Severe enterocolitis associated with antiepileptic-induced drug reaction with eosinophilia and systemic symptoms (DRESS) Eric A. Swanson MD, Lawrence Low MD, PhD, Bita V. Naini MD PII: DOI: Reference:
S0046-8177(14)00198-1 doi: 10.1016/j.humpath.2014.04.019 YHUPA 3312
To appear in:
Human Pathology
Received date: Revised date: Accepted date:
8 January 2014 4 April 2014 22 April 2014
Please cite this article as: Swanson Eric A., Low Lawrence, Naini Bita V., Severe enterocolitis associated with antiepileptic-induced drug reaction with eosinophilia and systemic symptoms (DRESS), Human Pathology (2014), doi: 10.1016/j.humpath.2014.04.019
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title: Severe enterocolitis associated with antiepileptic-induced drug reaction with eosinophilia and
RI P
T
systemic symptoms (DRESS) Authors:
SC
Eric A. Swanson, MD1; Lawrence Low, MD, PhD1; Bita V. Naini, MD
NU
All authors affiliated with the Department of Pathology and Laboratory Medicine, University of
MA
California, Los Angeles, 90095. 1These authors contributed equally to the preparation of this manuscript.
ED
Keywords:
Running title:
CE
colitis, hypersensitivity
PT
Drug reaction with eosinophilia and systemic symptoms (DRESS), anti-epileptic drugs, enteritis,
AC
DRESS-associated severe enterocolitis Conflict of Interest:
The authors have no conflict of interest to declare. Funding disclosures: None. Corresponding Author: Bita V. Naini, M.D. Assistant Professor of Pathology
ACCEPTED MANUSCRIPT DRESS induced enterocolitis
David Geffen School of Medicine at UCLA 10833 Le Conte Ave, 1P-172 CHS
T
Los Angeles, CA 90095-1732
RI P
T: 310-825-0863 F: 310-267-2058
AC
CE
PT
ED
MA
NU
SC
Pager: 310-206-8477, ID 23861
2
ACCEPTED MANUSCRIPT DRESS induced enterocolitis
Abstract Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but serious
RI P
T
drug-induced reaction with cutaneous, hematologic, and solid-organ injury. Anti-epileptic drugs are one of the most common classes of drugs implicated in DRESS. A high morbidity and
SC
mortality may result, especially if the offending drug is not withdrawn promptly. While DRESS may involve many organs, severe involvement of the gastrointestinal tract in DRESS and/or in
NU
association with anti-epileptic drugs has rarely been reported. We report detailed clinical and
MA
histopathologic findings of a fatal case of DRESS syndrome resulting from antiepileptic drug
AC
CE
PT
ED
treatment that was accompanied by severe enterocolitis, malabsorption, and cachexia.
3
ACCEPTED MANUSCRIPT DRESS induced enterocolitis
1. Introduction Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, potentially
RI P
T
life-threatening, drug-induced hypersensitivity reaction manifested by cutaneous as well as systemic symptoms [1]. It is characterized by skin rash, lymphadenopathy, eosinophilia, and
SC
multi-organ dysfunction. The etiology is related to recent therapeutic drug use. Antiepileptic drugs such as phenytoin and lamotrigine are the most frequently reported causes [2]. Patients can
NU
show a range of symptoms including hematologic, pulmonary, hepatic, renal, cardiac,
MA
neurologic, and endocrine abnormalities. Involvement of the gastrointestinal tract in DRESS has been described in a previous report of two cases, however the corresponding histologic findings
ED
have not been well described [3]. While DRESS is relatively rare, the frequent use of antiepileptic drugs and the potential severity of associated gastrointestinal injury warrant
PT
particular attention to this association. Here, we report a fatal case of severe enterocolitis that
AC
2. Case report
CE
resulted in malnutrition and cachexia secondary to phenytoin and lamotrigine-induced DRESS.
2.1. Case history
A 21 year old female with no significant past medical history was admitted to the hospital with new onset occipital lobe seizure disorder. She was treated with phenytoin, lamotrigine, levetiracetam, and phenobarbital. Three weeks after initiation of this drug regimen, she presented with complaints of a cutaneous rash, which was thought to be Stevens-Johnson syndrome secondary to drug reaction. The phenytoin and lamotrigine were discontinued, and she was given an oral steroid taper. Her clinical condition worsened over the next few weeks with symptoms of additional organ dysfunction including thrombocytopenia, hepatitis, pancreatitis, and colitis. Two months after the initial admission, her peripheral blood was notable for 4
ACCEPTED MANUSCRIPT DRESS induced enterocolitis
eosinophilia of 13.9% (absolute eosinophil count 1056/microliter). The patient was diagnosed with DRESS syndrome based on clinical and laboratory findings [Table 1]. Her gastrointestinal
T
symptoms were notable for intractable nausea, vomiting, and diarrhea, and abdominal pain.
