DRESS Syndrome: Improvement of Acute Kidney Injury and Rash with Corticosteroids Dawnielle Endly, DO,* Jonathan Alterie, BS,** David Esguerra, DO,*** Richard A. Miller, DO****

*Co-lead Author, Dermatology Resident, Nova Southeastern University College of Osteopathic Medicine/Largo Medical Center, Largo, FL **Co-lead Author, 4th-year Medical Student, Chicago College of Osteopathic Medicine, Chicago, IL ***Clinical Professor, Nova Southeastern University College of Osteopathic Medicine, Largo, FL ****Program Director, Dermatology Residency Program, Nova Southeastern University College of Osteopathic Medicine/Largo Medical Center, Largo, FL

Abstract DRESS syndrome (drug rash with eosinophilia and systemic symptoms) is a rare and potentially life-threatening idiosyncratic drug reaction that may involve a number of visceral organs. This syndrome often mimics other serious systemic disease processes, making the diagnosis complicated and often delayed. Herein, we present a unique case of DRESS syndrome accompanied by acute interstitial nephritis that responded to oral prednisone during a hospital stay.

Introduction superficial dermis. The patient reported minimal negative. An echocardiogram revealed a decrease DRESS syndrome is a drug reaction that symptomatic relief, but the rash progressed and in EF from 25% at baseline to 10% to 20% with usually manifests with fever, a pruritic macular became generalized with total body involvement. severe diffuse hypokinesis and severe biatrial and papular rash, hematologic abnormalities Due to clinical suspicion for a cutaneous drug enlargement. All clinical data was entered into (leukocytosis, eosinophilia, and/or atypical reaction, her primary care provider stopped the the RegiSCAR group diagnosis chart for DRESS lymphocytes), and internal organ involvement. furosemide and prescribed spironolactone a few syndrome and revealed a total of 7 (see Table 1), This drug reaction is characterized by a delayed days prior to her hospitalization. confirming a diagnosis of DRESS syndrome. onset, typically occurring two to eight weeks Upon admission, vital signs were all normal. Given multiple co-morbidities including 1 after exposure to the inciting medication. Cutaneous examination revealed diffuse uncontrolled diabetes, topical treatment with Despite the existence of a scoring system known erythematous and violaceous macules and papules a high-potency topical steroid was initially as RegiSCAR to aid in accurate and prompt with fine white scale and several linear erosions favored. The possible causative medication, diagnosis, the variability in the clinical course with serosanguinous crusts (Figures 1-3). Both furosemide, had already been stopped prior to and dermatologic manifestations often results in lower extremities had 2+ pitting edema up to the hospital admission. An echocardiogram revealed delays.2 hips. No obvious facial edema, vesicles or bullae, a decrease in ejection fraction to 15% to 20% or oral mucosal lesions were identified during with severe diffuse hypokinesis and severe biatrial hospitalization. enlargement. Her renal function continued to Case Report Initial laboratory results revealed various decline throughout her hospitalization, and A 68-year-old female with history of type 2 given the multitude of possible etiologies (pre- diabetes mellitus, systolic heart failure with an abnormalities. A complete blood count demonstrated an eosinophilia of 23% (normal renal from diuretics or heart failure exacerbation, ejection fraction (EF) of 25%, and Charcot- possible interstitial nephritis secondary to Marie-Tooth disease presented to the emergency 0-5%) and presence of atypical lymphocytes. A complete metabolic panel revealed many elevated DRESS syndrome), nephrology recommended department with progressive leg swelling and a renal biopsy to aid in definitive diagnosis. On a diffuse, itchy rash of about two months’ components including: aspartate transaminase (AST) of 102 U/L (15-37 U/L), alanine day four of her hospitalization, a renal biopsy duration. The rash began on the left flank and was planned, but the patient became anxious face approximately four weeks after starting transaminase (ALT) of 125 U/L (13-61 U/L), alkaline phosphatase of 263 U/L (45-117 U/L), and severely hypotensive while on the operating furosemide for fluid overload. No other new table. Unfortunately, the renal biopsy was not medications were initiated or modified in the blood urea nitrogen (BUN) of 65 mg/dL (7-18 mg/dL), and creatinine of 1.9 mg/dL (0.6-1.3 completed, and she required admission to the prior six months. She denied fevers, joint pain, or intensive care unit and vasopressors for several facial swelling associated with the rash. mg/dL) compared to her baseline creatinine of 1.0 mg/dL. Urinalysis was positive for leukocyte days while her renal function continued to She was evaluated by an outside provider one esterase, red blood cells 2-5/hpf (0-1/hpf ), and decline. week prior to hospitalization and was prescribed white blood cells of 10-15/hpf (0-1/hpf ). Urine The patient refused hemodialysis, but agreed a mid-potency topical steroid cream to be eosinophils were also found to be positive. A to systemic steroids as treatment for possible applied twice a day to the most pruritic areas. urine culture eventually grew Escherichia coli, interstitial nephritis secondary to DRESS A biopsy was obtained at that time, revealing and she was treated for a urinary tract infection. syndrome. The patient initially received two sparse perivascular lymphohistiocytic infiltrate Anti-nuclear antibody, blood cultures, a hepatitis intravenous doses of methylprednisolone 125 with frequent neutrophils and eosinophils in the panel, and rapid plasma regain (RPR) were all mg. She was then placed on an oral prednisone

