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 Table of Contents  
CASE REPORT
Year : 2019  |  Volume : 3  |  Issue : 2  |  Page : 61-65

Life-threatening adverse reaction to a commonly used drug (drug reaction with eosinophilia and systemic symptoms syndrome)


Department of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar

Date of Web Publication24-Jun-2019

Correspondence Address:
Dr. Mohamed Khalid A. Shariff
Department of Medicine, Hamad General Hospital, P. O. Box: 3050, Doha
Qatar
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/LJMS.LJMS_23_19

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  Abstract 


Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is one of the severe cutaneous adverse reactions with a mortality of 10% and is characterized by hematological abnormalities and organ involvement. Many drugs have been implicated in DRESS, and most often, it is related to aromatic anticonvulsants. We hereby report a case of DRESS syndrome precipitated due to allopurinol, the diagnostic challenge it presented, and the successful treatment with corticosteroids.

Keywords: Allopurinol, drug rash, drug reaction with eosinophilia and systemic symptoms, eosinophilia and systemic symptoms


How to cite this article:
A. Shariff MK, Alfitori GB, Soliman M, Gashir MB, Elzouki ANY. Life-threatening adverse reaction to a commonly used drug (drug reaction with eosinophilia and systemic symptoms syndrome). Libyan J Med Sci 2019;3:61-5

How to cite this URL:
A. Shariff MK, Alfitori GB, Soliman M, Gashir MB, Elzouki ANY. Life-threatening adverse reaction to a commonly used drug (drug reaction with eosinophilia and systemic symptoms syndrome). Libyan J Med Sci [serial online] 2019 [cited 2019 Jul 21];3:61-5. Available from: http://www.ljmsonline.com/text.asp?2019/3/2/61/261063




  Introduction Top


Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome also known as drug-induced hypersensitivity syndrome is a serious and life-threatening adverse drug reaction which is characterized by rash, fever, lymphadenopathy, hematologic abnormalities, and multiorgan involvement.[1] The most frequently involved organ is the liver, followed by the kidney and lungs. There are more than 44 drugs implicated in DRESS, and the most common are aromatic anticonvulsant, sulfonamides, dapsone, and allopurinol. Early recognition and initiation of treatment is of paramount importance as the mortality reported with DRESS syndrome is up to 10%.[2],[3] Diagnosis can be difficult or even delayed, as there are no globally accepted diagnostic criteria, and patients invariably present with nonspecific clinical findings.[4]

The exact pathogenesis of DRESS syndrome remains elusive to this date. Many theories have been proposed which include drug detoxification enzyme abnormalities leading to the accumulation of reactive drug metabolites, sequential reactivation of human herpes viruses (HHVs), and genetic predisposition associated with certain human leukocyte antigen alleles.[5] DRESS syndrome most often mimics more common conditions, and the delay between the onset of symptoms and the initiation of the drug (often 2–6 weeks) confounds the diagnosis further.[6],[7],[8],[9] Herein, we describe a case of DRESS syndrome secondary to allopurinol and the diagnostic challenge it presented.


  Case Report Top


A 35-year-old Filipino male recently diagnosed to have dyslipidemia and hyperuricemia was initiated on allopurinol and atorvastatin. Four weeks following the initiation of the treatment, he presented to the emergency department with fever and a morbilliform rash on his upper trunk and proximal upper extremities which was associated with itching. He was thought to have measles and was initiated on symptomatic treatment and discharged. Two days later, he presented with progression of the rash along with facial edema and bilateral periorbital puffiness [Figure 1]. The rash was maculopapular and blanchable and was associated with diffuse oral mucositis and thrush over the tongue. He was seen by the dermatologist, and a differential diagnosis of acute viral exanthema, acute generalized exanthematous pustulosis, or drug eruption was made. The patient was subsequently admitted to the ward, and two skin biopsies were obtained. Immediately afterward, the patient was started on antihistamines, intravenous immunoglobulin (IVIG) (1 g/kg), and only a topical corticosteroid cream given his high leukocyte count and fever on presentation. The patient was noted to have recurrent spikes of fever and rash progression to a follicular and pustular morphology. In addition, his liver enzymes started rising, and his leukocyte counts were persistently high with a significant eosinophil fraction. At this point, DRESS syndrome secondary to allopurinol was suspected.
Figure 1: Facial swelling and the maculopapular rash on presentation

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Both skin biopsies showed similar features [Figure 2], in which the epidermis showed orthokeratosis, focal parakeratosis, and mild acanthosis with marked spongiosis extending into the adnexal structure. The superficial dermis showed mild to moderate perivascular and periadnexal mononuclear inflammatory cell infiltrate admixed with large number of eosinophils and occasional neutrophils. Scattered interstitial inflammatory cells including eosinophils and nuclear debris are present. There were congested capillaries with red blood cell extravasation and dermal edema with focal lymphocytes exocytosis and interface changes. Fungal stain was negative. The histological features are consistent with drug rash with eosinophilia and systemic symptoms (DRESS).
Figure 2: Orthokeratosis and acanthosis with spongiosis extending into the adnexal structure along with perivascular and interstitial lymphocytes and eosinophils