RI P
Enteroscopy with biopsies was performed on day 145 to evaluate for gastrointestinal disease. She experienced a long clinical course in the hospital and over time she became malnourished and
SC
cachectic, eventually requiring total parenteral nutrition due to her gastrointestinal dysfunction.
NU
Due to persistent fevers, cytopenias, elevated ferritin levels, low NK-cell activity, and hemophagocytosis noted on a bone marrow biopsy, she was diagnosed with hemophagocytic
MA
lymphohistiocytosis (HLH), presumably secondary to DRESS syndrome. Human immunodeficiency virus (HIV) 1+2 immunoassay, human herpes virus-6 (HHV-6) polymerase
ED
chain reaction (PCR), and Epstein Barr virus (EBV) DNA quantitative PCR were negative. Over
PT
the following month, she underwent chemotherapeutic treatment and subsequently developed multiple infections and became tachycardic and hypotensive. She eventually died of multi-organ
CE
failure approximately 6 months after initial presentation with cutaneous drug injury [Table 2].
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2.2 Endoscopic and histopathologic findings Esophagogastroduodenoscopy (EGD) revealed duodenopathy with ulceration and submucosal hemorrhage. Multiple biopsies of the 2nd and 3rd portions of the duodenum were taken. Hematoxylin and eosin (H&E)-stained sections of duodenal biopsies demonstrated severe enteritis, characterized by extensive mucosal damage and architectural abnormality. There was marked villus atrophy and blunting with prominent gastric surface foveolar metaplasia. Goblet cells and Paneth cells were noticeably absent with sparing of the neuroendocrine cells. There was no increase in intraepithelial lymphocytes. The lamina propria showed a reactive proliferation of
5
ACCEPTED MANUSCRIPT DRESS induced enterocolitis
fibroblasts with relatively sparse mixed inflammatory cell infiltrate. There were no granulomas, pathogenic organisms or viral inclusions [Figs. 1A and 1B].
T
Sigmoidoscopy revealed erythematous, granular and friable mucosa with multiple rectal
RI P
and sigmoid colon ulcers. H&E-stained sections of biopsies taken from sigmoid and rectum demonstrated severe chronic colitis and mucosal damage with prominent crypt destruction and
SC
loss [Fig. 1C]. Epithelial cells were mucin depleted and there was complete absence of goblet
NU
cells with sparing of neuroendocrine cells. There was a conspicuous increase in epithelial apoptosis present mainly within the deep crypts [Fig 1C, inset]. The lamina propria was
MA
edematous with proliferation of small vessels. An area of surface erosion was present with underlying mixed inflammation composed of lymphocytes, plasma cells, histiocytes and
ED
neutrophils [Fig. 1D]. No evidence of cryptitis, crypt abscesses, or crypt necrosis was seen. No
PT
granulomas, pathogenic organisms, or viral inclusions were present. Absence of cytomegalovirus
AC
3. Discussion
CE
(CMV) infection was confirmed by negative immunohistochemical stain.
DRESS is a serious hypersensitivity drug reaction associated with the use of antiepileptic drugs such as phenytoin and lamotrigine. Clinically, it is characterized by skin rash, fever, lymphadenopathy, eosinophilia, and multi-organ dysfunction. It was first described in 1996 to differentiate the clinical findings of drug related dermatologic eruptions accompanied by systemic symptoms from more common cutaneous drug reactions [1]. The disease can cause severe morbidity and up to 10% mortality, most commonly due to liver failure. Other organs that may show dysfunction include kidney, lung, heart, pancreas, endocrine system, and brain [2].
6
ACCEPTED MANUSCRIPT DRESS induced enterocolitis
DRESS syndrome usually manifests within 2-8 weeks after initiation of drug therapy [1], and is characterized by a prolonged course despite the discontinuation of the offending drugs. In
T
our case, the first cutaneous eruptions developed 3 weeks after exposure to antiepileptic drugs,
RI P
and she was diagnosed with DRESS syndrome at 2 months. Our patient’s RegiScar score was six, which is considered ‘definite’ for the diagnosis of DRESS (RegiScar is a diagnostic scoring
SC
system developed by The European Registry of Severe Cutaneous Adverse Reactions to Drugs
NU
and Collection of Biological Samples to evaluate the probability of drug related hypersensitivity syndrome) [Table 1] [4]. The cause of DRESS syndrome was clinically attributed to the anti-
MA
epileptic drugs phenytoin and lamotrigine. The temporal relationship between the initiation of these drugs and the onset of symptoms, as well as various previous reported associations of these
ED
drugs and DRESS syndrome contributed to this conclusion [1-3,5-7].