Figure 1 Figure 2 Figure 3

Endly, Alterie, Esguerra, Miller Page 27 Table 1. RegiSCAR score for DRESS syndrome11 < 2 = no case, 2-3 = possible case, 4-5 = probable case, > 5 = definite case Current Case Features No Yes Unknown

o Fever (≥ 38.5 C) -1 0 -1 -1

Enlarged lymph nodes (≥ 2 sites, ≥ 1 cm) 0 1 0 0

Atypical lymphocytes 0 1 0 1

Eosinophilia 0 0

700-1,499 or 10%-19.9% 1

1,500 or ≥ 20% 2 2

Skin rash 0 0

Extent > 50% 0 1 0 1

At least 2 of: edema, infiltration, purpura, scaling -1 1 0 1

Biopsy suggesting DRESS -1 0 0 0

Internal organ involvement 0 0

1 1

2 or more 2 2

Resolution in more than 15 days -1 0 -1 0

Rule out ≥ 3 other potential causes (ANA, blood cultures, hepatitis panel, RPR, 0 1 0 1 chlamydia, etc.) Final Score 7 taper, and within a couple of days her BUN and arthralgias, fever, and a pruritic rash mimicking the higher melanin content in darker pigmented creatinine began to decline and urine output began malignant lymphoma while on carbamazepine.7 skin may form a melanin-minocycline complex 10 to increase. Additionally, there was substantial While anticonvulsants remain the most resulting in accumulation of the causative drug. It would be prudent for dermatologists to consider improvement in the patient’s rash and pruritus. frequently associated drug class, more and more alternative therapies, perhaps doxycycline, in this After a couple of days, the patient was taken off different medications, such as sulfonamides, specific patient population to help avoid DRESS of vasopressors and determined to be stable for minocycline, allopurinol, ampicillin, and syndrome and the potentially life-threatening transfer back to the general medicine floor. She dapsone, are being deemed likely culprits. sequelae that may result. was ultimately discharged to a rehabilitation For this reason, the former nomenclature, facility on a four-week prednisone taper. anticonvulsant hypersensitivity syndrome, has The most common skin finding reported in fallen out of favor. In one study reviewing 201 DRESS syndrome is a morbilliform or mixed Discussion potential cases of DRESS syndrome, aromatic macular and papular type of eruption. Exfoliative DRESS syndrome, or drug rash with eosinophilia anti-epileptic drugs were responsible for nearly dermatitis following a diffuse erythroderma, and systemic symptoms, is an uncommon drug 35% of cases.2 Also significant were the 12% of facial swelling, mucosal involvement, and vesicles reaction that classically has a delayed onset within cases reported to have sulfonamides, particularly have also been reported in a number of studies.1,2,4 two to eight weeks after starting the causative dapsone and sulfasalazine, as a possible Cacoub et al. found 97% of those suffering medication.1,3 Incidence of this syndrome ranges cause.2 Despite sulfonamides being commonly from DRESS syndrome in their study actually from 1 in 1,000 to 1 in 10,000 drug exposures, suspect, our review of the literature revealed had a rash.3 More specifically, 60% exhibited a with a mortality of 10%.3,4 Two studies noted a no reports of DRESS syndrome associated macular and papular rash, 54% had a generalized predilection for females, with a male-to-female with furosemide, a non-antibiotic sulfonamide, erythematous rash, and 39% had facial edema. ratio of 0.8:1.0.2,5 prior to this case. Other, less frequently noted In addition to the cutaneous manifestations, DRESS syndrome was first attributed to aromatic culprits are various antimicrobials, antivirals, internal organ involvement is another variable anti-epileptic medications dating as far back as the antidepressants, antihypertensives, NSAIDs and entity in DRESS syndrome. According to Husain 3,8 While rarely reported 1920s, and it was thus referred to as anticonvulsant biologic medications. et al., the most commonly affected visceral organ to cause DRESS syndrome, minocycline is one 4 hypersensitivity syndrome. A case reported in is the liver. They found nearly 70% of patients 1950 describes a classic patient who presented with antimicrobial worthy of highlighting, particularly with DRESS syndrome to have abnormal liver fever, an exfoliative rash, and jaundice while taking for dermatologists. Of note, several studies report function tests. The renal system is less commonly phenytoin.6 Another notable, early encounter minocycline-induced DRESS syndrome occurs involved. Effects on the kidney can lead to that highlighted this often challenging diagnosis primarily in patients with darker skin types hematuria, proteinuria and elevated BUN and 9,10 Maubec et al. proposes described a patient with lymphadenopathy, (Fitzpatrick V and VI). creatinine. The appearance of eosinophils in the

