Acute generalized exanthematous pustulosis due to clindamycin
- Author(s): Jr, Ronald J Sulewski;
- Blyumin, Marianna;
- Kerdel, Francisco A
- et al.
Published Web Locationhttps://doi.org/10.5070/D39gk9f1sn
Acute generalized exanthematous pustulosis due to clindamycin1. Resurrection Hospital, Chicago, IL
Ronald J Sulewski Jr MD1, Marianna Blyumin MD2, Francisco A Kerdel MBBS2
Dermatology Online Journal 14 (7): 14
2. University of Miami, Miller School of Medicine, Department of Dermatology & Cutaneous Surgery. firstname.lastname@example.org
Acute generalized exanthematous pustulosis (AGEP) is a rare skin eruption most commonly caused by medications. It is characterized by fever and the acute eruption of non-follicular pustules overlying erythrodermic skin. Histopathology shows subcorneal pustules with a background of dermal edema and spongiosis, leukocytoclastic vasculitis, perivascular eosinophils, and focal necrosis of keratinocytes. Three cases of clindamycin induced AGEP have been reported in the literature. A case of AGEP due to clindamycin is reported in a patient with numerous other drug allergies and without history of psoriasis. Presentation and treatment of AGEP are reviewed.
Acute generalized exanthematous pustulosis (AGEP) is most frequently caused by medications, mainly antibiotics. AGEP was first described in 1980 by Beylot et al. and named, in French, pustuloses exanthématique aiguës généralizés (PEAG) . A group of amicrobial pustuloses such as acute generalized pustular bacterid, acute generalized pustulosis manifestation of leukocytoclastic vasculitis, pustular necrotizing angeitis, pustular eruption with eosinophilic abscesses, generalized pustular drug rash, subcorneal pustules in erythema multiforme and in Sweet syndrome, and toxic pustuloderma were grouped together under the heading of AGEP [1, 2]. It is a pruritic eruption characterized by the acute onset of numerous small, non-follicular, sterile, superficial pustules amidst erythematous and edematous skin [3, 4]. The eruption usually begins on the face and intertriginous regions, and the patient commonly manifests associated systemic involvement, with an estimated mucosal involvement in 20 percent of the patients [2, 4, 5]. The incidence is between 1 and 5 per million per year .
Histologically, AGEP may demonstrate subcorneal pustules with a background of dermal edema and spongiosis, leukocytoclastic vasculitis, perivascular eosinophils, and focal necrosis of keratinocytes with negative immunofluorescence . AGEP erupts suddenly within 1 or 2 days of drug exposure and generally resolves in approximately 2 weeks with sequelae of generalized desquamation . The treatment is simply stopping the offending drug, topical steroids, and other symptomatic treatment (antipyretics, antipruritics, and emollients) . However, without the appropriate management the mortality for AGEP can be up to 5 percent .
An 82-year-old Caucasian female presented with a generalized pruritic rash. One week prior to presentation the patient had a dental procedure and was prophylactically treated with 2 doses of clindamycin. Two days after the clindamycin intake she developed a severe generalized pruritus. The next day she noticed erythematous papules and pustules on her right arm which disseminated to her extremities and trunk over two days. Treatment with oral diphenhydramine and triamcinolone 0.1 percent cream did not improve the eruption. On the day of the presentation, the patient began to complain of constitutional symptoms including fevers, chills, malaise, and arthralgias.
The patient's medical history was significant for fibromyalgia, idiopathic peripheral polyneuropathy, osteoarthritis, osteoporosis, obesity, hypertension, peripheral vascular disease, and bilateral lower extremity lymphedema. She denied personal history of psoriasis. Her medications included potassium supplements, losartan, escitalopram, and occasionally ibuprofen or aspirin for pain (last taken 3 weeks prior to presentation). She provided a long list of drug allergies (not documented) due to a variety of hypersensitivity reactions during prior hospitalizations which included penicillin, cephalosporins, sulfa-drugs, quinine, indomethacin, metoclopramide, silvadine, moxifloxacin ophthalmic drops, and topiramate, as well as a history of Steven Johnson Syndrome secondary to levofloxacin. Her sister had psoriasis and there was also a strong family history of cardiovascular disease. She denied the use of tobacco or alcohol.
On physical exam, a diffuse red papular eruption coalesced into plaques on her arms, legs, abdomen, and back studded with numerous, scattered, non-follicular pustules (Fig. 1). She also had a butterfly-shaped erythema of the face and sheets of desquamation on the back (Figs. 2 and 3). There was no involvement of the hair-bearing, nail, and mucosal regions. Her vital signs were within normal limits.
