Acta Clin Croat 2010; 49:479-484

Case Report

DRESS Syndrome with Mild Manifestations as a

Diagnostic and Therapeutic Problem:
Case Report
Marinko Artukovi1, Josipa Kutelega1 and Liborija Lugovi-Mihi2

1
University Department of Internal Medicine, Sveti Duh University Hospital; 2University Department of Derma-
tology and Venereology, Sestre milosrdnice University Hospital, Zagreb, Croatia

SUMMARY The group of severe cutaneous drug reactions with systemic symptoms includes
several syndromes: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exant-
hematous pustulosis, and drug reaction with eosinophilia and systemic symptoms (DRESS). These
reactions occur several days to six weeks after introducing the incriminating drug. The skin and
internal organs (liver, kidneys, lungs, etc.) are usually involved. A great possibility of lethal outco-
me is a critical characteristic of these syndromes. A patient with pyelonephritis diagnosed during
emergency room workup is described. Ciprofloxacin was prescribed and the patient was discharged.
After ten days, the patient came back with worsening condition, general inflammatory response,
skin changes, liver and kidney damage, and eosinophilia. DRESS syndrome was diagnosed based
on clinical and other findings. The diagnosis and treatment of severe drug reactions with cutaneous
and systemic symptoms pose a medical challenge.
Key words: Drug hypersensitivity prevention and control; Drug eruptions etiology; Drug eruptions
diagnosis; Drug eruptions therapy

Introduction less extensively affecting the skin and thus having

lower mortality (5%-15%). On the other hand, reac-
Severe forms of cutaneous drug reactions associat- tion called drug reaction with eosinophilia and sys-
ed with systemic symptoms are one of the biggest di-
temic symptoms (DRESS), which is a form of hyper-
agnostic and treatment challenges in allergology. Such
sensitivity syndrome, has a mortality of about 10%1.
reactions usually start several days to six weeks after
One more syndrome should also be mentioned, i.e.
drug introduction. They occur in the form of changes
acute generalized exanthematous pustulosis (AGEP)
on the skin and internal organs (liver, kidneys, lungs,
caused by medication. Unless properly treated, it is as-
etc.). Among severe cutaneous drug reactions with
sociated with a mortality of up to 5%. AGEP is char-
systemic symptoms, toxic epidermal necrolysis (TEN)
acterized specifically by hundreds or even thousands
is emphasized because of the highest mortality rate
(30%-35%). There also are Stevens-Johnson syndrome of sterile, non-follicular pustules2,3.
(SJS) and transitional forms, all similar to TEN, but The SJS-TEN is usually induced by a medication.
Nevertheless, other etiologies should also be taken
into consideration, e.g., graft versus host disease.
Correspondence to: Marinko Artukovi, MD, Department of Cli- There are reports on several cases of SJS-TEN associ-
nical Immunology, Rheumatology and Pulmonology, Sveti Duh
University Hospital, Sveti Duh 64, HR-10000 Zagreb, Croatia ation with infections (Mycoplasma pneumoniae), while
E-mail: [email protected] in some cases the etiology remained unexplained1.
Received August 6, 2010, accepted September 27, 2010 The SJS-TEN is most commonly associated with the