Page 28 DRESS Syndrome: Improvement of Acute Kidney Injury and Rash with Corticosteroids Table 2. Visceral organs most commonly the decision to begin systemic corticosteroids is Immune Responses. Allergol Int. 2006;55(1):1-8. 2 dependent upon the overall clinical picture and affected by DRESS 6. Chaiken BH, Goldberg BI, Segal JP. Dilantin whether there are signs of visceral involvement.8 Organ Rate sensitivity; report of a case of hepatitis with In the absence of internal organ involvement or jaundice, pyrexia, and exfoliative dermatitis. N when transaminase levels do not exceed five times Liver 75% Engl J Med. 1950;242(23):897-8. normal, patients may be treated conservatively Kidney 37% with topical corticosteroids. In addition, 7. Saltzstein SL, Ackerman LV. Lymphadenopathy treatment may include H1-antihistamines and induced by anticonvulsant Drugs and Mimicking Lung 32% emollients for symptomatic relief if pruritus is Clinically and Pathologically Malignant Spleen 15% present. In the presence of visceral involvement Lymphomas. Cancer. 1959;12(1):164-82. and/or elevated transaminase levels greater than 8. Husain Z, Reddy BY, Schwartz RA. DRESS Heart/Musculoskeletal 13% five times normal, 1 mg/kg/day of prednisone Syndrome: Part II: Management and Therapeutics. with a taper regimen over three to six months is J Am Acad Dermatol. 2013;68(5):709.e1-e9. Pancreas 4% warranted. In the case that no improvement is noted with oral prednisone, a three-day course of 9. Shaughnessy KK, Bouchard SM, Mohr MR, Table 3. RegiSCAR inclusion criteria* for 30 mg/kg of methylprednisolone intravenously Herre JM, Salkey KS. Minocycline-induced drug DRESS syndrome12 may be administered as pulse therapy.8 reaction with eosinophilia and systemic symptoms (DRESS) syndrome with persistent myocarditis. Hospitalization+ Even with cessation of the causative medication, J Am Acad Dermatol. 2010;62(2):315-8. mortality is reported to be around 10%.12,13 Reaction suspected to be drug-related+ However, just as there is variability in DRESS 10. Maubec E, Wolkenstein P, Loriot MA, Wechsler J, Mulot C, Beaune P, Revus J, Roujeau Acute skin rash+ syndrome’s clinical presentation, the mortality varies according to the patient’s comorbidities, JC. Minocycline-induced DRESS: evidence for Fever above 38°C presence or absence of visceral involvement, and accumulation of the culprit drug. Dermatology. 2008;216(3):200-4. Enlarged lymph nodes in at least two sites amount of time from disease onset to diagnosis and treatment. 11. Bocerquet H, Bagot M, Roujeau JC. Involvement of at least one internal organ+ Drug-induced pseudolymphoma and drug Lymphocytes above or below the laboratory Conclusion hypersensitivity syndrome (Drug Rash with limits As evident in this particular case, DRESS Eosinophilia and Systemic Symptoms: DRESS). Semin Cutan Med Surg. 1996;15(4):250-7. Eosinophilia+ syndrome is a challenging diagnosis of exclusion that has the potential to progress to a life- 12. Kardaun SH, Sioroff A, Valeyrie-Allanore Thrombocytopenia threatening illness warranting the use of systemic L, Halevy S, Davidovici BB, Mockenhaupt M, *At least 3 required for diagnosis corticosteroids. The clinical picture is often broad Roujeau JC. Variability in the clinical pattern +Inclusion criteria in current case and non-specific, requiring a detailed history. It of cutaneous side-effects of drugs with systemic urine, as seen in this case, may be an indicator is important to note the temporal evolution of symptoms: does a DRESS syndrome really exist? of interstitial nephritis. Though rare, the need for signs and symptoms, use sound physical exam Br J Dermatol. 