Clinical Dermatology Review

ORIGINAL ARTICLE
Year
: 2020  |  Volume : 4  |  Issue : 2  |  Page : 141--145

Retrospective analysis of a cohort of 16 patients with drug reaction with eosinophilia and systemic symptoms


Varadraj V Pai, Simantini Sakardhande, Pankaj Shukla, Karla Nadine Faleiro 
 Department of Dermatology, Goa Medical College, Bambolim, Goa, India

Correspondence Address:
Varadraj V Pai
Department of Dermatology, Goa Medical College, Bambolim - 403 002, Goa
India

Abstract

Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe adverse drug-induced reaction characterized by a triad of fever, skin rash, and symptomatic or asymptomatic internal organ involvement. Aims: The aim of this study is to determine the study of varied clinical manifestations and their therapeutic outcome in patients with DRESS. Materials and Methods: A hospital-based retrospective case series was conducted in the department of dermatology. The medical records of patients with DRESS syndrome, drug reaction with eosinophilia, and drug hypersensitivity syndrome within 3 years were reviewed and were entered into a specially prepared pro forma. Results: A total of 16 patients fulfilled the criteria and were studied with equal involvement in males and females. The latency period of 4–6 weeks was the most common duration for drug exposure. Anticonvulsants were associated with more than 50% of the cases. Other than skin, hematological and hepatic involvement was noted. The topical steroids with moisturizers reduced scaling and erythema in 62.5% of the patients. Conclusion: The manifestations in DRESS can be diverse ranging from cutaneous lesions such as maculopapular rash to systemic involvement. Anticonvulsants are the most commonly implicated drug. Topical steroids are effective in patients with limited skin involvement.



How to cite this article:
Pai VV, Sakardhande S, Shukla P, Faleiro KN. Retrospective analysis of a cohort of 16 patients with drug reaction with eosinophilia and systemic symptoms.Clin Dermatol Rev 2020;4:141-145


How to cite this URL:
Pai VV, Sakardhande S, Shukla P, Faleiro KN. Retrospective analysis of a cohort of 16 patients with drug reaction with eosinophilia and systemic symptoms. Clin Dermatol Rev [serial online] 2020 [cited 2020 Nov 26 ];4:141-145
Available from: https://www.cdriadvlkn.org/text.asp?2020/4/2/141/292476


Full Text



 Introduction



Drug reaction with eosinophilia and systemic symptoms (DRESS) is a distinct, severe, idiosyncratic reaction to a drug characterized by a triad of fever, skin rash, and symptomatic or asymptomatic internal organ involvement.[1],[2],[3] DRESS was described by Saltzstein and Ackerman as a hypersensitivity reaction to phenytoin and other antiepileptics which they referred to as drug-induced pseudolymphoma.[4],[5] Skin involvement in drug reactions is observed in 5%–10% of patients.[6] The incidence of DRESS is estimated at 1/1000–1/10,000 among people taking medicines. DRESS differs from other adverse cutaneous drug reactions in the frequency of extracutaneous manifestations such as hematological, hepatic, renal involvement, etc.[7]

The diagnosis of DRESS is difficult because of the varied pattern of cutaneous eruption and organ involvement and because this syndrome can mimic infectious or systemic conditions.[1],[2] The presence of various diagnostic criteria such as the International Registry of Severe Cutaneous Adverse Reactions (RegiS-CAR) significantly helps in the diagnosis.[7]

This study aimed to analyze the various clinical manifestation and therapeutic outcomes among patients with DRESS treated in the dermatology department.

 Materials and Methods



This was a hospital-based retrospective case series study conducted in the department of dermatology over 3 years. The medical records of patients with DRESS syndrome, drug reaction with eosinophilia, and drug hypersensitivity syndrome (DHS) within the last 3 years were reviewed and entered into a specially prepared pro forma. The diagnostic criteria proposed by the RegiS-CAR score [Table 1] were used to identify the cases with a diagnosis of DRESS syndrome (“possible,” “probable,” or “definite” case of DRESS).[4] Other patterns of drug reaction were excluded from the study. The data were analyzed for the demographic profile, latency period, offending drugs, clinical characteristics, the morphology of drug rash, hematological, and biochemical parameters. IgG/IgM for human herpesvirus-6 was not performed in the study group. The study was approved by the Institutional Ethics Committee.{Table 1}

 Results



Sixteen patients fulfilled the criteria for DRESS and were included in our study, with an equal number of males and females (8; 50%) with a male:female ratio is 1:1. The age group in our study ranged from 13 to 83 years. The age group of more than 60 years was the most commonly affected group with seven (43.7%) patients.

