Granulomatous interstitial nephritis associated with atypical drug-induced hypersensitivity syndrome induced by carbamazepine.
ABSTRACT We report the case of a 70-year-old female patient with granulomatous interstitial nephritis (GIN) induced by carbamazepine (CBZ). The patient had a 22-year history of bipolar disorder. Approximately 50 days before admission to our hospital, she was switched from valproic acid to 200 mg/day CBZ for mood swings. Forty days later, she presented with mild transient platelet depletion and liver dysfunction along with a C-reactive protein (CRP) level of 2.65 mg/dL. At that time, she discontinued CBZ without consulting the doctor. She subsequently developed high fever and a pruritic maculopapular rash. Laboratory tests revealed an elevated CRP level (11.98 mg/dL) and serum creatinine (sCr) of 1.6 mg/dL. Hence, she was admitted to our hospital, where she showed eosinophilia and immunoglobulin suppression. She was diagnosed with atypical drug-induced hypersensitivity syndrome (DIHS). All drugs prescribed by the previous doctor were discontinued. A lymphocyte transformation test showed CBZ positivity; a renal biopsy revealed many granulomatous lesions connected to arterioles, without angionecrotic findings. The patient had no history of allergic disorders or tuberculosis. Because of psychological instability, we treated her conservatively without steroid administration. She had a good recovery except for mild residual renal insufficiency (sCr, 1.0 mg/dL). Although granuloma formation has been observed in kidney biopsy specimens of rare cases with DIHS, no previous studies have reported on the relationship between arterioles and granuloma formation.
Article: Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpesviruses and antiviral and antidrug immune responses.[show abstract] [hide abstract]
ABSTRACT: A relationship between viral infections and the simultaneous or subsequent development of allergic inflammation has often been observed in various clinical situations. Recent studies suggest an intimate relationship between reactivations of herpesviruses including human herpesvirus 6 (HHV-6) and the development of a severe systemic hypersensitivity reaction referred to as drug-induced hypersensitivity syndrome (DIHS). This syndrome has several important clinical features that cannot be solely explained by drug antigen-driven oligoclonal expansion of T cells: they include paradoxical worsening of clinical symptoms after discontinuation of the causative drug. In view of the similarity to GVHD or immune reconstitution syndrome (IRS) in clinical manifestations and emergence of viral infections, the clinical symptoms observed during the course of DIHS and GVHD are likely to be mediated by antiviral T cells that can cross-react with the drug and alloantigens, respectively. In considering common intrinsic properties of the causative drugs to potentially induce immunosuppression, reconstitution of a valid immune response to these viruses, which is typically observed in IRS, may be the most crucial process that takes place after withdrawal of the causative drug in patients with DIHS. Thus, this syndrome should be regarded as a reaction induced by a complex interplay among several herpesviruses (EB virus, HHV-6, HHV-7, and cytomegalovirus), antiviral immune responses, and drug-specific immune responses. This review includes discussion of the pathomechanism, the clinical symptoms, laboratory findings, pathological findings and therapy.Allergology International 04/2006; 55(1):1-8.
Article: The variable clinical picture of drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms in relation to the eliciting drug.[show abstract] [hide abstract]
ABSTRACT: Drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) is a life-threatening adverse reaction characterized by skin rashes, fever, leukocytosis with eosinophilia or atypical lymphocytosis, lymph node enlargement, and liver or renal dysfunction. The syndrome develops 2 to 6 weeks after initiation of administration of a specific drug. It has been demonstrated that various herpesvirus reactivations, in addition to human herpesvirus 6, contribute to internal organ involvement and the relapse of symptoms observed long after discontinuation of the causative drugs. A better understanding of the interplay in the development of DIHS/DRESS has implications for safer and more efficient treatment of this syndrome.Immunology and allergy clinics of North America 09/2009; 29(3):481-501. · 3.18 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Every new drug has the potential for causing cutaneous adverse drug reactions. Usually the clinical pattern is well known and has been described in association with other drugs; new entities, however, are described frequently. This article reviews several of them.Dermatologic Clinics 11/2001; 19(4):697-709, ix. · 2.16 Impact Factor
Granulomatous interstitial nephritis associated with atypical
drug-induced hypersensitivity syndrome induced
Eriko Eguchi•Keiji Shimazu•Kensuke Nishiguchi•
Soushi Yorifuji•Atsuo Tanaka•Takashi Kuwahara
Received: 23 April 2011/Accepted: 22 August 2011/Published online: 23 September 2011
? The Author(s) 2011. This article is published with open access at Springerlink.com
patient with granulomatous interstitial nephritis (GIN)
induced by carbamazepine (CBZ). The patient had a
22-year history of bipolar disorder. Approximately 50 days
before admission to our hospital, she was switched from
valproic acid to 200 mg/day CBZ for mood swings. Forty
days later, she presented with mild transient platelet
depletion and liver dysfunction along with a C-reactive
protein (CRP) level of 2.65 mg/dL. At that time, she dis-
continued CBZ without consulting the doctor. She subse-
quently developed high fever and a pruritic maculopapular
rash. Laboratory tests revealed an elevated CRP level
(11.98 mg/dL) and serum creatinine (sCr) of 1.6 mg/dL.
