|Year : 2019 | Volume
| Issue : 5 | Page : 59-66
Drug reaction with eosinophilia and systemic symptoms syndrome
KC Shanoj, Sneha Joseph, Padmanabha Shenoy
Centre for Arthritis and Rheumatism Excellence, Kochi, Kerala, India
|Date of Web Publication||2-Dec-2019|
Dr. Padmanabha Shenoy
Centre for Arthritis and Rheumatism Excellence, Nettoor, Kochi - 682 040, Kerala
Source of Support: None, Conflict of Interest: None
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a delayed form of severe cutaneous adverse reaction (SCAR) seen in association with certain drugs, especially anticonvulsants and allopurinol. Unlike other SCARs, DRESS is associated with significant systemic involvement such as fever, lymphadenopathy, eosinophilia, renal failure, transaminitis, and myocarditis. Because of delayed onset of symptoms and a persistent course even after discontinuation of culprit drug, DRESS can mimic a variety of rheumatological disorders. Even though glucocorticoids are the mainstay of treatment, unlike other SCARs, DRESS is associated with a high incidence of viral reactivation, especially with members of the human Herpesviridae family. Early identification of the viral activation and prompt therapy is critical in the management of DRESS.
Keywords: Drug induced, hypereosinophilia, rash
|How to cite this article:|
Shanoj K C, Joseph S, Shenoy P. Drug reaction with eosinophilia and systemic symptoms syndrome. Indian J Rheumatol 2019;14, Suppl S1:59-66
| Introduction|| |
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse reaction (SCAR) associated with skin rash, fever, eosinophilia, lymphadenopathy, and multiple internal organ involvement. DRESS typically presents 3 weeks to 3 months after the initiation of culprit drug, with many of the systemic manifestations appearing weeks to months after the onset of symptoms, making the diagnosis and management even more challenging. Because of these varied presentations, DRESS can mimic infection, sepsis, systemic lupus erythematosus, and adult-onset Still's disease.
Most of the initial description of DRESS was named as per the culprit drugs, such as hydantoin syndrome and dapsone syndrome. The term DRESS syndrome was first introduced by Bocquet et al. in 1996 to unify various severe drug reactions such as allopurinol hypersensitivity syndrome, sulfone syndrome, drug-induced pseudolymphoma, and anticonvulsant hypersensitivity syndrome. Japanese investigators coined the term drug-induced hypersensitivity syndrome (DIHS) to describe the same syndrome. The term DRESS will be used in this review from here on to describe this syndrome.
Most of the adverse drug reactions (ADRs) are dose-dependent and predictable. However, 20% of the ADRs are a dose-independent allergic reaction to the drug. Majority of allergic ADRs are milder and nonlife-threatening such as fixed drug eruption, maculopapular exanthema, and urticaria. On the other hand, SCAR is associated with extensive skin involvement and potentially life-threatening. Disorders included under SCAR are DRESS syndrome, Stevens-Johnson syndrome More Details (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP). The European Registry of SCAR (RegiSCAR) established for continuous surveillance of SCAR including DRESS, SJS, TEN, and AGEP established a diagnostic scoring for DRESS in 2007. Characteristic features of DRESS include significant systemic involvement, minimal epidermal lysis, and association with viral reactivation, especially with the viruses of the herpes family.,, In fact, many of the late complications of DRESS are due to the viral reactivation.
| Search Strategy|| |
A systematic search of the literature was conducted on the electronic database in the pubmed, using search criteria 'DRESS' and 'Drug Reaction AND Eosinophilia'. Only papers in the English language was selected for the review Search criteria yielded a total of around 5000 articles. With the consensus of the authors, about 50 articles were selected and the references in each article were also reviewed where necessary.