The latency period is the time from the introduction of the drug to the onset of clinical features of DRESS syndrome. It ranged from a week to 90 days, with a mean of 39.4 days. DRESS presenting within 2 weeks following the introduction of the drug was seen in only 6.25% (one patient). A latency period of 4–6 weeks was the most common duration for drug exposure as seen in eight (50%) patients in our cohort [Figure 1].{Figure 1}

The most common causative drugs were anticonvulsants seen in eight (50%) patients followed by nonsteroidal anti-inflammatory drugs, antitubercular therapy, and beta-lactam antibiotics seen in two (12.5%) patients each. One patient (6.25%) each had DRESS syndrome after the intake of dapsone and undetermined medication (others), respectively [Figure 2]. Among anticonvulsants causing DRESS, phenytoin was the most common 4 (25%), followed by lamotrigine and carbamazepine 2 (12.5%).{Figure 2}

Among the morphological patterns, the maculopapular rash was seen in 10 (62.5%), followed by exfoliative dermatitis in 6 (37.5%) patients [Figure 3]. Diffuse scaling and edema of the face were observed in all patients with exfoliative dermatitis with a characteristic dryness and chapping of the lips. Mucosal involvement in the form of erosions was seen in five patients. Fever at the time of presentation was seen in 12 (75%) cases. Significant lymphadenopathy was seen in eight (50%) patients, with the most common group of lymph node involvement being the axillary group.{Figure 3}

Laboratory parameters

Both eosinophilia and anemia were observed in 14 patients (87.5%). Eosinophilia >40 cells/mm3 was seen in 12 (75%) patients, and levels <500 cells/mm3 were noted in two (12.5%) patients. The liver was the most commonly involved organ with abnormalities consisting of elevated liver enzymes and or increased serum bilirubin detected in 11 (68.75%) patients. Renal involvement in the form of deranged renal parameters was seen in six (40%) patients [Figure 4].{Figure 4}

The therapeutic measures initiated included withdrawal of the offending drugs, topical steroids with moisturizers, antihistamines, and symptomatic care. Most patients (10; 62.5%) responded to these measures. Corticosteroids (prednisolone 1 mg/kg body weight) was started in six patients with extensive skin involvement not responding to topical steroid or/and associated with hepatic and renal involvement, which was tapered over 3–4 weeks. No mortality was noted in the study population.

 Discussion



Dress is one of the drug-induced severe cutaneous adverse reactions (scars) with cutaneous presentation and internal organ involvement. It is also termed as dhs or anticonvulsant hypersensitivity syndrome or drug-induced hypersensitivity syndrome (dihs) or drug-induced delayed multiorgan hypersensitivity syndrome. It is a life-threatening condition with a mortality rate of about 10%.[2],[3],[8],[9]

The list of causative drugs has been increasing with the usage of newer drugs. Various drugs such as antiepileptics, antibacterial, antipyretics, and antiviral are known to cause this syndrome.[10] There are reports of newer drugs causing DRESS such as anti-hepatitis C virus agents such as telaprevir and boceprevir, targeted therapies for malignancies such as sorafenib, vismodegib, and vemurafenib, anti-coagulant (rivaroxaban), uric acid-lowering agent (febuxostat).[8] In our study, consistent with the findings of previous reports, anticonvulsants were the most common causative agent. A literature review by Cacoub et al. revealed carbamazepine as the most common offender (27%) followed by phenobarbital and lamotrigine.[1] However, we found phenytoin as the most common offending drug.

Among the various criteria for the diagnosis of DRESS, Bocquet et al. proposed an eosinophilia ≥1500/μl and/or atypical lymphocytes and failure of at least two organs (skin being one of them).[11] The Japanese consensus group proposed a division of DIHS into typical or atypical. Recently, the RegiS-CAR scoring system has been developed which designates DRESS as “no,” “possible,” “probable,” and “definite.”[6] By applying RegiS-CAR scoring system to our study cohort, five patients were definite cases of DRESS syndrome, six patients were probable cases, and 5 were possible cases.

