TEN (50% body surface area involvement) before (A) and 3 weeks after (B) treatment with IVIg (0.75 g/kg/day for 4 days). TEN, exanthematic presentation There is a widespread confluent macular rash with crinkling of the epidermis in some areas and detachment of the epide

44、rmis in others, leaving oozing red erosions. This eruption was due to allopurinol. TEN, exanthematic presentation A macular rash that is still visible on the lower flank has coalesced, and dislodgment and shedding of the necrotic epidermis has led to large, oozing, extremely painful erosions. This r

45、esembles scalding. The eruption was due to a sulfonamide. TEN, non-exanthematic diffuse presentation. This 60-year-old man developed diffuse erythema over almost the entire body, which then resulted in epidermal crinkling, detachment, and shedding of epidermis leaving large erosions. This is reminis

46、cent of scalding. 70 Toxic epidermal necrosis 71 Toxic epidermal necrosis v Prodrome of upper respiratory tract symptoms, fever and painful skin v StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two rare, potentially fatal, adverse cutaneous drug reactions of differing severit

47、y, characterized by mucocutaneous tenderness and erythema as well as extensive exfoliation v SJS is characterized by 30% v The medications most frequently incriminated are non-steroidal anti-inflammatory drugs, antibiotics and antiepileptics. TEN and SJS usually occur 7-21 days after initiation of t

48、he responsible drug Key features v The average mortality rate is 1-5% for SJS and 25-35% for TEN; it can be even higher in elderly patients and in those TEN patients with a very large surface area of epidermal detachment v Exfoliation is due to extensive death of keratinocytes via apoptosis; the lat

49、ter is mediated by interaction of the death receptorligand pair FasFasL v Optimal medical management of SJS and TEN requires early diagnosis, immediate discontinuation of the causative drug(s), and rapid initiation of supportive care and specific therapy v Specific therapies that have the potential

50、to selectively block keratinocyte apoptosis, such as high-dose IVIg, may provide added benefit over supportive care alone Key features (CONT) Clinical features that distinguish StevensJohnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SjsTen overlap. Rapid diagnosis Rapid identification R

51、apid withdrawal of the causative drug High-quality supportive treatment Ideally in intensive care units with modern equipment and trained nursing staff SCORTEN Prognostic factorsPoints Age 40 years1 Heart rate 120 bpm1 Cancer or hematologic malignancy1 BSA involved on day 1 above 10%1 Serum urea lev

52、el (10 mmol/l)1 Serum bicarbonate level (14 mmol/l)1 SCORTENMortality rate (%) 0-13.2 212.1 335.8 458.3 =590 Scorten Allopurinol Aminopenicillins Amithiozone (thioacetazone)*, Antiretroviral drugs Barbiturates Carbamazepine Chlormezanone*, Phenytoin antiepileptics Lamotrigine Phenylbutazone*, Piroxi

53、cam Sulfadiazine* Sulfadoxine Sulfasalazine Trimethoprimsulfamethoxazole Medications most frequently associated with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). WHAT causes drug eruption? Question Skin reactions to drugs received by at least 1000 patients DrugsReaction rate

54、(per 1000 recipients) Ampicillin52 Penicillin G16 Cephalosporins13 Packed red blood cells8.1 Heparin7.7 Nitrazepam6.3 Barbiturates4.7 Chlordiazepoxide4.2 Diazepam3.8 Propoxyphene3.4 Guaifenesin2.9 Furosemide2.6 Phytonadione0.9 Flurazepam0.5 Chloral hydrate0.2 Mechanisms of cutaneous drug-induced rea

55、ctions Immunologically Mediated Drug Reactions v IgE-dependent drug reactions (formerly type I, GellCoombs classification): urticaria, angioedema and anaphylaxis. v Cytotoxic drug-induced reactions (antibody against a fixed antigen; formerly type II): petechiae secondary to drug-induced thrombocytop

56、enia. v Immune complex-dependent drug reactions (formerly type III): vasculitis, serum sickness and certain types of urticaria. v Possible delayed-type, cell-mediated drug reactions (formerly type IV) versus undefined: exanthematous, fixed and lichenoid drug eruptions, as well as StevensJohnson synd

57、rome (SJS) and TEN Logical approach to determine the cause of a drug eruption Characteristics of major drug-induced eruptions Topical provocation or rechallenge with the suspected drug may be helpful in patients with fixed drug eruptions. However, the risk of inducing a more severe reaction often li

58、mits the use of a rechallenge in the case of other types of reactions (both for ethical as well as medico-legal reasons). Furthermore, the recurrence rate is not 100% with rechallenge (e.g. there are refractory periods) and a negative result may give an erroneous sense of security The suspect drug s

59、hould be withdrawn as soon as possible The usual practice is to discontinue all drugs that are non-essential However, in some cases, it is necessary to weigh the risks versus the benefits for each particular drug and to determine if a similar-acting, but non- cross-reactive, drug is available as a s

60、ubstitute Only a small fraction of drug eruptions are life-threatening or lead to disabling sequelae. Management begins with the withdrawal of the suspect drug as soon as possible. However, in many patients, several drugs may be incriminated. As there is no clinical or laboratory test which permits