Download Rifaximin induced Stevens–Johnson syndrome in a patient of acute

C as e R epo rt
A bs tra ct
Rifaximin induced Stevens–Johnson syndrome
in a patient of acute on chronic liver failure
Stevens–Johnson Syndrome (SJS) forms part of a spectrum of severe adverse
cutaneous reactions that can eventually culminate into toxic epidermal
necrolysis (TEN), a potentially fatal condition. Drugs, most commonly allopurinol,
antivirals, antiepileptics, sulfonamides and other antibiotics are implicated in this
disease, even though, many case reports and series describe a variety of associations
with many other classes of drugs. Infectious and inflammatory conditions also
predispose to this severe cutaneous disease. Here, we present a patient who was
initially diagnosed as a case of acute on chronic liver failure in hepatic encephalopathy
grade I, in whom the introduction of rifaximin therapy led to aggressive cutaneous
reactions, leading to SJS, which was managed with intensive supportive treatment
because of which the patient improved substantially and was discharged after
14 days of onset of a potentially fatal condition. Rifaximin therapy leading to SJS‑TEN
has been reported only once before.
Key words: Acute on chronic liver failure, cirrhosis, drug reaction, hepatic
encephalopathy, rifaximin, Stevens–Johnson syndrome, toxic epidermal necrolysis
INTRODUCTION
Cyriac Abby Philips,
Chetan Ramesh Kalal,
Amrish Sahney,
K. N. Chandan Kumar
Department of Hepatology,
Institute of Liver and Biliary
Sciences, Vasant Kunj,
New Delhi, India
Address for the Correspondence:
Dr. Cyriac Abby Philips,
Department of Hepatology,
Institute of Liver and Biliary
Sciences, D‑1, Vasant Kunj,
New Delhi ‑ 110 070, India.
E‑mail: [email protected]
Access this article online
Website: www.oghr.org
DOI: 10.4103/2348-3113.152334
Quick response code:
Stevens–Johnson Syndrome (SJS) consists of a spectrum of severe cutaneous adverse reactions
affecting the skin and mucous membranes. It is the initiating part that culminates into severe toxic
epidermal necrolysis (TEN). SJS was initially considered to resemble erythema multiforme with
mucosal involvement but is now thought to form a single disease entity.[1] It is less severe than TEN,
but the etiology, genetic susceptibility, and pathological mechanisms are same for SJS‑TEN. In 1993, a
consensus definition[2] for differentiating these overlapping conditions was proposed by Bastuji‑Garin
et al. Accordingly, classification into five categories were proposed – bullous erythema multiforme, SJS,
overlap SJS – TEN, TEN with spots and TEN without spots. SJS is named after the 1922 description
by Stevens and Johnson. Most authors give credit for the first description of SJS to Hebra in 1860,[3]
but there is a mention in an 1822 publication by Alibert and Bazin[4] that probably refers to the same
disease. SJS and TEN differ only by their extent of skin detachment. The condition is mainly caused
by drugs, but infective etiology and other unknown risk factors in the presence of susceptibility play
a role in its development. Identification of the cause is of utmost importance because in the presence
of drug‑induced SJS and withdrawing the offending agent almost always yield good results. A variety
of drugs are found to be associated with SJS and TEN. In SJS and TEN the distribution of gender
is almost equal (slightly more females) and a female preponderance of approximately 65% is seen in
SJS/TEN‑overlap, whereas more men or boys develop erythema multiforme majus (almost 70%). The
mortality is almost 10% for patients with SJS, approximately 30% for patients with SJS/TEN‑overlap
and almost 50% for patients with TEN. The onset of the reaction, age of the patient, underlying
diseases and the amount of skin detachment are factors associated with mortality in SJS‑TEN. In
contrast, no patient with erythema multiforme majus dies as a consequence of the disease state.[5]
Large studies have shown that the highest risk for short‑term drug‑induced SJS was documented
with trimethoprim‑sulfomethoxazole and other sulfonamide antibiotics. Other reported associations
with SJS/TEN include infectious diseases such as those caused by human immunodeficiency virus,
herpesvirus, mycoplasma pneumoniae and hepatitis A virus and noninfectious conditions such
as radiotherapy, lupus erythematosus and collagen vascular disease.[6] Genetic factors associated
with SJS‑TEN include human leukocyte antigen (HLA)‑B12 phenotype and the HLA‑B*5801 and
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Philips, et al.: Rifaximin induced SJS in ACLF
HLA‑B*1502. The risk of carbamazepine‑induced SJS/TEN was
significantly higher in patients with HLA‑B*1502 in Indian patients.[7]
The median latency time between the beginning of use and onset
of SJS/TEN (also called index‑day) is usually <4 weeks for most
drugs whereas it was much longer for drugs with no associated risk.