|Figure 1||Figure 2|
|Figure 1. Erythematous plaques studded with pustules on the left arm|
Figure 2. Erythematous, edematous, butterfly-shaped plaques on the face
|Figure 3. Erythema with pustules and superficial exfoliation on the upper back|
The patient was admitted to the inpatient dermatology unit for the management of this acute and severe skin eruption. Her diagnostic studies included a complete blood count with a differential, complete metabolic panel, anti-nuclear antibodies, erythrocyte sedimentation rate, C-reactive protein, and rapid plasma reagin test which were significant for a white blood cell count of 15,900 per microliter with 83.4 percent neutrophils and 3.2 percent eosinophils, sodium of 130 mEq/L, blood urea nitrogen of 32 mg/dL, creatinine of 1.4 mg/dL, and plasma glucose of 226 mg/dL. Skin biopsy from the left abdomen demonstrated spongiform pustulations, subcorneal pustules, and perivascular and diffuse dermal infiltrate of lymphocytes and eosinophils (Figs. 4 and 5). The direct immunofluorescent pattern was not specific indicating the non-immunologic process of the eruption.
|Figure 4||Figure 5|
|Figure 4. Spongiform pustulations with subcorneal pustule|
Figure 5. Diffuse dermal infiltrate of lymphocytes and eosinophils
Clindamycin was identified as the most likely culprit for the patient's rash and added to her list of drug allergies; she was also educated to avoid this medication in the future. The patient was treated with intravenous methylprednisolone, hydrocortisone cream 1 percent, hydroxyzine, doxepin, acetaminophen, air mattress for comfort, and whirlpool baths twice daily. The patient's redness and pustulosis stopped spreading in 1 day and resolved in 5 days status post commencement of therapy. Her laboratory analyses normalized and symptoms of malaise and pruritus also resolved in 5 days. She was discharged in stable condition with minimal residual skin exfoliation on the extremities. The patient was free of skin eruptions at her 2-week follow-up visit. However, she was lost to long-term follow-up.
To our knowledge there are only 3 prior reports of AGEP caused by clindamycin ingestion in the currently published literature [8, 9, 10]. Although many medications can cause AGEP, the most common group is antibiotics, especially beta-lactams and macrolides. In a review of 63 cases, Roujeau et al. noted only 18 percent of culprit medications to be non-antibiotics . Other etiologies were viruses (B19 and enterovirus), mercury, spider bites, and other medications [5, 11, 12]. Sulfonamides are notably not a frequent cause of AGEP although they often cause other severe skin eruptions . There have been cases of AGEP in all age ranges and in pregnant women [5, 13, 14]. Our patient had no other exposures and her medical history, clinical and pathological examinations, and laboratory analyses were consistent with AGEP caused by exposure to clindamycin.
The differential diagnosis of AGEP includes various other pustular eruptions. There are many follicular or localized pustular outbreaks such as acne and bacterial folliculitis, which can easily be discerned from AGEP. More disseminated eruptions that require differentiation from AGEP are pustular psoriasis (von Zumbusch type), subcorneal pustular dermatosis (Sneddon-Wilkinson disease), IgA pemphigus, drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN).
The major way to separate AGEP and pustular psoriasis is via history, acute nature of the presentation as well as the exposure to drugs commonly associated with AGEP. The median time frame from ingestion of drug and beginning of AGEP was 1 day out of 55 cases in one review . AGEP also has shorter duration of pustules, fever, and less severe short-lived systemic involvement versus pustular psoriasis. Although drugs such as lithium and beta-blockers can induce pustular psoriasis flares, there are no reports of lithium causing AGEP, and one report of nadoxolol causing a pustular dermatosis, with no reports of beta-blocker-induced AGEP [5, 15].
Our patient's medical history indicated an exposure to clindamycin within 1 week prior to her skin eruption. This time frame was parallel to the reports of average period for AGEP to occur. Although the patient had a family history of psoriasis, she lacked other notable psoriatic features such as nail changes, geographic tongue, characteristic arthritis, involvement of palms and soles, and sparing of the face . Also, her skin histopathology was not consistent with pustular psoriasis, as there was no papillo-acanthosis .
Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) can also present with a disseminated pustular rash. However, it is a cyclic disease which usually occurs in an afebrile patient with recurrent, large, localized, flaccid pustules which usually start in the flexures . The pathology is also distinct from AGEP. It shows a sterile subcorneal pustule with acantholysis only in older lesions and no background of spongiosis or change beneath the epidermis .
IgA pemphigus is another vesiculopustular, intraepidermal blistering disease that may clinically and histologically mimic AGEP and Sneddon-Wilkinson disease. It has a positive direct immunofluorescence with IgA binding to keratinocytes and generating a chicken-wire pattern . The lack of systemic symptoms, flaccid vesicles, annular pattern, and positive immunofluorescence distinguishes between IgA pemphigus and AGEP.
Drug rash with eosinophilia and systemic symptoms (DRESS) is another systemic drug eruption, which typically has a less pronounced pustular component than AGEP. DRESS also has accompanying lymphadenopathy, eosinophilia, mononucleosis, and often has severe visceral involvement (hepatitis, nephritis, pneumonitis, with or without myocarditis) . While AGEP can present with some systemic involvement, it usually is limited to a slight decrease in creatinine clearance or elevation of aminotransferases .