| Etiology|| |
Aromatic antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine are the most common culprit agents to cause DRESS, accounting for 35% of cases. Allopurinol was the second most common cause of DRESS as per the RegiSCAR study. Febuxostat can also cause DRESS in patients with chronic kidney disease. Among the antimicrobials, sulfonamides, especially sulfasalazine and dapsone, were the most commonly reported drugs, followed by penicillins, antitubercular drugs, and cephalosporins. Other classes of drugs that are reported to cause DRESS include nonsteroidal anti-inflammatory drugs (NSAIDs), sorafenib, hydroxychloroquine, amitriptyline, omeprazole, and nevirapine to name a few [Table 1].,,
|Table 1: Common drugs causing drug reaction with eosinophilia and systemic symptoms syndrome|
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| Clinical Features|| |
DRESS typically starts as a flu-like illness with fever, rash, sore throat, and lymphadenopathy. In most of the cases, symptoms appear 3 weeks to 3 months following the initiation of an offending drug. However, on re-exposure, symptoms can appear earlier with more severe manifestation. Clinical features and onset of symptoms vary with the culprit drug [Table 2]. Fever is seen in 64%-90% of cases,,, which is almost always present in dapsone-induced DRESS (100%) but seen in only 50% of cases in patients with allopurinol-induced DRESS. Fever is usually high grade and tends to last weeks after continuation of the culprit drug. In most of the cases, fever is accompanied by the presence of pruritic skin rash. The rash usually begins as erythematous macules, pustules, or eczema-like lesions which is mildly pruritic and symmetric in distribution. Associated facial edema with pinhead-sized pustules is seen in 79% of the cases and considered as a hallmark of DRESS., Typically, skin rash involves more than half of the body surface, which later tends to become confluent with associated blister formation. However, epidermal necrosis and bullae are not seen in DRESS. Mucosal surfaces, palms, and soles are usually spared in DRESS; however, their involvement does not rule out the diagnosis. As in case of fever, skin rash tends to persist for weeks to months even after discontinuation of culprit drug.
| Internal Organ Involvement|| |
Internal organ involvement in DRESS is associated with significant morbidity and mortality, most commonly affecting the hematopoietic, hepatic, and renal system. Frequently, the appearance of organ involvement can be delayed even weeks to months after the onset of skin rash and can be missed as a complication of DRESS being mistakenly labeled as infection or autoimmune diseases.,
| Hematological Manifestations|| |
Eosinophilia is the most common hematological manifestation of DRESS reported in 57%-95% of cases.,,, Most often, eosinophilia is mild to moderate but can be severe enough to mimic hypereosinophilic syndrome. Atypical lymphocytosis is seen in up to 67% of cases. Neutrophilia is reported in 78% of cases, especially in the early phase of DRESS; on the other hand, monocytosis is more common in the later phase, seen in 69% of cases. Cytopenias such as anemia, lymphopenia, and thrombocytopenia may be seen but are less frequent manifestations of DRESS.
Lymphadenopathy is seen in 54%-71% of DRESS,,, more common with NSAIDs (60%) and least common in allopurinol-induced DRESS. Because of prolonged fever and splenomegaly, DRESS can mimic lymphoma. Histopathology also simulates lymphoma, justifying the earlier term pseudolymphoma.
| Visceral Manifestations|| |
The most common visceral involvement is transient transaminitis, which is usually self-limiting. Hepatic involvement is seen in 75%-94% of cases and can be a delayed presentation. Paradoxical worsening of the symptoms can occur after the withdrawal of the culprit drug. Late-onset hepatitis may be associated with viral reactivation, especially with cytomegalovirus (CMV). Apart from hepatitis, cholestasis is also described in association with DRESS. Even though rare, fulminant hepatic failure can complicate DRESS which is the most common cause of mortality.,,,
Renal involvement is more frequent with allopurinol (60%) compared with other drugs., Most of the cases are transient with a mild increase in blood urea nitrogen and serum creatinine. Urine analysis may show the presence of eosinophils. Biopsy studies have demonstrated interstitial nephritis with intense lymphocyte infiltrates and tubular necrosis with an absence of deposits in immunofluorescence. Most of the cases resolve without any sequela. However, there are case reports of progressive renal failure in patients with DRESS syndrome. Risk factors for renal involvement in DRESS are preexisting renal disease and old age.
Cardiac involvement was considered to be rare in DRESS. However, a recent retrospective analysis by Intarasupht et al. reported a prevalence of 19.1%. Heart involvement in DRESS can be due to hypersensitivity myocarditis or acute necrotizing eosinophilic myocarditis. Clinical features are often delayed with dyspnea, chest pain, tachycardia, hypotension, and features of congestive cardiac failure. Hypersensitivity myocarditis is usually self-limiting. On the other hand, necrotizing myocarditis has a mortality rate of 50%, with a median survival rate of 3-4 days., Minocycline- and ampicillin-associated DRESS has a higher incidence of cardiac manifestations compared to other agents. Cardiac manifestations can also cause long-term sequelae such as thromboembolism, valvular regurgitation, and restrictive cardiomyopathy.