Hence, she was admitted to our hospital, where she showed
eosinophilia and immunoglobulin suppression. She was
diagnosed with atypical drug-induced hypersensitivity
syndrome (DIHS). All drugs prescribed by the previous
doctor were discontinued. A lymphocyte transformation
test showed CBZ positivity; a renal biopsy revealed many
granulomatous lesions connected to arterioles, without
angionecrotic findings. The patient had no history of
allergic disorders or tuberculosis. Because of psychological
instability, we treated her conservatively without steroid
administration. She had a good recovery except for mild
residual renal insufficiency (sCr, 1.0 mg/dL). Although
granuloma formation has been observed in kidney biopsy
specimens of rare cases with DIHS, no previous studies
We report the case of a 70-year-old female
have reported on the relationship between arterioles and
Drug-related rash with eosinophilia and systemic
symptoms ? Granulomatous interstitial nephritis ?
Granuloma ? Carbamazepine
Drug-induced hypersensitivity syndrome ?
Drug-related rash with eosinophilia and systemic symp-
toms (DRESS) or drug-induced hypersensitivity syndrome
(DIHS) is a life-threatening multiorgan systemic reaction
characterized by rash, fever, lymphadenopathy, hepatitis,
and leukocytosis with eosinophilia . These conditions
are caused by a limited number of drugs, including car-
bamazepine, phenytoin, phenobarbital, zonisamide, allo-
purinol, dapsone, salazosulfapyridine, and mexiletine .
Renal dysfunction associated with DIHS/DRESS has
been reported to occur in 10% of cases and is attributable to
acute interstitial nephritis (AIN) [2, 3]. In rare cases with
DIHS, granuloma formation has also been described, i.e.,
granulomatous interstitial nephritis (GIN) [4–6].
Here we describe the case of a patient with bipolar
disorder and biopsy-proven GIN that developed during the
course of carbamazepine-induced DIHS/DRESS.
A 70-year-old woman was admitted to our hospital because
of high fever and acute kidney injury. She had been visiting
a psychiatric clinic for bipolar disorder since the age of
48 years and another medical clinic for mild hypertension
E. Eguchi (&) ? K. Shimazu ? K. Nishiguchi ? S. Yorifuji ?
A. Tanaka ? T. Kuwahara
Department of Nephrology, Saiseikai Nakatsu Hospital,
2-10-39 Shibata, Kitaku, Osaka, Osaka 530-0012,
Clin Exp Nephrol (2012) 16:168–172
since the age of 63 years. She had no history of allergic
disorders or tuberculosis.
Approximately 50 days before admission, she was
switched from valproic acid to 200 mg/day carbamazepine
(CBZ) for mood swings. Approximately 40 days after ini-
tiation of CBZ, she presented with purpura on the legs. She
visited her regular physician. Laboratory analyses revealed
platelets of 10.6 9 104/lL, aspartate aminotransferase
(AST) of 62 IU/L, alanine aminotransferase (ALT) of
107 IU/L, C-reactive protein (CRP) of 2.65 mg/dL, and
serum creatinine (sCr) of 0.76 mg/dL. Tranexamic acid
(750 mg/day) and levofloxacin (LVFX, 300 mg/day) were
prescribed. At that time, she discontinued CBZ without
consulting her doctor. Three days later, she developed fever
of[38?C, although the purpura had disappeared. She vis-
ited our hospital, where laboratory results showed an
increased platelet count (12.8 9 104/lL), slightly deterio-
rating liver dysfunction (AST, 70 IU/L; ALT, 123 IU/L),
and an elevated CRP level (4.7 mg/dL). We suspected some
viral infection as the cause of her symptoms and bed rest
was prescribed. Four days after the onset of fever, a pruritic
maculopapular rash appeared on the trunk and extremities.
Because of the prolonged high fever and an elevated CRP
level (7.13 mg/dL), she was referred to our hospital again.
