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CASE REPORT
Cyclophosphamide Therapy for Corticoresistant Drug Reaction With
Eosinophilia and Systemic Symptoms (DRESS) Syndrome in a Patient
With Severe Kidney and Eye Involvement and Epstein-Barr
Virus Reactivation
Emilie Laban, MD,1 Eva Hainaut-Wierzbicka, MD,1 François Pourreau, MD,2
Mokrane Yacoub, MD,3 Emilie Sztermer, MD,4 Gérard Guillet, MD,1Guy Touchard, MD,2
and Frank Bridoux, MD, PhD2
DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome is a severe adverse drug
reaction with significant mortality, characterized by erythroderma, fever, lymphadenopathy, and visceral
involvement. We report a case of multivisceral DRESS syndrome with posterior multifocal placoid
pigment epitheliopathy and acute tubulointerstitial nephritis responsible for dialysis-dependent acute
kidney failure in the context of reactivation of Epstein-Barr virus infection. Because of resistance of the
skin and kidney manifestations to prolonged corticosteroid therapy, a 6-month course of oral cyclophosphamide resulted in complete recovery of all symptoms. To our knowledge, this is the first case showing
the efficacy of cyclophosphamide in severe DRESS syndrome.
Am J Kidney Dis 55:e11-e14. © 2010 by the National Kidney Foundation, Inc.
INDEX WORDS: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome; cyclophosphamide; kidney failure; acute interstitial nephritis; posterior multifocal placoid pigment
epitheliopathy.
D
RESS (drug reaction with eosinophilia and
systemic symptoms) syndrome is a rare
and severe drug-induced reaction with systemic
involvement, mainly of the liver, lung, heart, and
pancreas. DRESS syndrome, which also is known
as drug hypersensitivity syndrome, typically appears after a 2- to 6-week exposure to a triggering drug. An increasing number of medications
have been associated with DRESS syndrome,
but most often the condition is triggered by
anticonvulsants, allopurinol, and sulfasalazine.
The mortality rate is estimated at 10%-20%.1
Kidney failure, mainly related to acute tubulointerstitial nephritis, occurs in 10% of cases, with
recovery of kidney function usually obtained
after withdrawal of the causative drug and corticosteroid therapy.2-6
We report a patient who developed corticosteroid-resistant DRESS syndrome with ocular
and severe kidney involvement in the setting of
Epstein-Barr virus (EBV) reactivation. Treatment with cyclophosphamide resulted in complete resolution of symptoms.
CASE REPORT
A 48-year-old white woman was hospitalized for sudden
vision loss and diffuse pruriginous maculopapular erythroderma with facial edema and palate erosions. Clinical examination findings otherwise were normal, with neither lymph-
adenopathy nor fever. Her recent medical history included
depression and recent tendonitis, for which she had used
alprazolam (6 weeks before, for 1 day), fluoxetine (4 weeks
before, for 1 day), and ibuprofen for 2 weeks before admission.
Biological investigations showed hypereosinophilia (eosinophils, 1,700/␮L) and hepatitis (alanine aminotransferase, 87 IU/L; ␥-glutamyl-transpeptidase, 219 IU/L; and
alkaline phosphatase, 270 IU/L). Serum creatinine level was
1.1 mg/dL (97 ␮mol/L). Estimated glomerular filtration rate
(eGFR), calculated using the 4-variable Modification of Diet
in Renal Disease Study equation, was 57 mL/min/1.73 m2
(0.95 mL/s/1.73 m2). Test results for antinuclear, anti-DNA,
and antineutrophil cytoplasmic antibodies and cryoglobulins
were negative. Complement levels were normal.
Ophthalmologic tests showed bilateral decreased visual
acuity (2/10) and anterior uveitis associated with acute
posterior multifocal placoid pigment epitheliopathy
From the Departments of 1Dermatology, 2Nephrology,
Pathology, and 4Ophthalmology, CHU Poitiers, Poitiers,
France.
Received July 17, 2009. Accepted in revised form October
29, 2009. Originally published online as doi:10.1053/j.ajkd.
2009.10.054 on January 28, 2010.
Address correspondence to Frank Bridoux, MD, PhD,
Department of Nephrology, CHU Poitiers, Hôpital Jean
Bernard, 2 rue de la milétrie, 86021 Poitiers, France.
E-mail: [email protected]
© 2010 by the National Kidney Foundation, Inc.
0272-6386/10/5503-0031$36.00/0
doi:10.1053/j.ajkd.2009.10.054
3
American Journal of Kidney Diseases, Vol 55, No 3 (March), 2010: e11-e14
e11
e12
Laban et al
Figure 1. Eye and kidney
lesions. (A) Bilateral ocular
fundi show bilateral acute posterior multifocal placoid pigment epitheliopathy with round
lesions at the posterior pole.
(B) Fluorescein angiography
shows early hypofluorescence
and late progressive impregnation of the lesions. (C, D) Kidney biopsy, light microscopy.
