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Dr. Roberts is a PGY-1 and Dr. Rhiannon is assistant professor in the Department of Medicine at the. University of Color
SGIM FORUM 2013; 36(9) SHARE

MORNING REPORT

Amoxicillin-induced DRESS Syndrome Joseph R. Roberts, MD (presenter), and Julia J. Rhiannon, MD, MSW (discussant, in italic) Dr. Roberts is a PGY-1 and Dr. Rhiannon is assistant professor in the Department of Medicine at the University of Colorado.

38-year-old Caucasian woman with no prior medical history presents to the emergency department with a rash on her lower back that has spread over the course of three days to cover her anterior trunk, face, upper back, and extremities. The spreading rash is associated with fevers of 103° F with rigors, nausea, vomiting, and progressive epigastric pain. Given the acuity of the rash, the initial differential in this case includes infection, autoimmunity, and a hypersensitivity reaction. In a febrile patient, it is important to rule out sources of infection that could generate a fever, such as pneumonia, urinary tract infection, skin infection, or acute abdomen. An acute rash can provide clues as to possible autoimmunity or drug reaction, and the history of any antecedent events or new medications can suggest causality. A thorough history and physical exam can help to narrow the differential diagnosis. Judicious use of labs guided by clinical suspicion will help us to rule in or out various pathophysiologic entities. On further history, it is discovered that the patient had taken a twoweek course of amoxicillin for a dental extraction that was completed six weeks prior to presentation. The rash is initially maculopapular but progressively coalesces and becomes confluent, particularly on the back, chest, and face. The facial rash is associated with edema (sparing the eyes) and erythroderma. Concern for progressive desquamation is noted. Cervical lymphadenopathy and hepatomegaly are also noted. Initial laboratory testing reveals an aspartate aminotransferase of 1,074 U/L; an alanine aminotransferase of 1,493 U/L, concerning for acute he-

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patitis; and a total bilirubin of 1.4 mg/dL, alkaline phosphatase of 235 U/L, WBC of 6.67 x 1,000/mcL, hemoglobin of 13.3 g/dL, hematocrit of 39.3%, and platelets of 164 x1,000/mcL. Hepatitis serologies are all negative, and EBV serologies are consistent with past infection. CMV IgM is negative, with IgG positive. HSV 1/2 is negative, as is antismooth muscle antibody, anti-mitochondrial antibody, and the antinuclear antibody. Blood cultures and urinalysis are also negative. Given the findings on history and physical exam, the diagnosis of DRESS syndrome is considered. DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), also known as drug-induced hypersensitivity syndrome (DIHS), is a relatively common disorder occurring in one out of every 1,000 to 10,000 new drug exposures.1 Its clinical presentation consists of fever, mucocutaneous rash, lymphadenopathy, hematologic abnormalities and atypical lymphocytes (most often eosinophilia), and hepatitis. It occasionally involves other organs presumably due to eosinophilic infiltration.2 It commonly has onset of three weeks to three months after exposure to drug therapy.2 DRESS is associated with a 10% mortality rate, usually due to organ failure thought to be from eosinophil infiltration, making early recognition and treatment especially important. The diagnosis of DRESS is made based on the characteristic presentation (e.g. rash, fever, adenopathy, and hepatitis) with a known drug exposure and a negative infectious workup. The patient had already completed the prescribed amoxicillin course six weeks prior and was started on systemic steroid therapy

with a planned prolonged taper. Transaminases continued a downward trend in the hospital, and the rash began to resolve at time of discharge. Application of the RegiSCAR scoring criteria described by Karduan et al. yielded a point total of 5, designating this as a probable case of DRESS.3 Despite the fact that this patient did not have eosinophilia, the literature shows variable occurrence of eosinophilia in confirmed cases; it is not required to make the diagnosis.4 Amoxicillin is a widely used antibiotic and is often a first-line agent, largely due to its safe administration. Due to its heavy use in outpatient settings, an accurate gauge on prescription rates is challenging. Studies have shown that 52% of dentists use it as first-line therapy for infection5 and that it is the most frequently dispensed prescription among infants and children.6 Another study suggests a high rate of amoxicillin prescribing due to its placebo effect.7 Despite its common uses, amoxicillin has only been implicated as a cause of relapse of DRESS syndrome. While there are many documented cases of amoxicillin provoking a penicillin-like hypersensitivity allergy, this is a distinct and separate clinical entity from DRESS. DRESS syndrome has been reported with other antibiotics (e.g. minocycline, streptomycin, sulfamethoxazole, vancomycin)—and notably amoxicillin plus clavulanic acid—but amoxicillin as the primary instigator has not been demonstrated. DRESS syndrome often presents very similarly to an acute viral hepatitis, and should be worked up as such. But given the 10% mortality rate and the length of time it takes for autoimmune serologies to be recontinued on page 2

