Article Type : Case Report
Authors : Contreras D, Pecson IS, Galvis AE
Keywords : DRESS syndrome; Eosinophilia; Adverse drug reaction; HHV-6 reactivation; Bactrim adverse reaction
Drug Reaction with Eosinophilia and
Systemic Symptoms (DRESS) is a rare and potentially life-threatening systemic
drug reaction with skin involvement. We present the unusual case of DRESS in a
16-year-old male that was treated with TMP-SMX for acne and was initially misdiagnosed
with Steven Johnson Syndrome. Our case serves as an example to healthcare
providers treating adverse drug reactions to have a high clinical suspicion for
DRESS as delay in diagnosis and treatment can result in disseminated disease
and higher patient mortality risk.
Drug Reaction with
Eosinophilia and Systemic Symptoms (DRESS) is a rare and potentially
life-threating systemic drug reaction with skin involvement. The estimated
incidence is from 1/1,000 to 1/10,000 after drug exposure [1-4]. Common drugs
associated with DRESS syndrome include aromatic anticonvulsants (phenytoin,
phenobarbital, carbamazepine, lamotrigine) and antibiotics (TMP-SMX,
minocycline, vancomycin), along with many other drugs that are continuously
being added to the list of triggers. Symptoms are usually delayed 2-6 weeks
after drug introduction. The classic signs include fever, rash, internal organ
involvement and hematological abnormalities. Although DRESS is more prevalent
in adults than children, it is important to distinguish this syndrome from
other conditions as the mortality rate is 10%. It can be a challenge to arrive
at the correct diagnosis since not all signs and symptoms may be evident at
presentation. In addition, therapy for DRESS is distinct from other T-cell
derived drug reactions [5]. General knowledge of this syndrome would be
beneficial to have when a cutaneous adverse drug reaction is suspected. In this
report, we describe a case of DRESS syndrome secondary to prolonged antibiotic
use of TMP-SMX in a teenage male. Our goal is to emphasize the clinical
presentation of DRESS syndrome, highlight certain unique characters of this
case, and review the diagnostic criteria and management of DRESS syndrome.
A 16-year-old male with a history of mild
intermittent asthma and under a 5-week course of TMP-SMX for acne treatment
presents with a rash. One week prior to admission, he experienced headache,
generalized itchiness, and emesis which prompted him to discontinue TMP-SMX.
Three days prior to admission, he developed an erythematous rash on his chest
and fever. Two days prior to admission, he went to an urgent care where he was
given amoxicillin and a steroid injection. The following day, the rash started
to spread covering about 90% of his body surface area. He was seen at an outside
hospital and was transferred to our hospital for suspected Steven Johnson
Syndrome (SJS). Initial labs included WBC 18.4 x 109 cells/L with segments of
68%, bands 8 %, lymphocytes 6%, monocytes 2%, eosinophils 6%, atypical
lymphocytes 7%, metamylocytes 2%. Absolute eosinophil count (AEC) was 1100.
Total bilirubin 5.1, AST 250, ALT 820 and GGT 265. Physical exam was
significant for diffuse cutaneous lesions in the form of dusky non-blanching
erythematous macules with atypical target-like lesions without desquamation or
blisters. He had bilateral scleral icterus and some oropharyngeal mucosal
involvement, but no conjunctival association. He was started on
methylprednisone for cholestatic hepatitis and concern for SJS. An abnormal
ultrasound showed hepatomegaly of 19 cm. various serological tests were
obtained in an effort to find the cause of the hepatitis. This included viral
panels for cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human
immunodeficiency virus, which were negative. Respiratory viral panel,
autoimmune hepatitis panel and viral hepatitis panel were negative. The
mycoplasma pneumonia antibody was 686 U/ML with mycoplasma pneumonia IgM 1578
U/ML. However, mycoplasma pneumonia PCR was negative. On hospital day 6, WBC
was 20.4 x 109 cells/L with eosinophils 16% and atypical lymphocytes 14%. Total
bilirubin 10, direct bilirubin 7.7, AST 617 and ALT 2333. Due to an AEC of 3200
and atypical lymphocytes, there was a high suspicion for DRESS syndrome. Hence,
a skin biopsy of the right calf was performed, which demonstrated interface
dermatitis with superficial perivascular lymphoid histiocytic infiltrate with
eosinophils and extravasated erythrocytes. In addition, Human Herpes Virus 6
(HHV-6) Qualitative PCR was collected, which later returned positive. After
hospital discharge, there was close follow up and management of an oral steroid
taper by the allergy/immunology and gastroenterology departments (Figure 1).