Toxic epidermal necrolysis (TEN) is an important disease to rule out when confronted with a generalized eruption. Significant mucosal involvement, full thickness epidermal necrosis, and a sparse inflammatory infiltrate distinguish it from AGEP . AGEP also lacks Nikolsky's sign, although traction pressure on a confluent area of pustules can lead to a superficial epidermal detachment in AGEP, possibly mistaken for epidermal sloughing.
A variety of tests have been used to confirm the etiology of AGEP. The sensitivity of patch testing to drugs in AGEP is approximately 50 percent . Systemic reactions have been reported with patch testing with acetaminophen and diltiazem . Different tests that have been used to elucidate the cause of AGEP are in vitro tests such as macrophage migration inhibition factor (MIF) test, the mast cell degranulation (MCD) test , and the lymphocyte transformation test (LTT) . Because of the patient's classic presentation and confirmatory histopathology no patch testing was performed to confirm the patient's reaction to clindamycin, and the patient was warned to avoid contact with clindamycin.
Although no systemic treatment is required besides stopping the offending drug [2, 19], because of the patient's age and co-morbidities she was admitted to the inpatient dermatology service and treated with intravenous and topical steroids, antipyretics, and antipruritics. She had a rapid response with no further complications.
References1. Beylot C, Bioulac P, Doutre MS. Acute generalized exanthematic pustuloses (four cases). Ann Dermatol Venereol. 1980;107(1-2):37-48. PubMed
2. Sidoroff A, Halevy S, Bavinck JN, Vaillant L, Roujeau JC. Acute generalized exanthematous pustulosis (AGEP)--a clinical reaction pattern. J Cutan Pathol. 2001;28(3):113-9. PubMed
3. Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI (eds.) Fitzpatrick's Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003, pp. 625-627, 1332.
4. Bolognia JL, Jorizzo JL, Rapini RP, et al (eds.) Dermatology. Philadelphia: Mosby, 2003, pp. 131, 134, 136, 341, 457.
5. Roujeau JC, Bioulac-Sage P, Bourseau C, Guillaume JC, Bernard P, Lok C, Plantin P, Claudy A, Delavierre C, Vaillant L, et al. Acute generalized exanthematous pustulosis. Analysis of 63 cases. Arch Dermatol. 1991;127(9):1333-8. PubMed
6. McKee PH, Calonje JE, Granter SR (eds.) Pathology of the Skin, 3rd ed. Philadelphia: Mosby, 2005, pp. 154-155, 205, 212-213, 651-652.
7. Roujeau JC. Clinical heterogeneity of drug hypersensitivity. Toxicology. 2005:15;209(2):123-9. PubMed
8. Kapoor R, Flynn C, Heald PW, Kapoor JR. Acute generalized exanthematous pustulosis induced by clindamycin. Arch Dermatol. 2006;142(8):1080-1. PubMed
9. Schwab RA, Vogel PS, Warschaw KE. Clindamycin-induced acute generalized exanthematous pustulosis. Cutis. 2000;65(6):391-3. PubMed
10. Valois M, Phillips EJ, Shear NH, Knowles SR. Clindamycin-associated acute generalized exanthematous pustulosis. Contact Dermatitis. 2003;48(3):169. PubMed
11. Ofuji S, Yamamoto O. Acute generalized exanthematous pustulosis associated with a human parvovirus B19 infection. J Dermatol. 2007;34(2):121-3. PubMed
12. Davidovici BB, Pavel D, Cagnano E, Rozenman D, Halevy S; EuroSCAR; RegiSCAR study group. Acute generalized exanthematous pustulosis following a spider bite: report of 3 cases. J Am Acad Dermatol. 2006;55(3):525-9. PubMed
13. Valkova S. Food-induced acute generalized exanthematous pustulosis in a pregnant woman. Skinmed. 2006;5(4):199-201. PubMed
14. Reich A, Szepietowski JC, Baran E. Severe acute generalized exanthematous pustulosis in a pregnant woman. Skinmed. 2006;5(4):197-9. PubMed
15. Bernard P, Bedane C, Catanzano G, Robbe J, Bonnetblanc JM. Acute generalized exanthematic pustulosis. An atypical case due to nadoxolol? Dermatologica. 1991;182(2):115-8. PubMed
16. Wolkenstein P, Chosidow O, Flechet ML, Robbiola O, Paul M, Dume L, Revuz J, Roujeau JC. Patch testing in severe cutaneous adverse drug reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Contact Dermatitis. 1996;35(4):234-6. PubMed
17. Mashiah J, Brenner S. A systemic reaction to patch testing for the evaluation of acute generalized exanthematous pustulosis. Arch Dermatol. 2003;139(9):1181-3. PubMed
18. Buettiker U, Keller M, Pichler WJ, Braathen LR, Yawalkar N. Oral prednisolone induced acute generalized exanthematous pustulosis due to corticosteroids of group A confirmed by epicutaneous testing and lymphocyte transformation tests. Dermatology. 2006;213(1):40-3. PubMed
19. Mengesha YM, Bennett ML. Pustular skin disorders: diagnosis and treatment. Am J Clin Dermatol. 2002;3(6):389-400. PubMed
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