Acute on chronic liver failure (ACLF) is characterized by the acute
deterioration of liver function in a patient with known/unknown
underlying compensated. The Asian Pacific Association of Study of
Liver in 2009 defined ACLF as an acute hepatic insult manifesting
as jaundice and coagulopathy, complicated within 4 weeks by ascites
and/or encephalopathy in a patient with previously diagnosed or
undiagnosed chronic liver disease.[8,9] Even though SJS and TEN have
been reported numerous times in the presence of variable etiologies,
mostly drugs, its presence in a patient of ACLF that was induced by
rifaximin intake is a novel presentation and arguably the second case
to be reported on rifaximin and the first, in the presence of ACLF.
CASE REPORT
A 38‑years‑old alcohol consumed patient with a recent intake
14 days back presented to our out‑patient department with
complaints of worsening anorexia and lethargy associated with
progressive noncholestatic jaundice and painless abdominal
distension since a period of 3 weeks. The patient denied comorbid
illnesses and has not been on any medications otherwise, including
complementary and alternative therapy. The patient denied prior
allergies or hypersensitivity reactions. On examination, the patient
was conscious and oriented with poor alertness without asterixis
and was hemodynamically stable. Pallor was evident as was icterus;
there were no clubbing, peripheral lymphadenopathy; and mild
bilateral nontender pedal pitting edema was present. The abdominal
examination revealed firm hepatosplenomegaly in the presence
of grade 2 ascites. The rest of the systemic examination was
essentially normal. Laboratory investigations revealed the presence
of anemia, thrombocytopenia with normal peripheral leucocyte
counts of 12,000 cells/cumm. There was macrocytic anemia on
peripheral smear and the markers of infection such as serum
procalcitonin and baseline cultures were all negative. Liver function
tests showed marked abnormality with total bilirubin of 8.4 mg/dL
with a direct fraction of 5.43 mg/dL, hypoalbuminemia, aspartate
aminotransferase of 220 IU/dL and alanine aminotransferase of
80 IU/dL. The prothrombin time was 16.8 s (control 12.0 s) with an
international normalized ratio of 2.24 and a discriminant function
of 30.5. The kidney function tests were normal. The markers of
hepatotropic viruses and retroviral assays were negative. The imaging
findings were suggestive of cirrhosis with portal hypertension with
moderate ascites. A diagnosis of ACLF with acute insult being
alcoholic hepatitis and chronic being alcoholic cirrhosis was made.
The patient was started on nutritional measures with protein rich,
high‑calorie diet and lactulose for adequate purging. Rifaximin at the
dose of 400 mg every 8th hourly was started and antibiotics were held
in the absence of overt sepsis or infection. Sixteen hour after start
of rifaximin therapy, the patient complained of feeling of impending
111
doom and restlessness. This was followed by eruptions of diffuse
maculopapular erythematous lesions, which started on the face and
upper chest which then spread aggressively to the other parts of the
body, most prominent on the anterior chest, abdomen and at the
back with subsequent involvement of both eyes [Figure 1]. Later on,
oral and mucosal involvement commenced and desquamation of the
skin over the body began to appear. The patient became febrile and
toxic subsequently and a suspected diagnosis of a severe cutaneous
adverse drug reaction, possibly SJS was made. Using the Naranjo
Scale (Naranjo, Busto, Sellers et al. [1981]), rifaximin as a possible
cause of the drug reaction was determined. Subsequently, rifaximin
was discontinued and antihistamines, aggressive hydration measures
along with tapering doses of corticosteroid therapy was initiated.
The patient was shifted to a high dependency unit and adequate
skin antiseptic measures, daily dressings over the desquamated
and peeled skin areas, hydration, nutritional supplementation and
broad spectrum antibiotics (Cephalosporins, 4th generation) were
continued. The patient slowly but steadily improved within 6 days
of stopping the offending drug and supportive measures with
resolution and healing of skin and oral and mucosal lesions. He
was subsequently discharged 2½ weeks after initial admission to
the hospital.
DISCUSSION
The initial symptoms of SJS‑TEN are nonspecific and include
symptoms such as fever, stinging eyes and discomfort upon
b
a
c
d
e
Figure 1: (a) Diffuse maculopapular and spotty erythematous lesions
over the body with denudation and scaling; (b) denuded areas over the
back, Nikolsky’s Sign; (c) denudation over prepucial surface and glans
penis; (d) oro‑mucosal involvement; (e) bilateral eye involvement with
conjunctivitis and dry sclerotic areas over the sclera
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Philips, et al.: Rifaximin induced SJS in ACLF
swallowing with loss of general well‑being. These symptoms precede
cutaneous manifestations by a few days typically. Early on in the
disease common sites of cutaneous involvement include presternal
region of the trunk and the face, and also the palms and soles.