PT
Involvement of the gastrointestinal tract in DRESS syndrome is uncommon. To our knowledge, there are only rare published reports that describe gastrointestinal involvement in a
CE
spectrum of anti-convulsant induced drug reactions [Table 3]. Most cases have reported
AC
eosinophilic inflammation involving different areas of the gastrointestinal tract. In our case report, eosinophils were not the predominant inflammatory infiltrate. This may potentially be related to the timing of the biopsies (day 145), which were taken after the peripheral eosinophilia had resolved. In rare circumstances, mucosal erosion and ulceration have been reported. However, a detailed histopathologic description of gastrointestinal injury in DRESS syndrome has not been described. Here, we reported a case of DRESS syndrome secondary to antiepileptic drug use that resulted in severe enterocolitis, malabsorption, and death. We described the histopathologic pattern of injury seen within the small bowel and colonic mucosa. The small bowel and colon
7
ACCEPTED MANUSCRIPT DRESS induced enterocolitis
demonstrated severe damage of the mucosa with abnormal architectural features and loss of normal epithelial cells. It is also important to consider more common causes of enteritis and
T
colitis that may show similar histologic findings. The differential diagnosis includes infection,
RI P
and treatment for DRESS syndrome with immune suppression may exacerbate an underlying infection. In our case, there was no clinical, serologic, stool, or histologic evidence of pathogenic
SC
organisms. In particular, CMV infection was ruled out via serologic, histologic and
NU
immunohistochemical studies. In addition, more common causes of enterocolitis such as inflammatory bowel disease and ischemia were excluded. The diagnosis of drug related
MA
gastrointestinal injury was made based on the pattern of clinical presentation; special attention was attributed to the temporal association between the use of offending drugs and onset of
ED
gastrointestinal symptoms.
PT
The pathogenesis of DRESS syndrome is unclear. Various mechanisms such as drug detoxification effects causing reactive metabolite formation and subsequent severe immunologic
CE
response have been implicated in its development [8]. Interestingly, the histologic pattern of
AC
injury in our case is quite reminiscent of that seen in graft-versus-host disease and autoimmune enteropathy, supporting an abnormal immune-mediated attack against intestinal epithelium. Reactivation of latent viral infection, in particular HHV-6 infection, is also considered a cofactor in the disease process and has been reported in some cases [9], although HHV-6 PCR was negative in our case. Immediate withdrawal of the offending drug is the first line therapeutic option in cases of DRESS syndrome [10]. It is particularly important for the pathologist to raise the possibility of drug injury in the appropriate clinical setting to ensure timely cessation of the drug. In addition, systemic corticosteroids can be administered based on the severity of clinical symptoms and
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laboratory values. Alternative therapies can include intravenous immune globulin (IVIG) administration, plasmapheresis, and additional immunosuppressive therapies [10].
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In one prior report, the authors presented two cases of DRESS syndrome with
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gastrointestinal involvement [3]. In one case, the patient developed erosive esophagitis and colitis with ulceration after treatment with leflunomide for psoriatric arthritis. The differential
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diagnosis included an infectious etiology, and corticosteroid treatment was not initiated. The
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patient died of massive gastrointestinal hemorrhage. In the second case, the patient developed colitis with ulceration after lamotrigine treatment for epileptic seizures. She was treated with
MA
systemic and local corticosteroids, and the patient achieved complete remission in 2 months. In our case, phenytoin and lamotrigine were discontinued when the patient presented with
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cutaneous symptoms three weeks after initiation of therapy. However, the patient’s clinical
PT
course continued to deteriorate with systemic spread of the disease to other organ systems; she eventually developed symptoms consistent with hemophagocytic lymphohistiocytosis (HLH)
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secondary to DRESS syndrome. HLH is a serious, life threatening condition characterized by
AC
excessive immune system activation and dysregulation, leading to inappropriate activation of Tlymphocytes and macrophages. Primary causes of HLH may be associated with immunodeficiency. In this case, serologic studies were negative for HIV antibodies. She also had no other history of immunodeficiency, malignancy, or rheumatologic condition. The association between HLH and drug-induced hypersensitivity reactions and DRESS syndrome with administration of lamotrigine, phenobarbital, and phenytoin has been well reported [5-7,9,11]. The histology of HLH is characterized by hemophagocytosis of hematopoietic precursors within the bone marrow, spleen, lymph nodes, or liver. In our case, increased hemophagocytic cells
9
ACCEPTED MANUSCRIPT DRESS induced enterocolitis
were present in a bone marrow biopsy. HLH was also implicated in the cause of our patient’s end organ damage and death.
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4. Summary
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DRESS syndrome with gastrointestinal involvement is an uncommon but important entity that can affect patients receiving anti-epileptic drug therapy. In this report, we present a
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fatal case of DRESS syndrome with severe gastrointestinal involvement resulting in severe
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malabsorption and cachexia. It is important for pathologists to recognize and include antiepileptic-associated drug injury as a possible cause of enterocolitis in the appropriate clinical
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setting. Early recognition of drug reaction as an etiology of gastrointestinal mucosal pathology,
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and prompt cessation of the offending drugs are essential steps in improving patient outcomes.