The DRESS syndrome is characterized by delayed onset and prolonged and protracted evolution of the disease.[8] It can classically begin 1–8 weeks after starting drug therapy.[2] Similar findings were noted in our study, wherein 4–6 weeks was the most common latency period. The symptoms usually start with fever, pruritus, followed by cutaneous lesions over the next 1–2 weeks. Hematological and internal organ involvement is subsequently noted. Skin involvement is seen in 90% of the cases with lesions ranging from exanthema, erythroderma (with or without pustules), blisters, or pustules.

After skin rash and systemic symptoms, hypereosinophilia was the third most frequently reported feature in patients having a DRESS.[1] Fever is usually of high grade, ranging from 38°C to 40°C and may persist for several days following the stoppage of the offending drug.[2] Similar finding was noted in our study. Generalized lymphadenopathy (usually axillary, cervical, and inguinal nodes) is another common feature of the initial presentation of DHS.[2]

Oral ulcers, strawberry tongue, and pharyngitis may also be seen. The liver is the most frequent internal organ to be involved with features ranging from altered liver function test to fulminant hepatic necrosis.[2]

Hematological changes were characteristically present with eosinophilia with levels >40/mm3, seen in 80% of cases. These levels are toxic to the endothelial cells and can lead to the cardiac, gastrointestinal, central nervous system, pulmonary, and renal abnormalities.[2] The anemia noted in our patients was mostly microcytic hypochromic type, although autoimmune hemolytic anemia is known to occur in DRESS.

Hepatic enzyme levels are elevated in up to 95% of the cases of liver involvement.[12] Renal involvement is seen in 11% of the patients. Allopurinol is the drug commonly associated with renal abnormalities. Respiratory features can be in the form of impaired pulmonary function, acute interstitial pneumonitis, lymphocytic interstitial pneumonia, pleuritis, and acute respiratory distress syndrome. Minocycline-induced DRESS commonly affects the lungs. Other systems involved can be cardiac in the form of myocarditis, neurological like meningitis, gastroenteritis, and endocrinal like thyroiditis.[5],[8] In our study, hepatic and renal involvement was commonly noted.

Duration of disease is usually more than 15 days but can also last from a few months to up to 1 year.[13] The risk factors for a prolonged course of the disease include lymphocytosis, increased hepatic enzymes, drugs, and reactivation of several herpes viruses.[8]

Histopathological features in DRESS are nonspecific with the presence of interface dermatitis, spongiosis, perivascular infiltrate comprising lymphocytes, eosinophils, and neutrophils.[8],[12]

Determining the drug implicated can be challenging when multiple drugs are used and the clinical judgment may be required to identify the offending agent. However, drug patch test and lymphocyte transformation test have been tried with variable results.[14]

Treatment comprises early recognition of the syndrome, discontinuation of the offending drug, supportive care, and close observation, with strict attention to hydration and electrolyte balance, particularly in case of erythrodermas. Systemic corticosteroid therapy for DRESS syndrome is currently the most widely accepted and used treatment. Although an early administration of systemic steroids is generally recommended for all cases of DRESS syndrome, studies have shown that systemic steroids may promote viral reactivation and may be associated with long-lasting, relapsing corticosteroid dependent DRESS.[14],[15] However, in our study, most patients with predominant or limited skin involvement responded to topical steroids with other skincare measures. Funck-Brentano et al. also noted the good response to topical steroids in their study.[15]

Other systemic modalities tried include intravenous immunoglobulin, cyclosporin, cyclophosphamide, and plasmapheresis. Topical corticosteroid and systemic antihistamines may help in alleviating the symptoms.[2],[14]

 Conclusion



Even though small sample size is a limitation of our study, the availability of various diagnostic criteria helps in overcoming the clinical challenges in the diagnosis of DRESS. Aromatic anticonvulsants remain one of the most common causative drugs. Topical steroids with skincare measures provide a good response in patients with limited skin involvement.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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