(C) Acute interstitial nephritis
with diffuse inflammatory infiltrate within the cortex (periodic
acid–Schiff; original magnification, ⫻100). (D) Interstitial infiltrate shows numerous plasma
cells, lymphocytes, macrophages, and severely damaged
tubules (hematoxylin and eosin
stain; original magnification,
⫻400).
Fifteen days after admission (Fig 2), the patient developed
severe kidney failure with a creatinine level of 5.1 mg/dL (453
␮mol/L, corresponding to an eGFR of 10 mL/min/1.73 m2
[0.17 mL/s/1.73 m2]), 24-hour urinary protein excretion of
0.22 g, and slight microscopic hematuria, associated with
asymptomatic pancreatitis (lipase, 1,341 IU/L; normal, ⬍60
IU/L; and amylase, 793 IU/L; normal, ⬍100 IU/L). The
eosinophil count was 5,900/␮L. Oral prednisone (1 mg/
kg/d) therapy led to a rapid decrease in serum lipase,
eosinophil, and creatinine levels to 200 IU/L, 1,700/␮L, and
Serum creatinine (µmol/L)
(APMPPE; Fig 1A and B). Intraocular pressure was normal.
A skin biopsy showed vacuolization of epidermal basal
cells, lymphocytic exocytosis, and infiltration of the superficial dermis by mononuclear cells and eosinophils. Direct
immunofluorescence study results were negative.
Ibuprofen therapy was stopped on admission, and 3 intravenous methylprednisolone pulses (500 mg/d) resulted in improvement in skin lesions and correction of biological abnormalities
within 5 days. However, skin eruption relapsed, accompanied
by fever spikes. Blood cultures were negative.
Drug exposure and main clinical
manifestations:
Therapy:
IV corticosteroid pulses (days 2-3)
Figure 2. Course of the
case: drug exposure, clinical
manifestations, and evolution
of kidney function with treatment. Abbreviation: IV, intravenous.
1.
2.
3.
4.
5.
6.
Alprazolam
Fluoxetine
Ibuprofen
Vision loss and erythroderma
Acute myocarditis
General condition recovering
Oral corticosteroids (day 15 to month 6)
IV cyclophosphamide (day 34)
Oral cyclophosphamide (day 51 to month 6)
Dialysis (day 31 to day 56)
Cyclophosphamide in Severe DRESS Syndrome
2.3 mg/dL (203 ␮mol/L; corresponding to an eGFR of 24
mL/min/1.73 m2 [0.40 mL/s/1.73 m2]), respectively. Kidney
and abdominal ultrasound scans were normal.
On day 27, while the patient was receiving 1 mg/kg of
prednisone, she developed asymptomatic electrocardiographic signs characterized by T-wave inversion in the
inferior territory without echocardiographic changes, but
with a serum troponin-T level of 3.5 ␮g/L (normal, ⬍0.01
␮g/L), suggestive of acute myocarditis.
On day 31, serum creatinine level reached 5.7 mg/dL (502
␮mol/L; eGFR, 8 mL/min/1.73 m2 [0.13 mL/s/1.73 m2]). A
kidney biopsy showed acute interstitial nephritis with diffuse interstitial inflammatory infiltrates composed of lymphocytes, plasma cells, macrophages, eosinophils, and neutrophils, focally showing a granulomatous pattern with scattered
giant cells. Proximal and distal tubules showed severe tubulorrhexis. No viral inclusions were observed. Glomeruli,
intrarenal arterioles, and arteries were unremarkable (Fig 1C
and D). Immunohistochemical studies showed a prominent
CD4⫹ T-cell infiltrate admixed with foci of CD8⫹ T cells,
CD68⫹ macrophages, and CD20⫹ B cells. Results of immunofluorescence study with anti-immunoglobulin, C3, C1q,
and C4d conjugates were negative.
Computed tomography of the thorax, abdomen, and pelvis and bone marrow biopsy showed normal findings. Hemodialysis therapy was started on day 31. Prednisone (1 mg/
kg/d) was reinforced on day 34 by 1 intravenous pulse of
cyclophosphamide (750 mg/m2), relayed by oral cyclophosphamide (100 mg/d) on day 51. Dialysis independence was
obtained on day 56.
Analysis of serum for cytomegalovirus and human herpesvirus 6 (HHV-6) DNA using polymerase chain reaction and
tests for hepatitis B, hepatitis C, and HIV were negative.
However, a significant increase in EBV DNA viral load (0.6
log) was detected between weeks 5 and 7 from admission.
EBV immunoglobulin G level was 1,106 U/mL without
detectable EBV immunoglobulin M (Polyantigenic Enzygnost; Dade-Behring, www.dadebehring.com). Results of immunohistochemical studies of the skin biopsy specimen
using a specific anti-EBV latent membrane protein monoclonal antibody (Dako, www.dako.com) were negative.