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ACCEPTED MANUSCRIPT DRESS induced enterocolitis
Acknowledgements: The authors would like to thank Dr. Galen Cortina, M.D, PhD. for his valuable contributions to
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this report.
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REFERENCES
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1. Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity
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syndrome (Drug rash with eosinophilia and systemic symptoms: DRESS). Semin Cutan Med Surg 1996;15:250-257.
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2. Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: Part I. Clinical perspectixves. J Am
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Acad Dermatol 2013;68:693.e1-14.
3. Do-Pham G, Charachon A, Duong TA, et al., Drug reaction with eosinophilia and systemic
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symptoms and severe involvement of digestive tract: description of two cases. Br J Dermatol 2011;165:207-9.
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4. Kardaun SH, Sidoroff A, Valeyrie-Allanore L, et al. Variability in the clinical pattern of
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cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 2007;156:609-611.
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5. Larroche C. Hemophagocytic lymphohistiocytosis in adults: Diagnosis and treatment. Joint
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Bone Spine 2012;79:356-61.
6. Ben m'rad M, Leclerc-Mercier S, Blanche P, et al. Drug-induced hypersensitivity syndrome: clinical and biologic disease patterns in 24 patients. Medicine 2009;88:131-140. 7. Gumus H, Kumandas S, Per H, Karakukcu M. Hemophagocytic syndrome associated with high-dose lamotrigine. Pediatr Int 2007;49:672-673. 8. Camous X, Calbo S, Picard D, Musette P. Drug reaction with eosinophilia and systemic symptoms: an update on pathogenesis. Curr Opin Immunol 2012;24:730-5. 9. Descamps V, Bouscarat F, Laglenne S, et al. Human herpesvirus 6 infection associated with anticonvulsant hypersensitivity syndrome and reactive haemophagocytic syndrome. Br J Dermatol 1997;137:605-608. 12
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10. Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: Part II. Management and therapeutics. J Am Acad Dermatol 2013;68:709.e1-9.
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with antiepileptic drug. Pediatr Neurol 2004;30:358-360.
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11. Yang Y-C, Jou S-T, Chang Y-H, Liang J-S, Lee W-T. Hemophagocytic syndrome associated
12. Anttila V-J, Valtonen M. Carbamazepine-induced eosinophilic colitis. Epilepsia
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1992;33:119-121.
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13. Eland IA DA, Vink R, Zondervan PE, Stricker BH. Colitis may be part of the antiepileptic drug hypersensitivity syndrome. Epilepsia 1999;40:1780-1783.
MA
14. Fervenza FC, Kanakiriya S, Kunau RT, Gibney R, Lager DJ. Acute granulomatous interstitial nephritis and colitis in anticonvulsant hypersensitivity syndrome associated with
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lamotrigine treatment. Am J Kidney Dis 2000;36:1034-1040.
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15. Shakeer VK, Devi SR, Chettupuzha AP et al. Carbamazepine-induced eosinophilic enteritis. Indian J Gastroenterol 2002;21:114-115.
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16. Atkinson RJ, Dennis G, Cross SS, McAlindon ME, Sharrack B, Sanders DS. Eosinophilic
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colitis complicating anti-epileptic hypersensitivity syndrome: an indication for colonoscopy? Gastrointest Endosc 2004;60:1034-1036. 17. Powell N, Munro JM, Rowbotham D. Colonic involvement in Stevens-Johnson syndrome. Postgrad Med J 2006;82:e10. 18. Balatsinou C, Milano A, Caldarella MP, et al. Eosinophilic esophagitis is a component of the anticonvulsant hypersensitivity syndrome: description of two cases. Dig Liver Dis 2008;40:145148.
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Figure 1 Histopathologic changes seen in the duodenum (A, B) and sigmoid colon (C, D) of a patient with DRESS syndrome-associated severe enterocolitis. A, B) Duodenum
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showing marked villus atrophy and blunting with complete absence of goblet cells and
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Paneth cells with prominent gastric surface foveolar metaplasia (original magnification x 200). C) Sigmoid colon with severe mucosal damage with prominent crypt destruction
SC
and loss. Epithelial cells are mucin depleted and goblet cells are absent. The lamina
NU
propria is edematous and relatively pauci-cellular (original magnification x 100). An increase in epithelial apoptosis is present mainly within the deep crypts (inset, original
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magnification x 1000). D) Sigmoid colon shows areas of ulceration with loss of
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epithelial cells (original magnification x 200).
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Figure 1A
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DRESS induced enterocolitis
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Figure 1B
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DRESS induced enterocolitis
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Figure 1C
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DRESS induced enterocolitis
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Figure 1D
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DRESS induced enterocolitis
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Table 1: RegiSCAR Scoring system for classifying drug reactions with eosinophilia and systemic
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symptoms (DRESS) [4]. The patient’s score of 6 is considered definite for the diagnosis of DRESS syndrome.