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Systemic corticosteroids were initiated for definitive treatment. Improvement was monitored by vital signs, rash resolution, daily liver function tests (LFTs), and leukocyte counts. There was a pronounced decline of his LFTs and leukocyte counts over the course of his admission. In addition, his fever subsided and his rash started to abate. The periorbital swelling remarkably diminished [Figure 3], and eventually, the patient was discharged. The patient was subsequently followed in the outpatient for 8 weeks until his LFTs normalized and the corticosteroids were gradually tapered off and discontinued [Graph 1], [Graph 2], [Graph 3].
Figure 3: Resolution of maculopapular rash on discharge

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  Discussion Top


DRESS syndrome is a subtype of severe cutaneous adverse reactions, which is a clinical syndrome characterized by a triad of fever, rash, and internal organ involvement. The estimated incidence is 1 in 1000–1 in 10,000 drug exposures with a mortality rate of around 10%.[10] Many drugs have been implicated in its causation most commonly anticonvulsants, allopurinol, and sulfonamides. The syndrome is also known as drug-induced pseudolymphoma, anticonvulsant hypersensitivity, and drug-induced hypersensitivity.[11] The incidence of allopurinol-induced DRESS syndrome is more controversial and in one study was found to constitute 5.3% of the total cases of DRESS syndrome in one study.[12]

The pathogenesis of DRESS syndrome remains elusive to this date; yet, many theories have been proposed which include detoxification defects leading to reactive metabolite formation, causing subsequent exaggerated immunomediated reactions.[9] The risk of allopurinol-induced DRESS syndrome is increased in patients with renal impairment and concomitant use of thiazide diuretics.[13] Allopurinol-induced DRESS syndrome is thought to be caused by hypersensitivity to a metabolite of allopurinol known as oxypurinol. The presence of comorbid renal impairment or concomitant use of thiazide diuretics results in excessive accumulation of oxypurinol, with subsequent development of DRESS syndrome in susceptible patients.[7] In addition, the reactivation of herpes viruses including Epstein–Barr virus and HHV-6 and-7 has been proposed a potential immunologic trigger for DRESS syndrome. In fact, the detection of HHV-6 reactivation has been recently proposed as a diagnostic marker for DRESS syndrome.[5],[14]

DRESS syndrome has a diverse clinical presentation. However, most commonly, it presents as a diffuse maculopapular rash but can also be vesicular or pustular in its onset as in our case. Internal organ involvement is found invariably in the vast majority of the cases. The pattern of rash and the organs involved vary from patient to patient. In a review of 172 cases of DRESS syndrome done by Cacoub et al., organ involvement was present in 88% of the cases. The liver was the most commonly involved internal organ, as 59% of the cases had documented liver involvement and typically presented as transaminitis but occasionally as fulminant hepatic failure. Renal involvement was seen in 8% of cases, and pulmonary, cardiac, and nervous system involvement was seen in <5% of cases.[6]

Several criteria have been suggested to better delineate the DRESS syndrome; RegiSCAR group has suggested a series of inclusion criteria and scoring system. The Japanese consensus group has proposed another criteria for the drug-induced hypersensitivity syndrome, a synonym for DRESS [Table 1].[11],[15],[16],[17],[18] Our patient fulfilled the inclusion criteria of RegiSCAR, by a score of six points and fulfilled five on the Japanese Criteria.
Table 1: RegiSCAR and Japanese consensus group criteria

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Classically, there is a 2–6 weeks' delay between the onset of the symptoms and the initiation of the culprit drug. However, the symptoms might occur earlier if the drug is readministered.[10] Fever and rash are the most common symptoms, with spikes of fever ranging from 38°C to 40°C, and often persisting for prolonged periods mimicking an underlying infection. The fever persists in spite of discontinuation of drug. The rash usually affects the face, upper trunk, and extremities. In due course of time, the rash becomes purplish and results in scaling as in our patient.

Our patient presented initially with a maculopapular rash, mucosal blistering, limb and periorbital edema, fever, eosinophilia, a drop in hemoglobin, and transaminitis. Although the presentation was highly consistent with DRESS syndrome, the differential diagnosis of infectious or autoimmune processes and other severe drug reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis were considered, but the histological features excluded these two entities. Extensive laboratory investigations were done [Table 2], including a skin biopsy. The skin biopsy revealed spongiotic dermatitis, consistent with DRESS syndrome. There was a dramatic improvement in the rash as evident by the photographs before his discharge. In addition, there was a gradual improvement in his LFTs after initiating steroids, and he was discharged in a week and was subsequently followed in the outpatient for 8 weeks until his LFTs normalized and the corticosteroids were gradually tapered off and discontinued [Graphs 1-3].
Table 2: Investigations of the indexed patient