Acta Clin Croat, Vol. 48, No. 3, 2009 479

M. Artukovi et al. DRESS syndrome with mild manifestations as a diagnostic and therapeutic problem: Case report

usage of certain drugs, e.g., sulfonamides, anticon- The pathophysiology of DRESS and SJS-TEN
vulsants, some nonsteroidal anti-inflammatory drugs is similar. It is a drug-induced immune reaction, an
(NSAIDs) and allopurinol1. Rarely, SJS-TEN is de- allergic hypersensitivity reaction type IV. Some au-
scribed as a consequence of antiresorptive therapy, thors consider the possibility of enzyme defects (slow
particularly alendronate. Also, there is a significantly acetylators) in the metabolism14. Full complexity of
increased risk for the development of this syndrome the immunopathogenesis in DRESS syndrome is best
in HIV infection and autoimmune diseases (e.g., sys- illustrated through a two-way relationship with au-
temic lupus erythematosus)1,4. toimmune diseases. Autoimmunity increases the risk
When it comes to AGEP and the incriminat- of DRESS syndrome, while DRESS can lead to the
ing drugs, the main cause of AGEP are antibiotics, occurrence of autoimmune reaction15,16. A common
in particular beta-lactams and macrolides; however, factor for this bilateral connection could be viral coin-
other etiologies are possible, such as viruses (B19 and fection (especially herpesvirus reactivation, HHV6,
enterovirus), mercury, bite of a spider, or other medi- EBV)17-19.
cations3. Inflammatory response in patients with DRESS
DRESS syndrome is also known as a drug induced usually begins with high or low fever. The patient de-
hypersensitivity syndrome (DIHS). Generally, it is a velops maculopapular skin rash, lymphadenitis and
reaction to the medication. DRESS is clinically de- pharyngitis in the next day or two19,20. Then there
fined by a triad of symptoms including fever, skin rash, are organosystemic manifestations, most commonly
and internal organ involvement that can be symptom- hepatitis, eosinophilia, blood dyscrasias and nephritis.
atic or asymptomatic. The most common organs in- The presence of three of these criteria is sufficient to
volved are the liver, kidneys and lungs5. Eosinophilia diagnose DRESS syndrome. Other possible findings
(1500/mL) is an obligatory laboratory finding in in DRESS patients include pneumonitis, hepatosple-
DRESS syndrome6. Leukocytosis and lymphocytosis nomegaly, oral ulcers, exudative tonsillitis, strawberry
are also common5. tongue, periorbital or facial edema, myopathy, flu-like
Such reactions to drugs are known for a long time. symptoms, disseminated intravascular coagulopathy,
For instance, the anticonvulsant hypersensitivity syn- colitis, and hypothyroidism5.
drome (AHS) was first described in 1950 by Chaiken Although the diagnosis can be set by lymphocyte
et al.7. In 1996, Bocquel et al. proposed the acronym transformation test and patch test, DRESS is mainly
DRESS for drug reaction with eosinophilia and sys- diagnosed by the time of onset (the time elapsed from
temic symptoms, a syndrome that unites numerous taking the medication to the occurrence of disease),
syndromes, also drug reactions with common char- clinical examination, laboratory tests, and recovery
acteristics: AHS, dapsone syndrome, etc.5,8. There- after the culprit drug discontinuation5. Sometimes
fore, DRESS syndrome is nowadays a frequently used additional diagnostic tests may be required.
term. When DRESS is timely and appropriately treated,
The incidence of DRESS syndrome remains un- organ damage can usually be reversed and the func-
clear. Because of the variable presentation along with tion of affected organs fully restored. For example,
various clinical and laboratory findings, proper rec- acute interstitial nephritis will spontaneously regress
ognition of the syndrome is very difficult and routine within weeks, if the precipitating agent is removed 21.
term utilization is not possible without uniformly ac- Early diagnosis, etiology determination and im-
cepted criteria. mediate discontinuation of suspect drug are most im-
As in SJS-TEN, in DRESS syndrome cutane- portant in therapeutic process. Development of this
ous lesions and systemic disorders occur due to the type of allergic reactions to drugs should be suspected
drug taken. DRESS is most often associated with at the first glance to skin or mucosa changes, mostly
anticonvulsants, sulfonamides, dapsone, allopurinol, associated with the use of anticonvulsants, sulfon-
minocycline and gold salts1,9,10. Some publications de- amides, allopurinol, or (in rheumatology) NSAIDs
scribe rare occurrence of this syndrome as a response and very rarely antiresorptive therapy. In therapeutic
to NSAIDs, quinolones, and antiresorptive drugs terms, it is crucial to stop the responsible medica-
(strontium ranelate)11-13. tion. In general, treatment of these allergic reactions