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Patient score 1 N/A 1 N/ A
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N/A 1 0
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Symptom Fever ≥38.5°C Enlarged lymph nodes Eosinophilia Atypical lymphocyt es Rash ≥50 percent of body surface area Rash suggestive of DRESS Skin biopsy suggesting alternative diagnosis Organ involvement: Disease duration >15 days 0 −2 Investigation for alternative cause Total score
2 0
1 6
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Total score
S0046-8177(14)00198-1 doi: 10.1016/j.humpath.2014.04.019 YHUPA 3312
To appear in:
Human Pathology
Received date: Revised date: Accepted date:
8 January 2014 4 April 2014 22 April 2014
Please cite this article as: Swanson Eric A., Low Lawrence, Naini Bita V., Severe enterocolitis associated with antiepileptic-induced drug reaction with eosinophilia and systemic symptoms (DRESS), Human Pathology (2014), doi: 10.1016/j.humpath.2014.04.019
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title: Severe enterocolitis associated with antiepileptic-induced drug reaction with eosinophilia and
RI P
T
systemic symptoms (DRESS) Authors:
SC
Eric A. Swanson, MD1; Lawrence Low, MD, PhD1; Bita V. Naini, MD
NU
All authors affiliated with the Department of Pathology and Laboratory Medicine, University of
MA
California, Los Angeles, 90095. 1These authors contributed equally to the preparation of this manuscript.
ED
Keywords:
Running title:
CE
colitis, hypersensitivity
PT
Drug reaction with eosinophilia and systemic symptoms (DRESS), anti-epileptic drugs, enteritis,
AC
DRESS-associated severe enterocolitis Conflict of Interest:
The authors have no conflict of interest to declare. Funding disclosures: None. Corresponding Author: Bita V. Naini, M.D. Assistant Professor of Pathology
ACCEPTED MANUSCRIPT DRESS induced enterocolitis
David Geffen School of Medicine at UCLA 10833 Le Conte Ave, 1P-172 CHS
T
Los Angeles, CA 90095-1732
RI P
T: 310-825-0863 F: 310-267-2058
AC
CE
PT
ED
MA
NU
SC
Pager: 310-206-8477, ID 23861
2
ACCEPTED MANUSCRIPT DRESS induced enterocolitis
Abstract Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but serious
RI P
T
drug-induced reaction with cutaneous, hematologic, and solid-organ injury. Anti-epileptic drugs are one of the most common classes of drugs implicated in DRESS. A high morbidity and
SC
mortality may result, especially if the offending drug is not withdrawn promptly. While DRESS may involve many organs, severe involvement of the gastrointestinal tract in DRESS and/or in
NU
association with anti-epileptic drugs has rarely been reported. We report detailed clinical and
MA
histopathologic findings of a fatal case of DRESS syndrome resulting from antiepileptic drug
AC
CE
PT
ED
treatment that was accompanied by severe enterocolitis, malabsorption, and cachexia.
3
ACCEPTED MANUSCRIPT DRESS induced enterocolitis
1. Introduction Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, potentially
RI P
T
life-threatening, drug-induced hypersensitivity reaction manifested by cutaneous as well as systemic symptoms [1]. It is characterized by skin rash, lymphadenopathy, eosinophilia, and
SC
multi-organ dysfunction. The etiology is related to recent therapeutic drug use. Antiepileptic drugs such as phenytoin and lamotrigine are the most frequently reported causes [2]. Patients can
NU
show a range of symptoms including hematologic, pulmonary, hepatic, renal, cardiac,
MA
neurologic, and endocrine abnormalities. Involvement of the gastrointestinal tract in DRESS has been described in a previous report of two cases, however the corresponding histologic findings
ED
have not been well described [3]. While DRESS is relatively rare, the frequent use of antiepileptic drugs and the potential severity of associated gastrointestinal injury warrant
PT
particular attention to this association. Here, we report a fatal case of severe enterocolitis that
AC
2. Case report
CE
resulted in malnutrition and cachexia secondary to phenytoin and lamotrigine-induced DRESS.
2.1. Case history
A 21 year old female with no significant past medical history was admitted to the hospital with new onset occipital lobe seizure disorder. She was treated with phenytoin, lamotrigine, levetiracetam, and phenobarbital. Three weeks after initiation of this drug regimen, she presented with complaints of a cutaneous rash, which was thought to be Stevens-Johnson syndrome secondary to drug reaction. The phenytoin and lamotrigine were discontinued, and she was given an oral steroid taper. Her clinical condition worsened over the next few weeks with symptoms of additional organ dysfunction including thrombocytopenia, hepatitis, pancreatitis, and colitis. Two months after the initial admission, her peripheral blood was notable for 4
ACCEPTED MANUSCRIPT DRESS induced enterocolitis
eosinophilia of 13.9% (absolute eosinophil count 1056/microliter). The patient was diagnosed with DRESS syndrome based on clinical and laboratory findings [Table 1]. Her gastrointestinal
T
symptoms were notable for intractable nausea, vomiting, and diarrhea, and abdominal pain.