Laboratory tests revealed deteriorating renal function (sCr,
1.6 mg/dL) without urinalysis abnormalities and a further
elevated CRP level (11.98 mg/dL), although liver function
improved (AST, 14 IU/L; ALT, 41 IU/L). She was hospi-
talized the next day.
On admission, her blood pressure was 130/70 mmHg,
pulse rate was 68 beats/min, and body temperature was
38.2?C. A diffuse skin rash was present on the trunk and
limbs. The chest, heart, and abdominal findings were
unremarkable. No superficial
swelling of the joints were observed.
Laboratory data on admission revealed eosinophilia and
immunoglobulin (Ig) suppression with no evidence of
paraproteinemia (Table 1). Complement levels were nor-
mal. Renal ultrasonography revealed symmetrical and
unobstructed kidneys with normal cortical echotexture.
Computed tomography findings of chest and abdominal
were unremarkable. No ophthalmological complications
As systemic drug allergy was suspected, all drugs pre-
scribed by the previous doctor were discontinued. The
lymphocyte transformation test showed CBZ positivity and
LVFX negativity;CBZ was therefore considered to be the
causative drug. Reactivation of human herpes virus
(HHV)-6 and HHV-7 was not detected. The patient was
diagnosed with DRESS and atypical DIHS because she
fulfilled all three criteria for DRESS diagnosis and five
of the seven criteria for DIHS diagnosis, which were as
follows: maculopapular rash developing approximately
6 weeks after initiation of CBZ, prolonged clinical symp-
toms 2 weeks after discontinuation of CBZ, fever[38?C,
renal dysfunction, and eosinophilia [2, 11].
insomnia and nocturnal delirium. Psychiatric consultation
disclosed a hypomanic state. Because her physical symp-
toms had not worsened, we decided to treat her conserva-
tively without steroids.
The general condition of the patient improved with
conservative therapy (Fig. 1). Approximately 10 days after
admission, her temperature returned to normal and the skin
rash disappeared. Approximately 10 days later, eosino-
philia improved and CRP levels normalized.
A renal biopsy was performed 11 days after admission
(Figs. 2, 3). Eight glomeruli were evident; one was scle-
rosed and the remaining were almost normal. The inter-
stitium showed patchy infiltration of inflammatory cells
and non-caseating granulomas with multinucleated giant
cells connected to some arterioles. The findings of an
immunofluorescent study were non-specific. The patient
was diagnosed with acute GIN.
One month after admission, the sCr level decreased to
1.0 mg/dL and Ig levels returned to normal.
Although olanzapine and lorazepam were administered
to control the hypomanic state, they were poorly tolerated
because of episodes of akathisia. Eventually, administra-
tion of Yokukansan, which is a traditional Chinese herb,
resulted in a reasonably stabilized mood without side
The patient was discharged and remained in a stable
condition throughout follow-up.
GIN is a relatively rare histological diagnosis, comprising
only a small proportion of all renal biopsies [7–10].
Common causes of GIN are drugs, sarcoidosis, infections,
and Wegener’s granulomatosis; drugs account for 25–45%
of GIN cases [7–10]. Medications associated with GIN
include anticonvulsants, antibiotics, non-steroidal anti-
inflammatory drugs, allopurinol, and diuretics [7–10].
Although the pathological mechanism underlying GIN is
not completely understood, a T-cell-mediated reaction is
likely responsible because of the predominance of mono-
nuclear cells (mainly T cells) in the interstitial infiltrates,
the presence of granulomas, and the absence of Ig depo-
sition in the tubules or interstitium .