480 Acta Clin Croat, Vol. 49, No. 4, 2010

M. Artukovi et al. DRESS syndrome with mild manifestations as a diagnostic and therapeutic problem: Case report

to drugs is symptomatic. In severe cases, treatment is general symptoms despite regression of dysuric prob-
carried out in intensive care units, according to the lems. New signs appeared including feeling of weight
principles of skin burn management: warm environ- in the muscles, itching, and mild exanthema mainly
ment, electrolyte disbalance correction, parenteral on the trunk skin and upper extremities, without
hyperalimentation and prevention of sepsis1. It is dif- mucosal ulceration. The patient was still subfebrile.
ficult to assess the efficacy of drugs described in some Laboratory findings showed an increase in leukocyte
case reports: intravenous immunoglobulin (IVIG), count (L 28x109/L), primarily on the account of eo-
cyclosporine, cyclophosphamide, pentoxifylline, and sinophilia (Eo 17.80x109/L, 63.5%) (Fig. 1), and in
thalidomide. Questionable is the use of corticoster- liver enzymes (AST 71.5 IU/L, ALT 104.4 IU/L, AP
oids in severe forms of TEN. In DRESS syndrome, 321 IU/L, GGT 119 IU/L) (Fig. 2); protein immuno-
corticosteroids may be useful to manage damage to electrophoresis yielded elevated levels of IgE (368 IU/
internal organs (hepatitis, nephritis, pneumonitis)1. mL). Leukocyturia and erithrocyturia persisted, with
The use of the mentioned treatment measures is as- 60% of dysmorphic and 40% of smooth red blood
sociated with mortality reduction and faster re-epi- cells. Escherichia coli was isolated from urine.
thelialization of skin lesions. These findings brought into question the efficacy of
In the future, the patient should completely avoid current therapy. Changes were indicative of possible
usage of the incriminating drug, even in allergic test- medication side effects, i.e. ciprofloxacin as a newly
ing. introduced drug still used. Therefore, ciprofloxacin
was removed from therapy. Amoxicillin with clavu-
Case Report lanic acid and mebendazole were introduced instead
of ciprofloxacin. There was a decrease in eosinophil
A female patient aged 57 presented to internal count (Eo 12.70x109/L, 57.6%) two days after cipro-
emergency clinic for the left lumbar pain. Clinically, floxacin discontinuation. Shortly after, the itch and
she had fever, chills, shivering and dysuria. Laboratory skin rash spontaneously regressed, and the patients
findings and abdominal ultrasonography verified the general condition improved. In the next two months,
clinical diagnosis of acute left-side pyelonephritis with eosinophil count and liver enzyme levels gradually de-
ipsilateral nephrolithiasis. Urine microbiology showed creased until final follow up values of Eo 1.11x109/L
Enterococcus faecalis. The patient was discharged with (14.9%) (Fig. 1), AST 17 IU/L, ALT 25.8 IU/L, AP
recommendation for ciprofloxacin therapy for 10 days, 107 IU/L, and GGT 37 IU/L (Fig. 2). There were
abundant rehydration, diclofenac and paracetamol as 100% of dysmorphic erythrocytes in the urine. Re-
needed. peat abdominal ultrasonography showed a wider
After 10 days of the introduction of ciprofloxacin, prominent pyramid in the left kidney, meaning that
the patient presented for follow up with worsening of the inflammation led to permanent damage.

Fig. 1. Trends in the number of eosinophils in circulating blood. Fig. 2. Changes in the levels of liver enzymes.

