Last updated:
9/20/2023
Years published: 2023
NORD gratefully acknowledges Hannah Stirton, MD, PGY-3 Dermatology, University of Toronto, Roni P. Dodiuk-Gad, MD, Clinical Associate Professor, Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology and Head, Inflammatory and Autoimmune Skin Diseases Unit, Dermatology Department, Emek Medical Center, Israel and Assistant Professor – Status Only, Department of Medicine, University of Toronto, Canada, and the DRESS Syndrome Foundation for the preparation of this report.
Summary
Drug reaction with eosinophilia and systemic symptoms (DReSS) is a rare disorder that can affect the skin, blood and any internal organs, most commonly the liver, kidney, lungs and heart. The cause of DReSS is multifactorial involving drug-exposure, genetic predisposition, viral reactivation and immune system responses. Clinical features of this condition are delayed after drug exposure, and proceed in a stepwise and variable fashion, making this syndrome challenging for both patients and physicians to recognize and diagnose. The prognosis for DReSS is highly dependent on the severity of the reaction and the speed with which diagnosis is made, the drug is discontinued and treatment is initiated. Possible outcomes of DReSS include complete recovery with no complications, illness related to end organ dysfunction, long term autoimmune disease and in rare cases, death. The mainstay treatment of DReSS is immediate withdrawal of the culprit drug, supportive treatment and immunosuppression depending on the severity of disease. Long term follow-up and slow treatment tapers are critical for preventing complications. Assessing viral reactivation is an important component in the management of the disease.
Introduction
DReSS is a rare drug reaction that can affect nearly any organ in the human body. Compared to other severe drug reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis (SJS and TEN), DReSS has a more varied clinical presentation making it more challenging to diagnose. The combination of the three features of fever, skin rash and elevated eosinophils (a specific type of white blood cell) has been recognized since the 1930s, but the term DReSS is more recent. As eosinophilia is not always present and other blood count changes may occur (such as low platelets or anemia), many different names have been used to define this syndrome. Originally recognized as anticonvulsant hypersensitivity syndrome, other terms have been proposed over time such as drug-induced pseudolymphoma, drug-induced delayed multiorgan hypersensitivity syndrome (DIDMOHS) and hypersensitivity syndrome. In 1996 the term DRESS (drug rash with eosinophilia and systemic symptoms) was proposed to encompass these similar reactions and differentiate them from other severe drug reactions without eosinophilia. The word “rash” in DReSS was subsequently changed to “reaction” due to its diverse skin findings. The lowercase “e” is often used to denote that eosinophilia is not always present and other blood count changes may be seen. The term DReSS became internationally recognized and gained popularity in multiple countries, although it is not used everywhere. More recently, some have suggested that the “D” in DReSS should be re-examined as vaccines have also been shown to trigger DReSS. Based on the diversity of the clinical features and non-drug causes of DReSS, a further change in nomenclature may be required in the future.
DReSS most commonly begins with a flu-like prodrome of malaise, sore throat, fever and swollen lymph nodes. The lag time between drug exposure and symptom onset is typically between 2-8 weeks (although longer and shorter times have been reported). Additionally, with re-exposure to the drug symptoms can develop in just hours or days.
Skin findings typically occur a few days after the flu-like illness and are varied in their presentation. Typically, more than 50% of total body surface area is involved with a symmetric distribution starting on the face, upper trunk and upper extremities. The most common rashes reported are numerous small red bumps (maculopapular or “morbilliform”), hive-like (urticated papular) and full body redness with scaling (exfoliative erythroderma). Additionally, there can be target-like lesions, eczema-like lesions, dark purple patches and plaques (purpura), or a combination of all of these. Swelling of the face is often dramatic and can be a distinguishing feature from other drug rashes. Mucosal involvement is less common and may include oral ulcers and lip erosions, crusting and inflammation.
The bone marrow and blood cell counts are often affected in DReSS. Hypereosinophilia is the most common finding, followed by an elevated total white blood cell count (leukocytosis), elevated atypical lymphocytes, low lymphocytes, low white cell count and low or high platelets. Depression of all blood cell lines (pancytopenia) is associated with a more severe prognosis.
Systemic features of DReSS can occur days to weeks after initial symptom onset. Hence, it is important to closely monitor the signs and symptoms of possible systemic involvement as they may occur days to weeks after the initial presentation of the rash. The liver is the internal organ most commonly impaired in DReSS, occurring in up to 97% of cases. Manifestations range from asymptomatic elevation of liver enzymes to liver failure requiring liver transplant. The next most involved organ is the kidney which can present as mild acute kidney injury or severe kidney inflammation resulting in permanent end-stage renal disease. Elderly patients, allopurinol-associated DReSS, and those with pre-existing kidney disease are at the highest risk of renal impairment. The lung is the third most frequently impaired organ, with interstitial pneumonitis (lung inflammation) being the most common manifestation. Cardiac involvement in DReSS is becoming more frequently recognized, typically presenting as inflammation of the heart muscle or the lining around the heart (myocarditis or pericarditis). Heart involvement is often delayed in DReSS, occurring an average of 70 days after initial symptom onset. The most common signs and symptoms of cardiac DReSS are shortness of breath, chest pain, low blood pressure and elevated heart rate.
More infrequently there have been reports of DReSS causing inflammation in the pancreas, brain, meninges, colon, gallbladder and other organs.