RI P
Enteroscopy with biopsies was performed on day 145 to evaluate for gastrointestinal disease. She experienced a long clinical course in the hospital and over time she became malnourished and
SC
cachectic, eventually requiring total parenteral nutrition due to her gastrointestinal dysfunction.
NU
Due to persistent fevers, cytopenias, elevated ferritin levels, low NK-cell activity, and hemophagocytosis noted on a bone marrow biopsy, she was diagnosed with hemophagocytic
MA
lymphohistiocytosis (HLH), presumably secondary to DRESS syndrome. Human immunodeficiency virus (HIV) 1+2 immunoassay, human herpes virus-6 (HHV-6) polymerase
ED
chain reaction (PCR), and Epstein Barr virus (EBV) DNA quantitative PCR were negative. Over
PT
the following month, she underwent chemotherapeutic treatment and subsequently developed multiple infections and became tachycardic and hypotensive. She eventually died of multi-organ
CE
failure approximately 6 months after initial presentation with cutaneous drug injury [Table 2].
AC
2.2 Endoscopic and histopathologic findings Esophagogastroduodenoscopy (EGD) revealed duodenopathy with ulceration and submucosal hemorrhage. Multiple biopsies of the 2nd and 3rd portions of the duodenum were taken. Hematoxylin and eosin (H&E)-stained sections of duodenal biopsies demonstrated severe enteritis, characterized by extensive mucosal damage and architectural abnormality. There was marked villus atrophy and blunting with prominent gastric surface foveolar metaplasia. Goblet cells and Paneth cells were noticeably absent with sparing of the neuroendocrine cells. There was no increase in intraepithelial lymphocytes. The lamina propria showed a reactive proliferation of
5
ACCEPTED MANUSCRIPT DRESS induced enterocolitis
fibroblasts with relatively sparse mixed inflammatory cell infiltrate. There were no granulomas, pathogenic organisms or viral inclusions [Figs. 1A and 1B].
T
Sigmoidoscopy revealed erythematous, granular and friable mucosa with multiple rectal
RI P
and sigmoid colon ulcers. H&E-stained sections of biopsies taken from sigmoid and rectum demonstrated severe chronic colitis and mucosal damage with prominent crypt destruction and
SC
loss [Fig. 1C]. Epithelial cells were mucin depleted and there was complete absence of goblet
NU
cells with sparing of neuroendocrine cells. There was a conspicuous increase in epithelial apoptosis present mainly within the deep crypts [Fig 1C, inset]. The lamina propria was
MA
edematous with proliferation of small vessels. An area of surface erosion was present with underlying mixed inflammation composed of lymphocytes, plasma cells, histiocytes and
ED
neutrophils [Fig. 1D]. No evidence of cryptitis, crypt abscesses, or crypt necrosis was seen. No
PT
granulomas, pathogenic organisms, or viral inclusions were present. Absence of cytomegalovirus
AC
3. Discussion
CE
(CMV) infection was confirmed by negative immunohistochemical stain.
DRESS is a serious hypersensitivity drug reaction associated with the use of antiepileptic drugs such as phenytoin and lamotrigine. Clinically, it is characterized by skin rash, fever, lymphadenopathy, eosinophilia, and multi-organ dysfunction. It was first described in 1996 to differentiate the clinical findings of drug related dermatologic eruptions accompanied by systemic symptoms from more common cutaneous drug reactions [1]. The disease can cause severe morbidity and up to 10% mortality, most commonly due to liver failure. Other organs that may show dysfunction include kidney, lung, heart, pancreas, endocrine system, and brain [2].
6
ACCEPTED MANUSCRIPT DRESS induced enterocolitis
DRESS syndrome usually manifests within 2-8 weeks after initiation of drug therapy [1], and is characterized by a prolonged course despite the discontinuation of the offending drugs. In
T
our case, the first cutaneous eruptions developed 3 weeks after exposure to antiepileptic drugs,
RI P
and she was diagnosed with DRESS syndrome at 2 months. Our patient’s RegiScar score was six, which is considered ‘definite’ for the diagnosis of DRESS (RegiScar is a diagnostic scoring
SC
system developed by The European Registry of Severe Cutaneous Adverse Reactions to Drugs
NU
and Collection of Biological Samples to evaluate the probability of drug related hypersensitivity syndrome) [Table 1] [4]. The cause of DRESS syndrome was clinically attributed to the anti-
MA
epileptic drugs phenytoin and lamotrigine. The temporal relationship between the initiation of these drugs and the onset of symptoms, as well as various previous reported associations of these
ED
drugs and DRESS syndrome contributed to this conclusion [1-3,5-7].