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  Conclusion Top


The diagnosis of DRESS syndrome is challenging and is most often delayed due to its nonspecific presentation. However, given its significant mortality, failure to recognize it could be detrimental. It should be highly suspected in those patients who present with fever, widespread morbilliform skin rash, and eosinophilia within weeks of initiation of potentially causative drugs like allopurinol. The mainstay of treatment of allopurinol-induced DRESS syndrome is prompt discontinuation of the culprit drug, and immediate initiation of systemic corticosteroid,[15] with IVIG being used in refractory cases to prevent a fatal outcome.[19] However, in our case, the patient did not respond to the IVIG, and the rash gradually subsided 1 week after the initiation of systemic corticosteroids.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Tas S, Simonart T. Management of drug rash with eosinophilia and systemic symptoms (DRESS syndrome): An update. Dermatology 2003;206:353-6.  Back to cited text no. 1
    
2.
Kim DH, Koh YI. Comparison of diagnostic criteria and determination of prognostic factors for drug reaction with eosinophilia and systemic symptoms syndrome. Allergy Asthma Immunol Res 2014;6:216-21.  Back to cited text no. 2
    
3.
Chiou CC, Yang LC, Hung SI, Chang YC, Kuo TT, Ho HC, et al. Clinicopathological features and prognosis of drug rash with eosinophilia and systemic symptoms: A study of 30 cases in Taiwan. J Eur Acad Dermatol Venereol 2008;22:1044-9.  Back to cited text no. 3
    
4.
Boyd A, Mills D, Hook K, Kaila R. Seventeen-year-old sexually active male with rash. Am J Emerg Med 2016;34:764.e1-3.  Back to cited text no. 4
    
5.
Shiohara T, Iijima M, Ikezawa Z, Hashimoto K. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations. Br J Dermatol 2007;156:1083-4.  Back to cited text no. 5
    
6.
Cacoub P, Musette P, Descamps V, Meyer O, Speirs C, Finzi L, et al. The DRESS syndrome: A literature review. Am J Med 2011;124:588-97.  Back to cited text no. 6
    
7.
Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: Part I. Clinical perspectives. J Am Acad Dermatol 2013;68:693.e1-14.  Back to cited text no. 7
    
8.
Chen YC, Cho YT, Chang CY. Drug reaction with eosinophilia and systemic symptoms: A drug-induced hypersensitivity syndrome with variable clinical features. Dermatol Sin 2013;31:196-204.  Back to cited text no. 8
    
9.
Hamm RL. Drug-hypersensitivity syndrome: Diagnosis and treatment. J Am Coll Clin Wound Spec 2011;3:77-81.  Back to cited text no. 9
    
10.
Fiszenson-Albala F, Auzerie V, Mahe E, Farinotti R, Durand-Stocco C, Crickx B, et al. A 6-month prospective survey of cutaneous drug reactions in a hospital setting. Br J Dermatol 2003;149:1018-22.  Back to cited text no. 10
    
11.
De A, Rajagopalan M, Sarda A, Das S, Biswas P. Drug reaction with eosinophilia and systemic symptoms: An update and review of recent literature. Indian J Dermatol 2018;63:30-40.  Back to cited text no. 11
[PUBMED]  [Full text]  
12.
Um SJ, Lee SK, Kim YH, Kim KH, Son CH, Roh MS, et al. Clinical features of drug-induced hypersensitivity syndrome in 38 patients. J Investig Allergol Clin Immunol 2010;20:556-62.  Back to cited text no. 12
    
13.
Picard D, Janela B, Descamps V, D'Incan M, Courville P, Jacquot S, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): A multi-organ antiviral T cell response. Sci Transl Med 2010;2:46-62.  Back to cited text no. 13
    
14.
Drago F, Cogorno L, Broccolo F, Ciccarese G, Parodi A. A fatal case of DRESS induced by strontium ranelate associated with HHV-7 reactivation. Osteoporos Int 2016;27:1261-4.  Back to cited text no. 14
    
15.
Walsh SA, Creamer D. Drug reaction with eosinophilia and systemic symptoms (DRESS): A clinical update and review of current thinking. Clin Exp Dermatol 2011;36:6-11.  Back to cited text no. 15
    
16.
Kardaun SH, Sidoroff A, Valeyrie-Allanore L, Halevy S, Davidovici BB, Mockenhaupt M, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: Does a DRESS syndrome really exist? Br J Dermatol 2007;156:609-11.  Back to cited text no. 16
    
17.
Choudhary S, McLeod M, Torchia D, Romanelli P. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. J Clin Aesthet Dermatol 2013;6:31-7.  Back to cited text no. 17
    
18.
Osman A, Ibrahim W, Khanjar I, Abdulla N, Eltahir R, Alhamoud E. Sudden worsening of DRESS syndrome on tapering steroid dose with dramatic improvement on N-acetylcysteine and steroid dose escalation. Ibnosina J Med Biomed Sci 2014;6:101-5.  Back to cited text no. 18
  [Full text]  
19.
Shiohara T, Kano Y, Hirahara K, Aoyama Y. Prediction and management of drug reaction with eosinophilia and systemic symptoms (DRESS). Expert Opin Drug Metab Toxicol 2017;13:701-4.  Back to cited text no. 19
    


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