Lung involvement is usually mild in DRESS, presenting with impaired pulmonary function, pleuritis, or pneumonitis. Nevertheless, severe pulmonary involvement with acute respiratory distress syndrome can occur in a minority of patients, especially with the DRESS syndrome associated with minocycline or abacavir use.
Other rare manifestations reported in DRESS are neurological involvement such as meningitis or meningoencephalitis, arthritis, myositis, and pancreatitis.,
| Pathogenesis|| |
Role of immune cells
Cutaneous ADR (cADR) is a T-cell mediated hypersensitivity reaction against a drug or its metabolite. However, unlike other cADRs, the acute phase (day 1-11) of DRESS is associated with an exponential increase in peripheral T regulatory (Treg) cells, mainly induced Treg cells (iTreg). On the other hand, during resolution, Treg number drops with an associated increase in the Th17 lymphocytes. Even though the data regarding the above hypothesis are limited owing to the rarity of the condition, there seems to be a direct link between the imbalance of Treg cells and DRESS.
Ushigome et al. reported the depletion of proinflammatory monocytes in the early phase of DRESS, causing Treg expansion. What drives this unusual T-cell response is not well elucidated. An increase in the iTreg cells coincides with an increased risk of herpesvirus reactivation and various internal organ involvement. Similarly, many of the autoimmune manifestations are seen in the resolution phase of DRESS. The difference between acute and resolution phase is depicted in [Table 3].
|Table 3: Difference between acute and resolution phases of drug reaction with eosinophilia and systemic symptoms syndrome|
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Recently, Yazicioglu et al. compared peripheral B-lymphocytes in DRESS syndrome, maculopapular drug rash, and viral exanthem. Peripheral B-cells were significantly lower in DRESS in comparison with other two conditions. These findings add on to the complex picture of immune dysregulation in patients with DRESS.
In summary, the early phase of DRESS is associated with significant immunosuppression with associated viral reactivation and the late phase is associated with immune reconstitution and autoimmune phenomenon [Figure 1].
|Figure 1: Role and pathogenesis of viral reactivation in DRESS: In the presence of genetic and certain environmental factors, culprit drug induces immune dysregulation, causing a reduction in the proinflammatory monocytes, driving the expansion of Treg cells in association with a proportional decrease in the Th17 cells and B-lymphocytes. This specific immune deficiency state induces HHV reactivation. Later, as the immune reconstitution occurs, an increase in the Th17 cells drives autoi mmunit y in the later course of DRESS. FoxP3 = Master regulator of T regulatory lymphocytes, DRESS = Drug reaction with eosinophilia and systemic symptoms, HHV = Human herpesvirus, RoRγt = Master regulator of Th17 lymphocytes, T-bet = Master regulator of Th1 lymphocyte|
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Role of genetics
As expected in a T-cell-mediated hypersensitivity syndrome, human leukocyte antigen (HLA) is the most important susceptibility factor that predisposes to DRESS. Various associations between HLA and specific drugs are depicted in [Table 4]. Apart from HLA, drug metabolisms such as slow acetylators and cytochromeP polymorphisms also influence the susceptibility for DRESS.
|Table 4: Genetic factors in drug reaction with eosinophilia and systemic symptoms|
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Role of viral infection
Viral infections can influence the onset and course of DRESS syndrome. Preceding viral infections, especially herpes zoster, are common in patients with DRESS., Viral infection may be acting as a trigger in the initiation of immune dysregulation.
Unlike other autoimmune and hypersensitivity disorders, DRESS is associated with significant viral reactivation influencing the visceral organ involvement and overall prognosis. Up to 60%-80% of patients with DRESS show evidence of viral reactivation with members of the herpes family. Human herpesvirus-6 (HHV-6) is the first viral DNA that is detectable in DRESS, appearing 3-5 weeks after the onset of the symptoms. Recent studies have demonstrated sequential reactivation of other viruses in the herpes family. Followed by HHV-6 appearance, Epstein-Barr virus (EBV), HHV-7, and CMV DNA may become detectable in the serum. CMV reactivation usually occurs 3-7 weeks after the onset of DRESS. CMV reactivation is especially significant as it is associated with significant visceral involvement such as hepatitis, pneumonitis, gastroenteritis, and myocarditis.,, Prompt identification of viral reactivation and treatment with antiviral treatment is crucial in improving the overall outcome of DRESS.