PT
Involvement of the gastrointestinal tract in DRESS syndrome is uncommon. To our knowledge, there are only rare published reports that describe gastrointestinal involvement in a
CE
spectrum of anti-convulsant induced drug reactions [Table 3]. Most cases have reported
AC
eosinophilic inflammation involving different areas of the gastrointestinal tract. In our case report, eosinophils were not the predominant inflammatory infiltrate. This may potentially be related to the timing of the biopsies (day 145), which were taken after the peripheral eosinophilia had resolved. In rare circumstances, mucosal erosion and ulceration have been reported. However, a detailed histopathologic description of gastrointestinal injury in DRESS syndrome has not been described. Here, we reported a case of DRESS syndrome secondary to antiepileptic drug use that resulted in severe enterocolitis, malabsorption, and death. We described the histopathologic pattern of injury seen within the small bowel and colonic mucosa. The small bowel and colon
7
ACCEPTED MANUSCRIPT DRESS induced enterocolitis
demonstrated severe damage of the mucosa with abnormal architectural features and loss of normal epithelial cells. It is also important to consider more common causes of enteritis and
T
colitis that may show similar histologic findings. The differential diagnosis includes infection,
RI P
and treatment for DRESS syndrome with immune suppression may exacerbate an underlying infection. In our case, there was no clinical, serologic, stool, or histologic evidence of pathogenic
SC
organisms. In particular, CMV infection was ruled out via serologic, histologic and
NU
immunohistochemical studies. In addition, more common causes of enterocolitis such as inflammatory bowel disease and ischemia were excluded. The diagnosis of drug related
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gastrointestinal injury was made based on the pattern of clinical presentation; special attention was attributed to the temporal association between the use of offending drugs and onset of
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gastrointestinal symptoms.
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The pathogenesis of DRESS syndrome is unclear. Various mechanisms such as drug detoxification effects causing reactive metabolite formation and subsequent severe immunologic
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response have been implicated in its development [8]. Interestingly, the histologic pattern of
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injury in our case is quite reminiscent of that seen in graft-versus-host disease and autoimmune enteropathy, supporting an abnormal immune-mediated attack against intestinal epithelium. Reactivation of latent viral infection, in particular HHV-6 infection, is also considered a cofactor in the disease process and has been reported in some cases [9], although HHV-6 PCR was negative in our case. Immediate withdrawal of the offending drug is the first line therapeutic option in cases of DRESS syndrome [10]. It is particularly important for the pathologist to raise the possibility of drug injury in the appropriate clinical setting to ensure timely cessation of the drug. In addition, systemic corticosteroids can be administered based on the severity of clinical symptoms and
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laboratory values. Alternative therapies can include intravenous immune globulin (IVIG) administration, plasmapheresis, and additional immunosuppressive therapies [10].
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In one prior report, the authors presented two cases of DRESS syndrome with
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gastrointestinal involvement [3]. In one case, the patient developed erosive esophagitis and colitis with ulceration after treatment with leflunomide for psoriatric arthritis. The differential
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diagnosis included an infectious etiology, and corticosteroid treatment was not initiated. The
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patient died of massive gastrointestinal hemorrhage. In the second case, the patient developed colitis with ulceration after lamotrigine treatment for epileptic seizures. She was treated with
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systemic and local corticosteroids, and the patient achieved complete remission in 2 months. In our case, phenytoin and lamotrigine were discontinued when the patient presented with
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cutaneous symptoms three weeks after initiation of therapy. However, the patient’s clinical
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course continued to deteriorate with systemic spread of the disease to other organ systems; she eventually developed symptoms consistent with hemophagocytic lymphohistiocytosis (HLH)
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secondary to DRESS syndrome. HLH is a serious, life threatening condition characterized by
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excessive immune system activation and dysregulation, leading to inappropriate activation of Tlymphocytes and macrophages. Primary causes of HLH may be associated with immunodeficiency. In this case, serologic studies were negative for HIV antibodies. She also had no other history of immunodeficiency, malignancy, or rheumatologic condition. The association between HLH and drug-induced hypersensitivity reactions and DRESS syndrome with administration of lamotrigine, phenobarbital, and phenytoin has been well reported [5-7,9,11]. The histology of HLH is characterized by hemophagocytosis of hematopoietic precursors within the bone marrow, spleen, lymph nodes, or liver. In our case, increased hemophagocytic cells
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were present in a bone marrow biopsy. HLH was also implicated in the cause of our patient’s end organ damage and death.
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4. Summary
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DRESS syndrome with gastrointestinal involvement is an uncommon but important entity that can affect patients receiving anti-epileptic drug therapy. In this report, we present a
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fatal case of DRESS syndrome with severe gastrointestinal involvement resulting in severe
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malabsorption and cachexia. It is important for pathologists to recognize and include antiepileptic-associated drug injury as a possible cause of enterocolitis in the appropriate clinical
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setting. Early recognition of drug reaction as an etiology of gastrointestinal mucosal pathology,
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and prompt cessation of the offending drugs are essential steps in improving patient outcomes.
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Acknowledgements: The authors would like to thank Dr. Galen Cortina, M.D, PhD. for his valuable contributions to
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REFERENCES
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1. Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity
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syndrome (Drug rash with eosinophilia and systemic symptoms: DRESS). Semin Cutan Med Surg 1996;15:250-257.