Involvement (erythema and erosions) of the buccal, genital and/
or ocular mucosa occurs in >90% of patients. Ocular involvement
is frequent, and present variably, including acute conjunctivitis,
eyelid edema, erythema, crusts, and ocular discharge, to conjunctival
membrane or pseudomembrane formation or corneal erosion,
cicatrizing lesions, symblepharon, fornix foreshortening and corneal
ulceration.[10,11] In our patient, there was early involvement of
eyes with diffuse cutaneous lesions typical of SJS with not >10%
of body surface involvement. A second phase of this disease
is characterized by large areas of epidermal denudation. In the
absence of denudation, exerting tangential mechanical pressure
on several erythematous zones (Nikolsky sign) can produce
desquamation (but is not specific for TEN or SJS). Even though
histological examination including direct immunofluorescence
analysis of affected skin biopsy specimens is important to rule out
differential diagnoses such as autoimmune blistering diseases, bullous
fixed drug eruption, and acute generalized exanthematic pustulosis,
this was not done in this case in view of underlying coagulopathy and
also in the wake of strong clinical diagnosis of SJS. The extent of
skin involvement is a major prognostic factor. Necrotic skin, which
is already detached or detachable skin, should only be included in
the evaluation of the extent of skin involvement. Drug exposure
and resulting hypersensitivity reaction [Table 1] is the cause of a
large majority of cases of SJS/TEN. Allopurinol was the most
common cause of SJS/TEN in studies done in Europe and Israel.
The highest risk of induction of SJS‑TEN was found to be more
during the first 2 months of treatment. Interestingly, the long‑term
use of gluco‑corticosteroids for a variety of diseases does not change
the incidence of the occurrence of SJS‑TEN for the incriminated
drugs, but it does lengthen the interval between the beginning of
the intake of the drug and onset of SJS‑TEN.[12] Photo‑induced
TEN or SJS are only reported in very rare cases. The occurrence of
SJS‑TEN with use of rifaximin has been reported only once before.
Our case represents the continuum of that report which proves that
Table 1: List of common drugs that are of high,
moderate and low risk for SJS‑TEN
SJS‑TEN occurrence can be associated even with the least suspected
medication, such as rifaximin that is widely used in most patient of
decompensated cirrhosis for treatment of hepatic encephalopathy
and hepatopulmonary syndrome. Recently, a severity of illness
score for TEN was published, which combined seven independent
risk factors for mortality (age ≥ 40, heart rate ≥ 120/min, history
of cancer or hematologic malignancies, involved body surface
area > 10%, serum urea level > 10 mmol/L, serum bicarbonate
level < 20 mmol/L and serum glucose level > 14 mmol/L). Scoring
one point for each item, the predicted mortality was 3.2%, 12.1%,
5.3%, 58.3%, and 90.0% for 0–1, 2, 3, 4, and ≥ 5 points respectively.
An energy intake of 120% of the predicted basal metabolic rate
and intake of 3 g/kg protein result in adequate wound healing as
shown by expert studies.[13] The negative prognostic factors for
mortality in SJS‑TEN include the hypernatremia, increased blood
urea nitrogen (BUN), neutropenia, thrombocytopenia, visceral
involvement, and delayed presentation.[14‑16] Our patient had a raised
BUN after the start of cutaneous illness and thrombocytopenia was
evident even at admission in the presence of ACLF. In the presence
of severe TEN with impending organ failures, the use of intravenous
immunoglobulins or corticosteroids is advocated even though large
studies failed to show any improvement in mortality as compared to
supportive measures only. In our patient, the presence of SJS that did
not progress to TEN was a sign of wellness and eventual recovery
with aggressive management even in the presence of a serious illness
such as ACLF was seen. The importance of management of SJS
or TEN in the wake of ACLF is to prevent organ failures. Timely
therapeutic intervention, quick diagnosis and immediate removal
of the offending agent resulted in the patient not having unwanted
events during the hospital stay. Severe cutaneous adverse reactions
in liver disease patients, in the presence of a widely used drug like
rifaximin is a remote possibility, which when tackled well, can lead
to life salvage.
REFERENCES
1.
2.
High risk
Allopurinol
Moderate risk
No or low‑risk
Cephalosporines β‑blockers
3.
Carbamazepine
cotrimoxazole
(and other
sulfonamides and
sulfasalazine)
Macrolides
ACE inhibitors
4.
