Discussion
Drug reaction with eosinophilia and systemic symptoms (DRESS) or
drug-induced hypersensitivity syndrome (DiHS) is a severe adverse
idiosyncratic type IV hypersensitivity drug reaction characterized by an
extensive skin rash and systemic organ involvement, lymphadenopathy,
eosinophilia, and atypical lymphocytosis [1,2]. The combination of
certain genetic predispositions and drug-virus interactions has been
hypothesized to be the underlying pathogenesis of DRESS [2,3].
Certain Human leukocyte antigens (HLA) alleles have been associated with
an increased risk of developing drug-specific DRESS in certain
population groups [3]. Common drugs causing DRESS include aromatic
antiepileptics, allopurinol, and sulfonamide drugs [2-4]. Two main
theories describing the pathophysiology of DRESS involve drug-specific
T-cell reactions and viral reactivation [1,2]. Firstly, an immune
response against the drug reactivates viral infection. Secondly,
concomitant immune response to viral reactivation is responsible for
clinical manifestations of DRESS syndrome [1,4,5]. Human herpesvirus
including cytomegalovirus (CMV), Ebstein-Barr virus (EBV), human herpes
virus-6 (HHV-6), and human herpes virus-7 (HHV-7) is often associated
with DRESS syndrome [2,3]. Quantitative PCR of viral DNA is the
method of choice to determine active viral infection, primary or
reactivation [6]. HHV-6 and EBV appear to be detected earlier in the
course of the disease, followed by HHV-7 and CMV. This sequential viral
reactivation suggests that it is related to the clinical phase of DRESS
[2].
Clinical manifestations usually appear between 2 to 8 weeks after the
introduction of the triggering drug [1,2]. With re-exposure, the
time to onset is shorter with a more severe presentation [2,3]. The
cutaneous eruptions usually begin with morbilliform eruption and later
become edematous with follicular attenuation and can, less commonly,
present with urticaria, erythroderma, vesicles, bullae, and pustules.
Facial and neck edema is a hallmark, while mucosal involvement is rare
and mild [2,3]. The systemic manifestations that commonly present
and are part of the diagnostic criteria comprise fever, hematological
abnormalities (leukocytosis, eosinophilia, and/or positive atypical
lymphocytes), lymphadenopathy, and elevated liver function tests. Other
possible internal organ involvements include kidneys (interstitial
nephritis), lungs (pneumonitis), pancreas (pancreatitis), thyroid
(thyroiditis), and heart (myocarditis, pericarditis). These organ
involvements are the major causes of morbidity and mortality, which
range from 2-10% [2-4] The most severe and life-threatening
complication is fulminant liver failure [3,4]. Because of the
systemic involvement features, DRESS is commonly mistaken for sepsis; a
careful investigation must be undertaken to exclude sepsis as a cause of
the patient’s clinical manifestations. Other severe cutaneous adverse
reactions (SCAR) syndrome like Steven-Johnson syndrome/toxic epidermal
necrolysis (SJS/TEN) or AGEP should also be considered in the
differential diagnosis. However, the onset of eruption—shorter in
SJS/TEN and AGEP– can help distinguish DRESS from the rest [2].
Diagnostic criteria commonly utilized are the RegiSCAR criteria for
hospitalized patients with DRESS syndrome and a Japanese group’s
criteria for diagnosis of DRESS/DIHS; the main difference is the
inclusion of HHV-6 reactivation in the latter [3,4]. Patients who do
not initially fulfill the diagnostic criteria on admission may evolve
and eventually fulfill the criteria [2]. However, the diagnostic
gold standard remains drug re-challenge, which is not practical due to
life-threatening consequences [2,4]. An alternative is a patch test
of the offending drug, which is positive in approximately 60% of the
cases [7]. Previous data showed that around 10% of patients
diagnosed with DRESS syndrome had normal eosinophilic count, and 30-50%
had no lymphadenopathies, making the diagnosis more challenging. Proper
clinical history and temporal relation with drug exposure can increase
the accuracy of diagnosis and improve the overall prognosis [8].
Regardless of the proposed pathogenic mechanisms of DRESS syndrome,
there is no difference in management [1]. Early cessation of the
offending drug and all unnecessary drugs is essential for improved
prognosis and shorter duration [1,2]. Supportive therapies such as
intravenous fluids and antipyretics may be required to maintain
hemodynamics [2,3]. Corticosteroids are the first line of treatment,
either topical to relieve itchiness or systemic [2-4]. However, most
of the cases require systemic corticosteroid therapy. If oral therapy
fails or intravenous therapy is required, pulse therapy with
methylprednisolone is indicated [2]. Steroid tapering dose varies
from 1 to 3 months based on the clinical course [2,3,5]. In
steroid-refractory cases, immunosuppressive therapies such as
ciclosporin, cyclophosphamide, rituximab, or intravenous immunoglobulin
(IVIG) can be used [1,2]. Cutaneous and systemic involvement can
persist for several weeks to months after drug withdrawal or following
systemic corticosteroid tapering [2,3]. Follow-up is required as
patients can develop autoimmune phenomena or thyroid dysfunction
following DRESS syndrome.
Conclusion
The severity of cutaneous manifestations of DRESS syndrome varies, but
systemic involvement is the main cause of morbidity and mortality and
requires close monitoring during hospitalization. The disease course can
continue to progress even when the triggering drug is discontinued. Some
patients may not respond to oral corticosteroids and require high-dose
intravenous corticosteroid therapy, with disease flares that can also
occur during the steroid dose tapering. Future administration of the
drug-induced DRESS is contraindicated due to the potential risk of
recurrence and complications.