| Diagnosis|| |
The diagnosis of DRESS is challenging as many clinical and laboratory features are transient and appear during a later phase of the disease. There are two validated diagnostic criteria for the diagnosis of DRESS. The RegiSCAR group proposed a diagnostic score depending on the clinical and laboratory features. Total score qualifies the case as definite, probable, possManagement of DrugManagement of Drug Reaction with Eosinophilia and Systemic Symptomsible, or not a case. The Japanese counterpart Japan Severe Adverse Reaction (JSCAR) research group proposed a validation score based on the clinical and laboratory features for DIHS. A diagnosis of typical (definite) DIHS requires fulfillment of all seven criteria, including evidence of HHV-6 reactivation. On the other hand, the diagnosis of atypical (probable) DIHS is made in the presence of typical clinical features in the absence of evidence for HHV-6 reactivation. The diagnostic criteria in DRESS are depicted in [Table 5] and [Table 6].
|Table 5: Diagnostic criteria in drug reaction with eosinophilia and systemic symptoms syndrome|
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|Table 6: Diagnostic criteria of drug-induced hypersensitivity syndrome proposed by Japanese consensus group|
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| Management of Drug Reaction With Eosinophilia and Systemic Symptoms|| |
Because of the variability of clinical features and complications, the management of DRESS requires a high index of suspicion and a multidisciplinary approach. Withdrawal of the drug at the earliest suspicion of DRESS should be made. However, hypersensitivity to the drug can show class phenomenon so that unnecessary antibiotics in suspicion of infection should be avoided. Moreover, DRESS can be associated with paradoxical worsening after discontinuation of the drug, which can cause significant diagnostic and treatment dilemma.
Corticosteroids (CSs) are the mainstay in the management of DRESS, especially in the acute phase. Prednisolone is required at a dose of 1 mg/kg required for most of the patients with moderate and severe manifestations. In case of life-threatening conditions, pulse methylprednisolone or Intravenous immnunoglobulin (IVIG) may be required. As the disease tends to flare on tapering CS, slow tapering of CS is advocated, typically, over 2-3 months. However, slower taper over 3-12 months may be required for patients with severe manifestations. There are no randomized controlled trials in the treatment of DRESS supporting the utility of CS in the management of DRESS owing to the low prevalence of this disorder. There are reports of effective treatment of DRESS without systemic CS., Uhara et al. reported an effective treatment of 12 patients without the use of systemic CS. However, most such cases are milder without much visceral involvement, and avoidance of systemic steroid in DRESS syndrome can be associated with significant short- and long-term complications. Ushigome et al. reported a significant increase in the EBV reactivation in patients not receiving systemic CS in the early phase of the disease. EBV reactivation in DRESS was associated with a higher incidence of the autoimmune phenomenon. The current evidence favors the use of systemic GC in severe cases and topical CS in mild disease. In the absence of visceral involvement, the French Dermatology Society recommends the use of topical CS and antihistamine drugs. Viral DNA should be assessed during the course of the disease, and in the presence of viral reactivation with systemic signs, the French Dermatology Society recommends glucocorticoids plus antivirals (ganciclovir).
The evidence for the use of immunosuppressive drugs in DRESS is much less, especially in patients with insufficient response to GC. Cyclosporine was found to be useful in multiple case reports in severe DRESS.,,,, However, there are two case reports of fatal outcome with the use of cyclosporine in DRESS, both with cardiac involvement., Other immunosuppressive agents that have shown benefit in steroid-resistant cases are mycophenolate mofetil, cyclophosphamide, and rituximab.,
| Prognosis|| |
The prognosis of DRESS depends on the culprit drug, presence of viral reactivation, and systemic organ involvement. Allopurinol- and minocycline-induced DRESS are more severe with a prolonged course. Various complications of DRESS are depicted in [Table 7]. The mortality rate of DRESS was estimated to be 10%; however, recent RegiSCAR data showed a much lower mortality rate.,
|Table 7: Complications of drug reaction with eosinophilia and systemic symptoms syndrome|
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| Conclusion|| |
DRESS syndrome is a multisystem drug adverse reaction with fever and eosinophilia. Clinical presentation is often protracted with multiple flares which can confuse with various infections, rheumatological disorders, and malignancies. Viral reactivation and autoimmune phenomena complicate the course of the disease. Prompt recognition of complication is vital in the management of DRESS.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]