DReSS is a hypersensitivity reaction that results from a complex interaction between drug exposure, genetic predisposition and viral reactivation. Why some develop this condition while others do not, despite the same exposure, is thought to be a result of the cumulative effect of multiple risk factors.
Drugs are the clear cause of the development of DReSS syndrome. The most common DReSS-inducing drugs are anti-seizure medications, allopurinol, sulfa-containing medications (e.g., sulfamethoxazole, sulfasalazine, dapsone) and antibiotics such as rifampin, minocycline and vancomycin. Carbamazepine is the most common cause of DReSS both overall and within the anticonvulsant grouping. It is important to note that more recently vaccines and biological drugs have been shown to be capable of triggering DReSS.
The relationship between viral reactivation and DReSS has been studied extensively. Despite this, there is still much controversy surrounding this topic. Viral reactivation typically occurs 2-4 weeks after symptom onset and has been associated with longer disease duration, flares and more severe outcomes. Historically, human herpes virus-6 (HHV-6) has been most associated with DReSS, although other human herpes viruses have been reported including HHV-7, cytomegalovirus (CMV), Epstein-Barr virus (EBV) and herpes simplex virus (HSV). Despite the vast amount of research on this topic, it remains unknown whether viral reactivation is a causative factor that drives disease or an unintended consequence. Today, it is advised to assess viral reactivation as part of the management of this condition.
There are several well described genetic changes in the human leukocyte antigen (HLA) system that can increase a patient’s risk of DReSS. These HLA proteins are involved in how drugs are presented to the immune system. Importantly, certain high-risk HLA types are present in some ethnicities more than others, making ethnic background an important predisposing factor to DReSS. For example, Han-Chinese patients show a strong association with HLA-B*58:01 and allopurinol-induced DReSS. As a result, there is a strong recommendation to test for the HLA‐B*58:01 allele in selected subpopulations prior to the initiation of allopurinol. Similarly, multiple studies have shown association between HLA-A*31:01 and carbamazepine-induced DReSS among multiple ethnicities (most notably European, Chinese, Korean and Japanese). The Canadian Pharmacogenomics Network for Drug Safety recommends genetic testing for HLA-A*31:01 for all patients before initiation of carbamazepine therapy. There are many other well described associations between HLA alleles and particular drugs in certain ethnicities. Variants (mutations) in genes for several drug detoxification enzymes have also been linked to DReSS, providing another heritable risk factor for the development of DReSS.
While DReSS does occur in children, it is predominantly seen in adults with a mean age of onset between 40 and 60 years old. Female patients tend to be significantly younger than their male counterparts, and while several studies have found a slight female predominance in DReSS, many more have not replicated this finding. There is significant association between ethnic background and DReSS, with an abundance of research showing HLA alleles being a strong risk factor with exposure to certain drugs. Specific ethnicities at risk include Han-Chinese, Korean, Thai and Europeans with allopurinol exposure, the Chinese with dapsone, and European, Chinese, Korean and Japanese groups with carbamazepine.
Incidence rates of DReSS range from 3.89 per 10,000 inpatients in Spain, to 0.9 per 100,000 people in a West Indian population. Prevalence estimates include 2.18 per 100,000 in the US and 9.63 cases per 100,000 inpatients in Thailand.
The diagnosis of DReSS is clinical. There are two sets of diagnostic criteria that currently exist: The RegiSCAR criteria (Kardaun et al. 2007) and The Japanese Consensus Group criteria (Shiohara et al. 2007). For the RegiSCAR criteria, a score of 5 or higher denotes probable DReSS. For the Japanese Consensus Group criteria all seven criteria are required for a diagnosis of typical DIHS.
RegiSCAR criteria:
• Fever
• Enlarged lymph nodes
• Elevated eosinophils
• Atypical lymphocytes
• Skin rash over 50% BSA, clinically and on histologically consistent with DReSS
• Internal organ involvement
• Resolution ≥ 15 days
• Evaluation of other causes negative (ANA, blood culture, serology for hepatitis A/hepatitis B/hepatitis C, chlamydia, Mycoplasma pneumoniae)
Japanese Consensus Group criteria:
• Maculopapular rash >3 weeks following administration of drug
• Prolonged clinical symptoms after discontinuation of the causative drug
• Fever
• Liver abnormalities or other organ involvement
• White blood cell abnormalities
• Enlarged lymph nodes
• HHV-6 reactivation
The mainstay treatment of DReSS remains systemic steroids alongside identification and immediate withdrawal the culprit drug. All patients should be hospitalized, at least in the initial phase, to monitor for delayed systemic involvement and response to treatment. It should be clearly communicated to the patient that the causative drug needs to be avoided indefinitely. In non-serious DReSS with no systemic involvement or only stage I drug-induced liver injury or stage I kidney injury, high potency topical steroids alone may suffice. For DReSS with more severe organ involvement, oral prednisone at a dose ranging from 0.5-1 mg/kg/day is suggested with a gradual taper over 4-6 weeks, or longer. If a relapse occurs during steroid tapering, a more gradual taper is suggested or use of steroid-sparing agents. If control is not obtained with steroids, cyclosporine or alternative immunosuppressants, less evidence-based therapies such as intravenous immunoglobulin (IVIG), plasmapheresis or cyclophosphamide can be used. In cases of viral reactivation, anti-viral treatment is recommended.
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