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2. Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: Part I. Clinical perspectixves. J Am
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Acad Dermatol 2013;68:693.e1-14.
3. Do-Pham G, Charachon A, Duong TA, et al., Drug reaction with eosinophilia and systemic
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symptoms and severe involvement of digestive tract: description of two cases. Br J Dermatol 2011;165:207-9.
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4. Kardaun SH, Sidoroff A, Valeyrie-Allanore L, et al. Variability in the clinical pattern of
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cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 2007;156:609-611.
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5. Larroche C. Hemophagocytic lymphohistiocytosis in adults: Diagnosis and treatment. Joint
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Bone Spine 2012;79:356-61.
6. Ben m'rad M, Leclerc-Mercier S, Blanche P, et al. Drug-induced hypersensitivity syndrome: clinical and biologic disease patterns in 24 patients. Medicine 2009;88:131-140. 7. Gumus H, Kumandas S, Per H, Karakukcu M. Hemophagocytic syndrome associated with high-dose lamotrigine. Pediatr Int 2007;49:672-673. 8. Camous X, Calbo S, Picard D, Musette P. Drug reaction with eosinophilia and systemic symptoms: an update on pathogenesis. Curr Opin Immunol 2012;24:730-5. 9. Descamps V, Bouscarat F, Laglenne S, et al. Human herpesvirus 6 infection associated with anticonvulsant hypersensitivity syndrome and reactive haemophagocytic syndrome. Br J Dermatol 1997;137:605-608. 12
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10. Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: Part II. Management and therapeutics. J Am Acad Dermatol 2013;68:709.e1-9.
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with antiepileptic drug. Pediatr Neurol 2004;30:358-360.
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11. Yang Y-C, Jou S-T, Chang Y-H, Liang J-S, Lee W-T. Hemophagocytic syndrome associated
12. Anttila V-J, Valtonen M. Carbamazepine-induced eosinophilic colitis. Epilepsia
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1992;33:119-121.
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13. Eland IA DA, Vink R, Zondervan PE, Stricker BH. Colitis may be part of the antiepileptic drug hypersensitivity syndrome. Epilepsia 1999;40:1780-1783.
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14. Fervenza FC, Kanakiriya S, Kunau RT, Gibney R, Lager DJ. Acute granulomatous interstitial nephritis and colitis in anticonvulsant hypersensitivity syndrome associated with
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lamotrigine treatment. Am J Kidney Dis 2000;36:1034-1040.
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15. Shakeer VK, Devi SR, Chettupuzha AP et al. Carbamazepine-induced eosinophilic enteritis. Indian J Gastroenterol 2002;21:114-115.
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16. Atkinson RJ, Dennis G, Cross SS, McAlindon ME, Sharrack B, Sanders DS. Eosinophilic
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colitis complicating anti-epileptic hypersensitivity syndrome: an indication for colonoscopy? Gastrointest Endosc 2004;60:1034-1036. 17. Powell N, Munro JM, Rowbotham D. Colonic involvement in Stevens-Johnson syndrome. Postgrad Med J 2006;82:e10. 18. Balatsinou C, Milano A, Caldarella MP, et al. Eosinophilic esophagitis is a component of the anticonvulsant hypersensitivity syndrome: description of two cases. Dig Liver Dis 2008;40:145148.
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Figure 1 Histopathologic changes seen in the duodenum (A, B) and sigmoid colon (C, D) of a patient with DRESS syndrome-associated severe enterocolitis. A, B) Duodenum
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showing marked villus atrophy and blunting with complete absence of goblet cells and
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Paneth cells with prominent gastric surface foveolar metaplasia (original magnification x 200). C) Sigmoid colon with severe mucosal damage with prominent crypt destruction
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and loss. Epithelial cells are mucin depleted and goblet cells are absent. The lamina
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propria is edematous and relatively pauci-cellular (original magnification x 100). An increase in epithelial apoptosis is present mainly within the deep crypts (inset, original
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magnification x 1000). D) Sigmoid colon shows areas of ulceration with loss of
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epithelial cells (original magnification x 200).
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Figure 1A
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Figure 1B
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Figure 1C
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Figure 1D
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Table 1: RegiSCAR Scoring system for classifying drug reactions with eosinophilia and systemic
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symptoms (DRESS) [4]. The patient’s score of 6 is considered definite for the diagnosis of DRESS syndrome.
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Patient score 1 N/A 1 N/ A
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N/A 1 0
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Symptom Fever ≥38.5°C Enlarged lymph nodes Eosinophilia Atypical lymphocyt es Rash ≥50 percent of body surface area Rash suggestive of DRESS Skin biopsy suggesting alternative diagnosis Organ involvement: Disease duration >15 days 0 −2 Investigation for alternative cause Total score
2 0
1 6
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Total score