2007;156(3):609-11. skills, and closely interpret laboratory values to short-term hemodialysis has been documented. 13. Mockenhaupt M. Severe drug-induced skin make the diagnosis of DRESS syndrome. The Other potentially affected systems are lymphatic, reactions: clinical pattern, diagnostics and therapy. 2,4,8,11 culprit medication should be discontinued as hematologic, pulmonary and cardiovascular. J Dtsch Dermatol Ges. 2009;7(2):142-62. See Table 2 for a list of the most commonly soon as possible, and the decision to treat with affected visceral organs in DRESS syndrome. topical or systemic corticosteroids must be based on clinical severity. Correspondence: Dawnielle Endly, DO; Due to the variability in presentation, relatively [email protected] late onset, and long duration even after stopping the causative drug, DRESS syndrome is often References 1. Funck-Brentano E, Duong TA, Bouvresse S, a complex, delayed diagnosis. It is important Bagot M, Wolkenstein P, Roujeau JC, Chosidow that clinicians first exclude other clinically O, Valeyrie-Allanore L. Therapeutic management similar conditions such as lymphoproliferative of DRESS: a retrospective study of 38 cases. J Am diseases and autoimmune or infectious diseases. Acad Dermatol. 2015;72(2):246-52. When considering DRESS syndrome, the Registry of Severe Cutaneous Adverse Reactions 2. Kardaun SH, Sekula P, Valeyrie-Allanore L, (RegiSCAR) criteria aid in solidifying a diagnosis Liss Y, Chu CY, Creamer D, Sidoroff A, Naldi when confronted with these clinically challenging L, Mockenhaupt M, Roujeau JC; RegiSCAR cases (Table 1).12 Additionally, RegiSCAR study group. Drug reaction with eosinophilia requires three or more of the following major and systemic symptoms (DRESS): an original criteria for a solid diagnosis of DRESS syndrome: multisystem adverse drug reaction. Results from an acute rash, fever above 38°C, lymphadenopathy the prospective RegiSCAR study. Br J Dermatol. of at least two sites, involvement of at least one 2013;169(5):1071–80. internal organ, platelets below normal laboratory 3. Cacoub P. The DRESS Syndrome: A Literature limits, lymphocytes above or below the laboratory Review. Am J Med. 2011;124(7):588-97. limits and/or increased eosinophil counts (Table 3). Additional criteria to consider, though not 4. Husain Z, Reddy BY, Schwartz RA. DRESS necessarily required for a diagnosis of DRESS Syndrome: Part I. Clinical Perspectives. J Am syndrome, include hospitalization and/or a Acad Dermatol. 2013;68(5):69.e1-e14. 12 suspected drug-related etiology. 5. Shiohara T, Inaoka M, Kano Y. Drug Once DRESS syndrome is suspected, Induced Hypersensitivity Syndrome (DIHS): discontinuation of the offending agent is the first A reaction Induced BY Complex Inter Among step in treatment.1,8 According to Husain et al., Herpesviruses and Antiviral and Antidrug

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