Acta Clin Croat, Vol. 49, No. 4, 2010 481

M. Artukovi et al. DRESS syndrome with mild manifestations as a diagnostic and therapeutic problem: Case report

Additional serology did not confirm the presence lecting additional history data on the occurrence and
of viral or parasitic infection agents. Analysis of pe- diagnostic analysis, DRESS was suspected and subse-
ripheral blood smear yielded normal findings, except quently confirmed. Timely elimination of ciprofloxa-
for the still present mild eosinophilia, which was on cin prevented progression of the disease. The lesions
a decline. According to MSCT of the abdomen and regressed spontaneously, confirming the diagnosis.
values of tumor markers that were within the nor- Such mild forms of DRESS syndrome have already
mal limits, tumor etiology of eosinophilia was ruled been reported in the literature20. However, the mild
out. Additional studies for autoimmune etiology have form of skin reactions should not mislead us. Involve-
been planned. ment of the kidneys and liver, together with signifi-
The clinical symptoms in our patient regressed cant eosinophilia, were crucial in establishing the cor-
short after discontinuation of the culprit drug, so she rect diagnosis in our patient. Considerable difficulties
did not require differential treatment. Laboratory encountered on setting up the diagnosis impose the
findings normalized short after drug discontinuation, question of the actual prevalence of the disease.
only kidney function recovered gradually, over several In terms of pathophysiology, this reaction with
weeks. The patient has been referred for regular fol- maculopapular exanthema and eosinophilia in DRESS
low up of liver and kidney function, with additional is hypersensitivity reaction type IV, i.e. the mecha-
diagnostic workup that will rule out the possible dis- nism of cellular immunity22. Thereby, development of
ease of other target organs. She was advised to avoid DRESS includes Th2-lymphocytes and CD8+ cells20.
using ciprofloxacin for either diagnostic or therapeutic It is likely that Th2 cells induce type IVb hypersensi-
purpose in the future. A year after the occurrence of tivity response affecting the skin, while CD8+ T cells
DRESS syndrome, the patient was free from recur- cause damage to internal organs23.
rence. Study results have shown the mortality of DRESS
syndrome to be 10%22. It should be noted that liver in-
volvement is a poor prognostic sign, and together with
Discussion
icteric pruritus predicts the possible fatal outcome in
Regarding the severe systemic drug reactions with 20% of patients20. Early elimination of the causal drug
skin manifestations, one should always bear in mind results in better patient prognosis. Unfortunately, the
the possibility of reaction to the medication the patient factors that determine the severity of organ failure
has been taken; therefore, adequate information on it or the number of affected organs remain unknown,
should be taken from the patient. Sometimes it is dif- although the potential role of genetic factors is con-
ficult to distinguish types of drug reactions, especially sidered. Therefore, according to some authors, close
when there is an overlap of symptoms. In DRESS, patient relatives should avoid the same drug too22.
the most important laboratory finding is eosinophilia, Some authors believe that systemic corticosteroid
which distinguishes it from other severe systemic drug therapy is required in DRESS syndrome1. The rec-
reactions with skin manifestations22. Besides DRESS, ommended dose is prednisolone 40-60 mg/day for
another possible manifestation of drug reaction is SJS/ at least 6-8 weeks to avoid symptom relapse. In our
TEN, characterized by the presence of blisters (SJS patient, we did not use systemic steroids, but only
<10% and TEN >30% of total body surface area). In supportive therapy, rehydration, given that changes
most of these patients, the lining of the mouth, con- gradually regressed spontaneously. However, no ran-
junctiva, and genitals is affected. TEN also affects domized placebo-controlled study supports or rejects
areas on the inner epithelium surfaces (lung, gastro- this opinion 20,22. Several cases have been described of
intestinal tract), and multiple organ failure may occur, patients with DRESS and extensive internal organ
as in DRESS. TEN and DRESS may occasionally involvement, such as fulminant hepatitis, responding
have similar clinical presentation. Our patient had a favorably to systemic corticosteroids24. Taking into ac-
mild skin reaction, differentially presented in many count the respective therapy side effects (particularly
diseases and syndromes. Although the clinical picture infection and sepsis), we believe that systemic corti-
of her skin changes seemed insignificant, after col- costeroids are justified in severe forms of DRESS.

482 Acta Clin Croat, Vol. 49, No. 4, 2010

M. Artukovi et al. DRESS syndrome with mild manifestations as a diagnostic and therapeutic problem: Case report

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Mild forms of DRESS, as in our patient, in gen- tium ranelate and DRESS syndrome put into perspective.
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Saetak

sindrom DRESS s blagim manifestacijama kao dijagnostiki i terapijski problem:

Prikaz sluaja

M. Artukovi, J. Kutelega i L. Lugovi-Mihi

Teke oblike konih reakcija na lijekove povezanih sa sistemskim simptomima ini nekoliko sindroma: toksina epi-
dermalna nekroliza, Stevens-Johnsonov sindrom, akutna generalizirana egzantematozna pustuloza te reakcija na lijekove s
eozinofilijom i sistemskom reakcijom (DRESS). Kod takvih reakcija se nekoliko dana do 6 tjedana od uvoenja lijeka po-
jave promjene na koi, a esto su zahvaeni i unutarnji organi (jetra, bubrezi, plua i dr.). Zbog toga je u ovakvim oblicima
preosjetljivosti na lijekove velika smrtnost. Opisuje se sluaj bolesnice kojoj je ambulantno dijagnosticiran pijelonefritis,
te je bila otputena kui uz preporuku terapije ciprofloksacinom. Deset dana kasnije bolesnica se vratila u ambulantu s
pogoranjem klinike slike, loeg opeg stanja, uz pojavu konih eflorescencija, oteenje jetrene i bubrene funkcije te s
eozinofilijom. Na temelju klinikih nalaza i ostale obrade postavljena je dijagnoza sindroma DRESS. Dijagnoza i terapija
tekih oblika reakcija na lijekove i u dananje vrijeme predstavljaju medicinski izazov.
Kljune rijei: Preosjetljivost na lijekove prevencija i kontrola; Erupcije uzrokovane lijekovima etiologija; Erupcije uzro-
kovane lijekovima dijagnostika; Erupcije uzrokovane lijekovima - terapija

484 Acta Clin Croat, Vol. 49, No. 4, 2010