DRESS is a life-threatening multiorgan systemic reac-
tion accompanied by the stepwise development of fever,
skin rash, leukocytosis with eosinophilia, and liver or renal
dysfunction . DIHS is an almost identical disease
concept, although an association with HHV-6 reactivation
Clin Exp Nephrol (2012) 16:168–172169
and a prolonged course are emphasized in DIHS . The
criteria for DIHS diagnosis include a maculopapular rash
developing [3 weeks after initiation of therapy with a
limited number of drugs, prolonged clinical symptoms
2 weeks after discontinuation of the causative drug, fever
[38?C, liver abnormalities (ALT, [100 IU/L), leukocyte
Table 1 Laboratory data on
HPF high-power field
Specific gravity1.011Total protein6.0 g/dL
pH5.5 Albumin3.8 g/dL
Protein NegativeBlood urea nitorgen 21.3 mg/dL
Potassium 3.9 mEq/L
Calcium 8.7 mg/dL
Red blood cells
White blood cells
IgG 780 mg/dL
White blood cells8400/lL
Stab cells IgM37 mg/dL
Segmented cells 51%C3127 mg/dL
Eosinophils18%C4 33 mg/dL
Monocytes 7%CH50 56 U/mL
318 9 104/lL
Red blood cells
27.9 9 104/lL
Fig. 1 Clinical course and
changes in serum creatinine
(sCr) and C-reactive protein
170 Clin Exp Nephrol (2012) 16:168–172
abnormalities including leukocytosis ([11000/lL), atypi-
cal lymphocytosis ([5%) or eosinophilia ([1500/lL),
lymphadenopathy, and HHV-6 reactivation . Diagnosis
of definite or typical DIHS requires the presence of all
seven criteria. Probable or atypical DIHS is diagnosed in
patients fulfilling the first five criteria in whom HHV-6
reactivation cannot be detected. Renal dysfunction can
serve as a substitute for liver abnormalities. Recent studies
have demonstrated that other herpes viruses, such as
cytomegalovirus, Epstein–Barr virus, and HHV-7, can be
sequentially reactivated during the course of this syndrome
The clinical features of DIHS/DRESS, distinguished
from other types of drug reactions, include paradoxical
deterioration after withdrawal of the causative drugs and
frequent flare-ups as observed in immune reconstitution
syndrome (IRS) [1, 13]. A limited number of drugs such as
anticonvulsants have been reported to cause DIHS/DRESS
. Typically, a decrease in serum Ig levels, including IgG,
IgA, and IgM, is observed at the onset of DIHS/DRESS
. An increase in Ig levels is observed several weeks after
withdrawal of the causative drugs, and the levels finally
return to normal. This transient hypogammaglobulinemia is
immunomodulatory effect on the immune system by the
causative drugs [1, 14–16].
Superficial perivascular lymphocytic infiltration, pre-
dominantly consisting of T cells, and tissue eosinophilia
are common pathological findings of skin biopsy [1, 17].
Although only a small number of reports are available on
histological analyses of the other involved organs, renal
failure in some cases with DIHS/DRESS has been attrib-
uted to AIN . In rare cases with DIHS, granuloma for-
mation has also been observed and reported as GIN or
granulomatous necrotizing angiitis [4–6]. Our patient
showed granulomatous lesions connected to arterioles,
without findings of apparent angionecrosis. There have
been no previous reports of GIN similar to the present case,
and the significance of this finding is unclear.
Granulomas can be found in other organs, such as the
skin, liver, and colon, in association with DIHS/DRESS
[4–6, 18]. Furthermore, granuloma formation is a histo-
logical hallmark of IRS . Some researchers propose
that DIHS/DRESS is a manifestation of the newly observed
IRS . Further investigations into the pathogenesis of
these syndromes are expected.
Systemic corticosteroid therapy is recommended for
treating patients with DIHS/DRESS who do not show
improvement even after withdrawal of the causative drug
. The usual dosage is 40–60 mg/day prednisolone,
which should be carefully tapered to prevent flare-ups.
Mild cases that recover with only supportive care do not
require corticosteroids [1, 4]. The use of systemic corti-
costeroids may increase the risk of infectious complica-
tions including virus reactivation. Other treatment options
include intravenous IgG [1, 14]. Even after resolution of
clinical manifestations, a number of drugs should be
avoided because unexplained cross-reactivities to multiple
drugs with structures totally different from the original
causative drugs have been reported .
Fortunately, our case recovered with conservative ther-
apy. We believed that we might have difficulty in achiev-
ing a good psychiatric control if systemic corticosteroids
Fig. 2 Granulomatous interstitial nephritis. The granuloma is con-
nected to the wall of the arteriole and surrounded by diffuse
interstitial infiltration of lymphocytes. Periodic acid–Schiff stain,
Fig. 3 Numerous epithelioid cells comprising the granuloma appear
to be involved in the middle or outer layer of the arteriole wall. The
glomerulus (right lower side) is essentially normal. Periodic acid–
silvermethenamine stain, 9200
Clin Exp Nephrol (2012) 16:168–172171
were required. Only a limited number of options were
available for psychiatric management of the patient
because of intolerance to various psychotropic drugs and a
possible cross-reactivity to multiple drugs after developing
HHV-6 and HHV-7 reactivation was not detected in our
case. These viruses have been demonstrated to be involved
in the flare-up and severity of this syndrome; therefore, the
absence of a detectable HHV-6 and HHV-7 reactivation
may have accounted for the milder form of disease in our
case [19, 20].
In summary, we report a case of GIN associated with
CBZ-induced DIHS/DRESS. Supportive care after drug
discontinuation resulted in a good recovery. Early recog-
nition of this syndrome is the most important step in
treatment because a number of drugs such as anticonvul-
sants and antibiotics may worsen the clinical symptoms
due to unexplained cross-reactivities.