Diagnostic criteria
There are no standard
diagnostic criteria for DRESS syndrome. However, there are 3 different sets of
criteria that are commonly used (Table 1). Bocquet et al proposed the original
criteria which includes: (1) drug eruption; (2) hematologic abnormalities (i.e.,
eosinophilia > 1.5 x 109 cells/L and the presence of atypical lymphocytes);
and (3) systemic manifestations (i.e., adenopathy with lymph nodes > 2 cm;
hepatitis with transaminase levels twice the normal values, interstitial
nephritis; pneumonitis, and carditis) [6]. In retrospect, our patient met
diagnosis of DRESS upon admission under the Bocquet criteria. In 2007, The
European Registry of Severe Cutaneous Adverse Reactions to Drug and Collection
of Biological Samples (RegiSCAR) developed criteria which contain 7
characteristics of which the first three have to be met in addition to 3 out of
4 subsequent listed features [7]. In 2006, criteria proposed by the Japanese
Research Committee on Severe Cutaneous Adverse Reaction (J- SCAR) group also
comprise 7 standards which are all required for diagnosis of drug induced
hypersensitivity syndrome (DIHS) [8]. Their criteria highlight the role of
HHV-6 reactivation in DRESS syndrome (Table 1).
A retrospective study
comparing the criteria concluded that Bocquet’s criteria are simple to use and
appropriate to diagnose [9,10]. Furthermore, it was suggested to use in
conjunction the RegiSCAR criteria when suspecting DRESS. Interestingly, our
patient satisfied 6 out of 7 RegiSCAR criteria, 6 of 7 for J-SCAR and all for
Bocquet’s. The drug of suspicion was of the sulfonamide class, which is a known
trigger. The most common organ involved was the liver. He was also positive for
HHV-6, which is linked to DRESS and noted by J-SCAR criteria [6]. The most
common skin biopsy findings were perivascular lymphocytic infiltrate in the
papillary dermis with extravasated erythrocytes, eosinophils and dermal edema,
which our patient also demonstrated [3].
Pathogenesis
DRESS is believed to be an erroneous drug hypersensitivity reaction occurring in 2.18 out of 100,000 patients [11]. These patients are believed to have very reactive type II innate lymphoid cells that produce high levels of ST2, which in turn initiate the classical DRESS skin eruptions [12]. It has also been suggested that reactive drug metabolites may mediate immune response and induce reactivation or propagation of HHV-6 [9]. The association between HHV-6 active infection and cutaneous drug adverse reactions seems to be specific to DRESS. A prospective study showed that DRESS is a result of cutaneous and systemic manifestation of an immune response, mainly mediated by CD8+ T lymphocytes directed against herpes virus antigens which include (HHV-6, HHV-7, EBV and CMV) [10]. This is supported by the clinical features of DRESS which are consistent with viral infection. It has been proposed that testing for herpes virus activation be done for suspected cases as an aid in diagnosis. The main feature of HHV-6 is the virus capacity to infect T-cells. There have also been indications that specific human leukocyte antigen (HLA) variants may also put certain people at increased risk [1].
Table 1: The 3 most commonly used diagnostic criteria for DRESS [4,7,10].
