DRESS Syndrome in the Differential

Patient Presentation
A 10-year-old female was transferred to a children’s hospital with fever, lymphadenopathy and rash.
She was placed on lamotrigine 6 weeks previously by an adult neurologist for absence seizures after an electroencephalogram was abnormal.
Three weeks ago she developed a pruritic rash on the flexural areas of the knees that quickly spread over her body. The rash initially looked like welts.
The lamotrigine was stopped and antihistamines and prednisone were begun. The rash became more flat but still continued to be erythematous and pruritic.
Eight days prior to admission she began to have fever to 102° F. She also developed a cough and became more tired.
She saw her primary care physician who felt this was a new cold and a chest radiograph was negative.
On day 5 of the fever, she again saw her primary care physician. The cough had resolved.
The physical examination was unchanged with no mucositis and screening laboratory testing including a complete blood count, erythrocyte sedimentation rate and urinalysis were normal.
She had an equivocal rapid strep test and was started on penicillin for possible strep throat after a blood culture was drawn.
On day 8, she had an acute increase in temperature to 106.7° F, and new multiple lymph nodes of 1-2.5 cm in size in the bilateral posterior cervical and anterior cervical chains.
Her local physician transferred her for treatment for possible Kawasaki Disease.
The past medical history revealed some bronchospasm as a preschooler.
The family history was positive for hypothyroidism.
The review of systems was unremarkable with no weight changes or mucositis at any time including dysuria.
The pertinent physical exam showed her to be ill-appearing with a temperature of 39° C. Her other vital signs were normal and growth parameters were between 25-50% for age.
HEENT showed mild generalized swelling of her face. She had no mucositis but her lips were minimally dry. She had no oral or eye changes.
Lymphatic system had cervical lymphadenopathy noted previously, palpable axillary lymphadenopathy bilaterally 1-2.0 cm in size, and groin nodes bilaterally that were 0.5-1.5 cm in size.
Lungs and abdominal examination were normal. Heart showed a Grade II/VI systolic ejection murmur best at lower left sternal border that was consistent with a flow murmur.
Genitourinary examination showed no mucositis.
Skin examination showed generalized erythema over the entire body, with areas that were papular on the trunk and extremities. The rash was pruritic. She had some very mild peeling of the skin on her cheeks but none on her hands.
She had no nailbed or finger/foot changes.
Neurologically she was normal.
The work-up included a erythrocyte sedimentation rate of 33 mm/hr, hemoglobin of 11.6 mg/dl, hematocrit of 34%, and a white blood cell count of 9.7 x 1000/mm2 with 2640 segmented neutrophils, 2816 lymphocytes and 679 eosinophils.
Platelets were 177 x 1000/mm2. The urinalysis was normal as were liver function tests. Testing for Epstein Barr virus, Hepatitis A, Cytomegalovirus, Adenovirus and Mycoplasma were initially sent.
Blood and urine cultures were sent. Because of the significant fever for at least 8-9 days and new development of lymphadenopathy and no obvious cause for the constellation of symptoms, the patient was treated with intravenous immunoglobulin (IVIG) for Kawasaki Disease although the clinical picture and laboratory testing was not completely supportive of this diagnosis.
She was also started on high dose aspirin therapy.
The patient’s clinical course in the 36 hours after IVIG infusion showed continued fevers to 39.3° without resolution of the rash, nor development of mucositis.
She also had a normal echocardiogram.
At 1.5-2 days after IVIG infusion, she now had increasing erythrocyte sedimentation rate to 44 mm/hr, the complete blood count showed a platelet count of 98 x 1000/mm2, and a white blood cell count of 8.8 x 1000/mm2 but with eosinophilia of 2112. Liver function tests showed an aspartate aminotransferase of 1400 U/L, and a alanine aminotransferase of 857 U/L with normal synthetic function.
Previous testing was now negative for all the viruses and cultures and the ASO was pending (later negative). Infectious disease was consulted who agreed not to give another dose of IVIG as her clinical picture looked less like Kawasaki Disease and recommended monitoring her laboratory testing and clinical condition.
Other laboratories were sent to look for an autoimmune problem and other viruses.
On day 3 she had decreased lymphadenopathy and her fever had decreased to 38.0°. Dermatology was consulted and felt her history, physical examination and laboratory testing was consistent with the diagnosis of DRESS syndrome caused by the lamotrigine.
The patient was re-started on prednisone with a slow taper over 1 month time. The next day she was afebrile, her lymphadenopathy was almost gone, the eosinophilia was decreasing and her liver function tests were stable.
She was discharged the following day to follow-up with dermatology in 2 weeks and her regular physician in 2 days. After discussions with her local physician, infectious disease consultant, and family, she was also continued on low dose aspirin treatment until she had a follow-up echocardiogram at 6 weeks.
This was because she had been treated for Kawasaki Disease, and it was felt the aspirin therapy was a low risk compared to possibly undertreating the Kawasaki Disease.
She also had an appointment with a pediatric neurologist to re-evaluate her for possible seizures and the need for continuing an anticonvulsant medication.

Discussion
Kawasaki Disease (KD) is an acute, self-limited vasculitis of unknown etiology.
It is a clinical diagnosis as the etiology is unknown currently.