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
This article is distributed under the terms of the
1. Shiohara T, Inaoka M, Kano Y. Drug-induced hypersensitivity
syndrome (DIHS): a reaction induced by a complex interplay
among herpesviruses and antiviral and antidrug immune
responses. Allergol Int. 2006;55:1–8.
2. Kano Y, Shiohara T. The variable clinical picture of drug-
induced hypersensitivity syndrome/drug rash with eosinophilia
and systemic symptoms in relation to the eliciting drug. Immunol
Allergy Clin North Am. 2009;29:481–501.
3. Revuz J. New advances in severe adverse drug reactions. Der-
matol Clin. 2001;19:697–709.
4. Imai H, Nakamoto Y, Hirokawa M, Akihama T, Miura AB.
Carbamazepine-induced granulomatous necrotizing angiitis with
acute renal failure. Nephron. 1989;51:405–8.
5. Hegarty J, Picton M, Agarwal G, Pramanik A, Kalra PA. Car-
bamazepine-induced acute granulomatous interstitial nephritis.
Clin Nephrol. 2002;57:310–3.
6. Fervenza FC, Kanakiriya S, Kunau RT, Gibney R, Lager DJ.
anticonvulsant hypersensitivity syndrome associated with lamo-
trigine treatment. Am J Kidney Dis. 2000;36:1034–40.
7. Mignon F, Me ´ry JP, Mougenot B, Ronco P, Roland J, Morel-
Maroger L. Granulomatous interstitial nephritis. Adv Nephrol
Necker Hosp. 1984;13:219–45.
8. Viero RM, Cavallo T. Granulomatous interstitial nephritis. Hum
9. Bijol V, Mendez GP, Nose ´ V, Rennke HG. Granulomatous
interstitial nephritis: a clinicopathologic study of 46 cases from a
single institution. Int J Surg Pathol. 2006;14:57–63.
10. Joss N, Morris S, Young B, Geddes C. Granulomatous interstitial
nephritis. Clin J Am Soc Nephrol. 2007;2:222–30.
11. Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolym-
phoma and drug hypersensitivity syndrome (drug rash with
eosinophilia and systemic symptoms: DRESS). Semin Cutan Med
12. Kano Y, Hiraharas K, Sakuma K, Shiohara T. Several herpesvi-
ruses can reactivate in a severe drug-induced multiorgan reaction
in the same sequential order as in graft-versus-host disease. Br J
13. Shiohara T, Kurata M, Mizukawa Y, Kano Y. Recognition of
immune reconstitution syndrome necessary for better manage-
ment of patients with severe drug eruptions and those under
immunosuppressive therapy. Allergol Int. 2010;59:333–43.
14. Kano Y, Inaoka M, Shiohara T. Association between anticon-
vulsant hypersensitivity syndrome and human herpesvirus 6
reactivation and hypogammaglobulinemia. Arch Dermatol. 2004;
15. Moreno-Ancillo A, Cosmes Martı ´n PM, Domı ´nguez-Noche C,
Martı ´n-Nu ´n ˜ez G, Ferna ´ndez-Gala ´n MA, Lo ´pez-Lo ´pez R, et al.
Carbamazepine induced transient monoclonal gammopathy and
immunodeficiency. Allergol Immunopathol (Madr). 2004;32:
16. Młodzikowska-Albrecht J, Steinborn B, Zarowski M. Cytokines,
epilepsy and epileptic drugs–is there a mutual influence? Phar-
macol Rep. 2007;59:129–38.
17. Ang CC, Wang YS, Yoosuff EL, Tay YK. Retrospective analysis
of drug-induced hypersensitivity syndrome: a study of 27
patients. J Am Acad Dermatol. 2010;63:219–27.
18. Fernando SL, Henderson CJ, O’Connor KS. Drug-induced
hypersensitivity syndrome with superficial granulomatous der-
matitis—a novel finding. Am J Dermatopathol. 2009;31:611–3.
19. Tohyama M, Hashimoto K, Yasukawa M, Kimura H, Horikawa
T, Nakajima K, et al. Association of human herpesvirus 6 reac-
tivation with the flaring and severity of drug-induced hypersen-
sitivity syndrome. Br J Dermatol. 2007;157:934–40.
20. Oskay T, Karademir A, Ertu ¨rk OI. Association of anticonvulsant
hypersensitivity syndrome with Herpesvirus 6, 7. Epilepsy Res.
172Clin Exp Nephrol (2012) 16:168–172