Bocquet |
RegiSCAR |
J- SCAR |
Skin Eruption |
Skin eruption |
Maculopapular rash developing > 3 weeks after
starting offending drug |
blood eosinophilia
(>1.5×103/µL) or the presence of atypical lymphocytes |
Reaction suspected to be drug related |
Prolonged clinical symptoms after discontinuation of
causative drug |
Internal organ
involvement, including lymphadenopathies (>2 cm in diameter), hepatitis
(liver transaminases values > twice the upper normal limit), interstitial
nephritis, and interstitial pneumonia or carditis |
Hospitalization |
Fever (> 38 C) |
|
Fever (> 38 C) |
Liver abnormalities (ALT > 100 U/L) or other
internal organ involvement |
|
Lymphadenopathy involving 2 sites |
Leukocytosis, Atypical lymphocytosis and
Eosinophilia |
|
Involvement of at least 1 internal organ |
Lymphadenopathy |
|
Hematologic abnormalities (abnormal lymphocyte
count, eosinophilia or thrombocytopenia) |
HHV-6 reactivation |
The first step in treatment is to stop the suspected offending agent. It is important to take a detailed history as the patient may be taking different drugs. Thus, having a timeline of when signs and symptoms began is helpful as to distinguish SJS, TEN, AGEP and erythroderma from that of DRESS, considering each have a typical onset time of the skin eruption. In addition, knowing the other characteristic findings for each is also important (Table 2).
Table 2: Comparison of various severe cutaneous adverse reactions [7-8].
|
AGEP |
Erythroderma |
SJS |
TEN |
Time of onset |
48 hours |
1-3 weeks |
Days- 3 weeks |
Days to 3 weeks |
Skin manifestations |
Edema, pusutles, tense bullae |
Erythema and scaling of > 90% of BSA |
Dusky erythema, atypical target lesions ( < 10% of BSA) and mucocutaneos erosions |
Dusky erythema, atypical target lesions, erosions and bullae ( >
30% of BSA), mucosal involvment |
Systemic involvement |
Possible |
Possible |
Fever, malaise, tubular nephritis |
Fever, malaise, tubular nephritis, eye involvement, tracheobronchial
necrosis |
Therapy with systemic corticosteroids is the most widely accepted treatment [5]. Although no controlled studies have been published to date, improvement of symptoms and laboratory values are seen days after initiation of steroids. It is important to note that rash and hepatitis may still persist for weeks. Once outpatient status occurs, it has been recommended to undergo a prolonged steroid taper and appropriate lab monitoring.
Our case was a
diagnostic challenge as it originally presented without appreciating the
peripheral eosinophilia (consisting of an AEC of 1100) and with a molliform
rash with irregular borders that mimicked the outer edge of a target lesion,
leading to an initial diagnosis of SJS. The challenge with diagnosing DRESS on
initial presentation is that several cutaneous adverse drug reactions have
similar characteristics and lower DRESS incidence in children. However, having
general knowledge of the syndrome and becoming familiar with the proposed
criteria can aid in the prompt diagnosis. For instance, our case consisting of
morbilliform components are not entirely consistent with SJS. Moreover, our
patient presented with hepatitis which is much more consistent with DRESS and
is rarely seen in SJS. This case also supports the ongoing research of the
association of HHV-6 reactivation and DRESS syndrome. In conclusion, it would
be advantageous for pediatricians to be aware of the diagnostic criteria of
this potential life-threating drug reaction and the how to manage it.
The authors declare
that they have no financial relationships relevant to this article to disclose.
No external funding was
received for this study.
The authors declare
that they have no potential conflicts of interest to disclose.
The authors would like
to thank Dr. Mary Beth Hogan MD for proofreading and editing suggestions for this
article.
Patient consent was
obtained. Institutional Review Board review is not required for this activity,
for, as a case report, this work neither produces generalizable knowledge nor
is it an investigation of a US Food and Drug Administration-regulated product.