KD is defined as:

  • Fever of at least 5 days

  • Plus 4 or more of the following:
    • Polymorphous exanthem

    • Bilateral bulbar conjunctival injection without exudate
    • Changes in lips and oral cavity – erythema, cracked lips, strawberry tongue, diffuse injection
    • Cervical lymphadenopathy – more than 1.5 cm, usually unilateral
  • Exclusion of other diseases with similar findings
    • Viral infections – especially adenovirus, enterovirus, Epstein-Barr virus and measles

    • Scarlet fever
    • Staphylococcal scalded skin syndrome
    • Toxic Shock Syndrome
    • Bacterial cervical lymphadenitis
    • Drug hypersensitivity reactions
    • Stevens-Johnson syndrome
    • Juvenile rheumatoid arthritis
    • Rocky Mountain spotted fever
    • Leptospirosis
    • Mercury hypersensitivity reaction
  • Laboratory findings associated with KD include:
    • Leukocytosis with neutrophilia and immature forms

    • Elevated C-reactive protein
    • Elevated erythrocyte sedimentation rate
    • Thrombocytosis after week 1
    • Sterile pyuria

Some patients do not fulfill the full criteria for KD and/or have unusual presentations. The American Heart Association has a scientific statement to assist in evaluation and treatment for these patients. See To Learn More below.

Learning Point
DRESS syndrome, or drug rash with eosinophilia and systemic symptoms was first described by Bocquet et. al. in 1996.
The systemic findings can include lymphadenopathy, abnormal liver or kidney function, pulmonary or cardiac infiltrates and hematological problems (especially eosinophilia and activated lymphocytes).
It was first described with anticonvulsants, especially carbamazepine, phenytoin and phenobarbital, but later described associated with other anticonvulsants and other drugs such as allopurinol, dapsone, lamotrigine, mexiletine, minocycline, nevirapine, sulfasalazine and zonisamide.
It has also been associated with reactivated human herpes virus 6 (HHV-6).

DRESS symptoms begin usually 2-6 weeks after beginning drug therapy and despite discontinuing the medication may continue to have evolving symptoms.
“[C]linical criteria for this syndrome are not present on any given day and that the severity of these clinical symptoms at onset provides only a guide to prognosis and is not absolute: usually patient initially develops two or three features of this syndrome followed by a step-wise development of other symptoms.”Thankfully most symptoms resolve without sequelae over time. Interestingly, lamotrigine is always reported to cause fever in the literature.

DRESS syndrome is a clinical diagnosis and there is some controversy in the literature on what criteria should be used to diagnose it. Some dermatologists believe it would better be called Drug-induced Hypersensitivity Syndrome (DIHS).
A Japanese consensus group developed criteria for what they call DIHS
which includes:

  • Maculopapular rash that occurs more than 3 weeks after starting certain drugs
  • Prolonged clinical symptoms 2 weeks after stopping the drug
  • Fever more than 38° C.
  • Liver enzyme abnormalities (alanine aminotransferase > 100 U/ L), or other organ involvement.
  • At least one leukocyte abnormality = leukocytosis > 11 x 1000/mm2, atypical leukocytosis > 5%, or eosinophilia > 1.5 x 1000/mm2
  • Lymphadenopathy
  • HHV-6 reactivitation

Treatment is usually with IVIG and steroids.

The case patient met 6 of these criteria. HHV-6 was not tested for and therefore could not be used as a criterion.
This patient appeared to be at the intersection of two clinical entities, both of which progress over time.
Therefore it was difficult for the physicians to arrive at the diagnosis of DRESS syndrome early on; in the end it is also difficult to totally exclude the possible diagnosis of Kawasaki Disease.

Questions for Further Discussion
1. What other consultations may be helpful in establishing the diagnosis of Kawasaki Disease or DRESS syndrome?
2. What are the pros and cons of continuing to treat or not treat this patient for Kawasaki Disease?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Information prescriptions for patients can be found at MedlinePlus for these topics: Medicines and Allergy.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

PeyriËre H, Dereure O, Breton H, Demoly P, Cociglio M, Blayac J-P, Hillaire-Buys D. and the Network of the French Pharmacovigilance Centers.
Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.. British Journal of Dermatology, 2006;155(2); 422-428.

Shiohara T, Iijima M, Ikezawa Z, Hashimoto K. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations.
Br J Dermatol. 2007 May;156(5):1083-4.

Newberger JW, Takahasi M, Gerber MA, et. al. Diagnosis, Treatment and Long-term Management of Kawasaki Disease. Circulation 2004;110:2747-2771.Available from the Internet at: http://circ.ahajournals.org/cgi/content/full/110/17/2747 (cited 3/28/05).

ACGME Competencies Highlighted by Case

  • Patient Care
    1. When interacting with patients and their families, the health care professional communicates effectively and demonstrates caring and respectful behaviors.
    2. Essential and accurate information about the patients’ is gathered.
    3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
    4. Patient management plans are developed and carried out.
    5. Patients and their families are counseled and educated.
    7. All medical and invasive procedures considered essential for the area of practice are competently performed.
    8. Health care services aimed at preventing health problems or maintaining health are provided.
    9. Patient-focused care is provided by working with health care professionals, including those from other disciplines.

  • Medical Knowledge
    10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
    11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.

  • Practice Based Learning and Improvement
    12. Evidence from scientific studies related to the patients’ health problems is located, appraised and assimilated.
    13. Information about other populations of patients, especially the larger population from which this patient is drawn, is obtained and used.
    14. Knowledge of study designs and statistical methods to appraisal clinical studies and other information on diagnostic and therapeutic effectiveness is applied.
    15. Information technology to manage information, access on-line medical information and support the healthcare professional’s own education is used.
    16. Learning of students and other health care professionals is facilitated.

  • Systems Based Practice
    24. Cost-effective health care and resource allocation that does not compromise quality of care is practiced.
    25. Quality patient care and assisting patients in dealing with system complexities is advocated.
    26. Partnering with health care managers and health care providers to assess, coordinate, and improve health care and how these activities can affect system performance are known.

    Author
    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa Children’s Hospital

    Date
    March 3, 2008