The patient’s general condition and visual acuity recovered after 3 months. Skin lesions disappeared and kidney
function improved slowly with progressively tapered prednisone dosages and oral cyclophosphamide, which was
stopped after 6 months. EBV viral load became undetectable
at 6 months. Normalization of the eosinophil count was
achieved only after introduction of cyclophosphamide. Ten
months after admission, creatinine level was 1.2 mg/dL (102
␮mol/L) with eGFR of 53 mL/min/1.73 m2 (0.85 mL/s/1.73
m2) and 24-hour urine protein excretion was 0.2 g/d (Fig 2).
DISCUSSION
In the present case, the diagnosis of DRESS
syndrome was established on the association of
eosinophilia, erythroderma, and systemic symptoms, including hepatic, pancreatic, cardiac, and
kidney manifestations. Although a role for alprazolam and fluoxetine was not fully excluded,
e13
ibuprofen was the most likely causative drug.7
Contrasting with the usual manifestations of
DRESS syndrome, the clinical presentation was
marked by severe ocular lesions followed by
dialysis-dependent kidney failure despite rapid
withdrawal of the culprit drugs and steroid
therapy.
Ocular involvement is a rare feature of DRESS
syndrome, with only 2 previously reported cases,
both induced by lamotrigine. Schauer et al8 described a 63-year-old woman with DRESS syndrome, acute bilateral panuveitis, increased intraocular pressure, and decreased visual acuity,
associated with HHV-6 reactivation. Complete
recovery was obtained after withdrawal of the
anticonvulsant drug. Gitteau et al9 reported an
epileptic 19-year-old woman with acute bilateral
vision loss related to APMPPE 4 weeks after the
introduction of lamotrigine therapy. General and
ophthalmologic recovery occurred 6 weeks after
lamotrigine therapy withdrawal and oral prednisone. APMPPE is a rare entity characterized by
bilateral multifocal yellowish-white placoid lesions of the retinal pigment epithelium. It is
associated with various conditions, including systemic vasculitis, sarcoidosis, ulcerative colitis,
streptococcal infections, and after vaccination.10
In the present case, the severe loss in visual acuity
was secondary to both uveitis and APMPPE, without increased intraocular pressure. No infectious
or autoimmune cause was found, and EBV reactivation was diagnosed 5 weeks from the onset of
symptoms. Visual recovery occurred 50 days
after drug withdrawal with corticosteroid plus
cyclophosphamide therapy, suggesting that druginduced hypersensitivity should be considered as
a potential cause of APMPPE.
Kidney involvement in patients with DRESS
syndrome usually is mild, but some patients may
develop severe kidney failure.2-6 As described
here, kidney failure may be delayed and occur
after corticosteroid therapy withdrawal. Kidney
biopsy, rarely performed, shows acute immunoallergic interstitial nephritis associated with tubular necrosis in patients with dialysis-dependent
kidney failure.3,6 In this case, kidney involvement was particularly severe, characterized by
diffuse interstitial inflammation with focal granuloma and extensive acute tubular necrosis, which
probably accounted for the prolonged kidney
failure and resistance to corticosteroid treatment.
e14
Laban et al
DRESS syndrome frequently is associated with
reactivation of HHV, particularly HHV-6, and
less commonly cytomegalovirus and EBV.7,11
However, the pathogenic role of viral infection is
unknown. It has been suggested that reactivation
of herpesvirus may modify drug metabolism,
induce the production of reactive metabolites,
and enhance drug-induced T-cell activation, resulting in the prolonged course and recurrence of
the disease.12 In the present case, EBV replication, which was detected 5 weeks from the onset
and probably was favored by steroid-induced
immunosuppression, might have enhanced the
diffusion and severity of systemic symptoms.
Treatment of DRESS syndrome is based on rapid
withdrawal of the drug implicated as the causative agent, with a delayed stop associated with
poor prognosis. Systemic corticosteroid therapy,
commonly used in patients with severe visceral
involvement, should be used with caution because of the risk of recurrence through viral
reactivation.1,7,11 In the case of steroid-resistant
life-threatening symptoms, in patients with active herpesvirus infection, the indication and
choice of immunomodulating or immunosuppressive therapies is challenging. Various agents,
such as intravenous immunoglobulins12 and cyclosporine,13 have been used successfully. To our
knowledge, the present observation is the first
showing a beneficial effect of cyclophosphamide
in patients with DRESS syndrome. Cyclophosphamide, an alkylating drug capable of slowing
or stopping cell growth of lymphocytes and
polymorphonuclear leukocytes, has shown efficacy in various autoimmune diseases.14 Because
tolerance was good without increased EBV replication, cyclophosphamide deserves to be added
as an effective therapeutic option in DRESS
syndrome with severe systemic and kidney involvement resistant to steroid therapy.
ACKNOWLEDGEMENTS
Support: This work was supported by a grant from AREN
Poitou-Charentes.
Financial Disclosure: The authors declare that they have
no relevant financial interests.
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