Quinolones
Calcium channel blockers
Lamotrigine
Nevirapine
NSAIDs (oxicam
type) phenobarbital
Phenytoin
Tetracyclines
Thiazide diuretics
(with sulfonamide structure)
NSAIDs
(acetic acid type; Sulfonylurea antidiabetics
(with sulfonamide structure)
diclofenac)
Insulin
NSAIDs (propionic acid
type; ibuprofen)
NSAIDs: Nonsteroidal anti‑inflammatory drugs, SJS: Stevens–Johnson syndrome,
TEN: Toxic epidermal necrolysis, ACE: Angiotensin‑converting‑enzyme
5.
6.
7.
8.
Levi N, Bastuji‑Garin S, Mockenhaupt M, Roujeau JC, Flahault A,
Kelly JP, et al. Medications as risk factors of Stevens‑Johnson syndrome
and toxic epidermal necrolysis in children: A pooled analysis. Pediatrics
2009;123:e297‑304.
Bastuji‑Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC.
Clinical classification of cases of toxic epidermal necrolysis,
Stevens‑Johnson syndrome, and erythema multiforme. Arch Dermatol
1993;129:92‑6.
Hebra FV. Acute rashes and skin diseases. In: Virchow R, Editor. Guide to
the Special Pathology. 3rd ed Erlangen: Ferdinand Enke : 1860.
Rosenberg L, Rosenberg J. Erythema exsudativum multiforme with
conjunctivitis and stomatitis. Arch Derm Syphilol 1940;41:1066.
Rzany B, Mockenhaupt M, Baur S, Schröder W, Stocker U, Mueller J,
et al. Epidemiology of erythema exsudativum multiforme majus,
Stevens‑Johnson syndrome, and toxic epidermal necrolysis in
Germany (1990‑1992): Structure and results of a population‑based
registry. J Clin Epidemiol 1996;49:769‑73.
Fritsch PO, Sidoroff A. Drug‑induced Stevens‑Johnson syndrome/toxic
epidermal necrolysis. Am J Clin Dermatol 2000;1:349‑60.
Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, et al. Medical
genetics: A marker for Stevens‑Johnson syndrome. Nature 2004;428:486.
Jalan R, Stadlbauer V, Sen S, Mookerjee RP, Davies N, Hodges S, et al. Natural
history of acute decompensation of cirrhosis: The basis of the definition,
Oncology, Gastroenterology and Hepatology Reports| Jul-Dec 2015 | Vol 4 | Issue 2
112
Philips, et al.: Rifaximin induced SJS in ACLF
prognosis, and pathophysiology of acute‑on‑chronic liver failure.
Hepatology 2006;44 Suppl 1:371A‑2.
9. Sarin SK, Kumar A, Almeida JA, Chawla YK, Fan ST, Garg H, et al.
Acute‑on‑chronic liver failure: Consensus recommendations of the
Asian Pacific Association for the study of the liver (APASL). Hepatol Int
2009;3:269‑82.
10. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs.
N Engl J Med 1994;331:1272‑85.
11. Ducic I, Shalom A, Rising W, Nagamoto K, Munster AM. Outcome
of patients with toxic epidermal necrolysis syndrome revisited. Plast
Reconstr Surg 2002;110:768‑73.
12. Schneck J, Fagot JP, Sekula P, Sassolas B, Roujeau JC, Mockenhaupt M.
Effects of treatments on the mortality of Stevens‑Johnson syndrome
and toxic epidermal necrolysis: A retrospective study on patients
included in the prospective EuroSCAR Study. J Am Acad Dermatol
2008;58:33‑40.
113
13. Cartotto R, Mayich M, Nickerson D, Gomez M. SCORTEN accurately
predicts mortality among toxic epidermal necrolysis patients treated in a
burn center. J Burn Care Res 2008;29:141‑6.
14. Namdar T, von Wild T, Siemers F, Stollwerck PL, Stang FH, Mailänder P,
et al. Does hypernatremia impact mortality in Toxic Epidermal Necrolysis?
Ger Med Sci 2010;8:Doc30.
15. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and
Stevens‑Johnson syndrome: A review. Crit Care Med 2011;39:1521‑32.
16. Mockenhaupt M. The current understanding of Stevens‑Johnson syndrome
and toxic epidermal necrolysis. Expert Rev Clin Immunol 2011;7:803‑13.
How to cite this article: Philips CA, Kalal CR, Sahney A, Kumar
KC. Rifaximin induced Stevens-Johnson syndrome in a patient
of acute on chronic liver failure. Onc Gas Hep Rep 2015;4:110-3.
Source of Support: Nil, Conflict of Interest: None declared.
Oncology, Gastroenterology and Hepatology Reports| Jul-Dec 2015 | Vol 4 | Issue 2