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MORNING REPORT continued from page 1

sulted, it is crucial to consider DRESS when presented with this constellation of symptoms. Once recognized, the primary treatment for DRESS syndrome involves stopping the offending agent. Case series have shown DRESS syndrome as usually beginning with fever accompanied almost uniformly with a rash. In one recent series of 29 cases, a fever of more than 38° C was present in 89% of patients, with lymphadenopathy present in 55%. The most common organs affected in DRESS include the liver, kidney, and lung; 69% of patients had a single organ involved, while17% had two organs involved. More recent studies suggest 89% of patients had eosinophilia, contrasting with earlier reports estimating eosinophilia at 30%.4,8 The need for systemic corticosteroid therapy is not well established in the literature. The proposed mechanism of action is the inhibition of eosinophil accumulation, which is thought to be the main cause of organ dysfunction. Such attenuation is likely supported by the general antiinflammatory effect of corticosteroidmediated inhibition of the NF-kB pathway, thus potentiating clinical improvement as well. Moreover, many documented cases show a dramatic improvement with corticosteroids, as well as relapse after tapering or withdrawing steroid therapy.9-11 Further research is needed to determine exactly what the risk of recurrence of DRESS syndrome is when exposed to novel drugs of either the same or different class. Additionally, no clear predisposing factors, aside from a prior episode of DRESS,

and literature review. BMC Infectious Dis 2010; 10:49. 5. Kudiyirickal MG, Hollinshead F. Antimicrobial prescribing practice “Take-home” Points for Learning by dentists: a study from two 1. DRESS often includes an acute primary care centres in UK. hepatitis and should be in the Minerva Stomatol 2011; differential of an acute febrile rash. 60(10):495-500. 2. The patient should be queried 6. Chai G, Governale L, McMahon regarding any new recent AW, Trinidad JP, Staffa J, Murphy medications. D. Trends of outpatient 3. Diagnosis is made by noting a prescription drug utilization in US characteristic presentation (e.g. children, 2002-2010. Pediatrics rash, fever, adenopathy, and 2012; 130(1):23-31. hepatitis) in the setting of known 7. Murphy M, Bradley CP, Byrne S. drug exposure, while ruling out Antibiotic prescribing in primary infection. care, adherence to guidelines 4. Therapy includes removal of the and unnecessary prescribing—an offending agent, with provision Irish perspective. BMC Fam of corticosteroids and supportive Pract 2012; 13(1):43. care. 8. Tanno LK, et al. Drug reaction with eosinophilia and systemic References symptoms (Dress): What we still 1. Fiszenson-Albala F, Auzerie V, have to learn? World Allergy Mahe E, Farinotti R, Durand-Stocco Organization Journal 2012; C, Crickx B, et al. A 6-month 5(Suppl 2):S39. prospective survey of cutaneous 9. Hellman C, Lonnkvist K, Hedlin drug reactions in a hospital setting. G, Hallden G, Lundahl J. DownBr J Dermatol 2003; 149:1018-22. regulated IL-5 recepatientor 2. Roujeau JC, Stern RS. Severe expression on peripheral blood adverse cutaneous reactions to eosinophils from butesonidedrugs. N Engl J Med 1994; treated children with asthma. 331:1272-85. Allergy 2002; 54:323-8. 3. Kardaun SH, Sidoroff A, ValeyrieAllanore L, et al. Variability in the 10. Chopra S, Levell NJ, Cowley G, Gilkes JJH. Systemic clinical pattern of cutaneous corticosteroids in the phenytoin side-effects of drugs with hypersensitivity syndrome. Br J systemic symptoms: does a Dermatol 1996; 134:1109-12. DRESS syndrome really exist? Br 11. Yamamoto Y, et al. Therapeutic J Dermatol 2007; 156:609-11. potential of inhibition of the NF4. Gentile I, Talamo M, Borgia G. Is kappaB pathway in the the drug-induced hypersensitivity treatment of inflammation and syndrome (DIHS) due to cancer. J Clin Invest 2001; herpesvirus 6 infection or to 107(2):135-42. allergy-mediated viral reactivation? Report of a case SGIM have been implicated in the disease, and this also warrants investigation.

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