sign in sign up
<<
Home , Sulfonamide (medicine)

Case Report 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, and other are implicated in this

Abstract 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

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 Cyriac Abby Philips, epidermal necrolysis (TEN). SJS was initially considered to resemble with Chetan Ramesh Kalal, mucosal involvement but is now thought to form a single disease entity.[1] It is less severe than TEN, Amrish Sahney, but the etiology, genetic susceptibility, and pathological mechanisms are same for SJS‑TEN. In 1993, a K. N. Chandan Kumar consensus definition[2] for differentiating these overlapping conditions was proposed by Bastuji‑Garin Department of Hepatology, et al. Accordingly, classification into five categories were proposed – bullous erythema multiforme, SJS, Institute of Liver and Biliary Sciences, Vasant Kunj, overlap SJS – TEN, TEN with spots and TEN without spots. SJS is named after the 1922 description New Delhi, India 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 Address for the Correspondence: disease. SJS and TEN differ only by their extent of skin detachment. The condition is mainly caused Dr. Cyriac Abby Philips, Department of Hepatology, by drugs, but infective etiology and other unknown risk factors in the presence of susceptibility play Institute of Liver and Biliary a role in its development. Identification of the cause is of utmost importance because in the presence Sciences, D‑1, Vasant Kunj, of drug‑induced SJS and withdrawing the offending agent almost always yield good results. A variety New Delhi ‑ 110 070, India. E‑mail: [email protected] 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

Access this article online 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 Website: www.oghr.org and almost 50% for patients with TEN. The onset of the reaction, age of the patient, underlying DOI: 10.4103/2348-3113.152334 diseases and the amount of skin detachment are factors associated with mortality in SJS‑TEN. In Quick response code: 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 ‑sulfomethoxazole and other antibiotics. Other reported associations with SJS/TEN include infectious diseases such as those caused by human immunodeficiency virus, herpesvirus, 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

Oncology, Gastroenterology and Hepatology Reports| Jul-Dec 2015 | Vol 4 | Issue 2 110 Philips, et al.: Rifaximin induced SJS in ACLF

HLA‑B*1502. The risk of ‑induced SJS/TEN was doom and restlessness. This was followed by eruptions of diffuse significantly higher in patients with HLA‑B*1502 in Indian patients.[7] maculopapular erythematous lesions, which started on the face and The median latency time between the beginning of use and onset upper chest which then spread aggressively to the other parts of the of SJS/TEN (also called index‑day) is usually <4 weeks for most body, most prominent on the anterior chest, abdomen and at the drugs whereas it was much longer for drugs with no associated risk. back with subsequent involvement of both eyes [Figure 1]. Later on, oral and mucosal involvement commenced and desquamation of the Acute on chronic liver failure (ACLF) is characterized by the acute skin over the body began to appear. The patient became febrile and deterioration of liver function in a patient with known/unknown toxic subsequently and a suspected diagnosis of a severe cutaneous underlying compensated. The Asian Pacific Association of Study of adverse drug reaction, possibly SJS was made. Using the Naranjo Liver in 2009 defined ACLF as an acute hepatic insult manifesting Scale (Naranjo, Busto, Sellers et al. [1981]), rifaximin as a possible as jaundice and coagulopathy, complicated within 4 weeks by ascites cause of the drug reaction was determined. Subsequently, rifaximin and/or encephalopathy in a patient with previously diagnosed or was discontinued and antihistamines, aggressive hydration measures [8,9] undiagnosed chronic liver disease. Even though SJS and TEN have along with tapering doses of corticosteroid therapy was initiated. been reported numerous times in the presence of variable etiologies, The patient was shifted to a high dependency unit and adequate mostly drugs, its presence in a patient of ACLF that was induced by skin antiseptic measures, daily dressings over the desquamated rifaximin intake is a novel presentation and arguably the second case and peeled skin areas, hydration, nutritional supplementation and to be reported on rifaximin and the first, in the presence of ACLF. broad spectrum antibiotics (Cephalosporins, 4th generation) were continued. The patient slowly but steadily improved within 6 days CASE REPORT of stopping the offending drug and supportive measures with A 38‑years‑old alcohol consumed patient with a recent intake resolution and healing of skin and oral and mucosal lesions. He 14 days back presented to our out‑patient department with was subsequently discharged 2½ weeks after initial admission to complaints of worsening anorexia and lethargy associated with the hospital. progressive noncholestatic jaundice and painless abdominal distension since a period of 3 weeks. The patient denied comorbid DISCUSSION illnesses and has not been on any otherwise, including The initial symptoms of SJS‑TEN are nonspecific and include complementary and alternative therapy. The patient denied prior symptoms such as fever, stinging eyes and discomfort upon 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, with normal peripheral leucocyte b counts of 12,000 cells/cumm. There was macrocytic anemia on peripheral smear and the markers of such as serum a 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 c d 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, e high‑calorie diet and lactulose for adequate purging. Rifaximin at the Figure 1: (a) Diffuse maculopapular and spotty erythematous lesions dose of 400 mg every 8th hourly was started and antibiotics were held over the body with denudation and scaling; (b) denuded areas over the back, Nikolsky’s Sign; (c) denudation over prepucial surface and glans in the absence of overt sepsis or infection. Sixteen hour after start penis; (d) oro‑mucosal involvement; (e) bilateral eye involvement with of rifaximin therapy, the patient complained of feeling of impending conjunctivitis and dry sclerotic areas over the sclera

111 Oncology, Gastroenterology and Hepatology Reports| Jul-Dec 2015 | Vol 4 | Issue 2 Philips, et al.: Rifaximin induced SJS in ACLF swallowing with loss of general well‑being. These symptoms precede SJS‑TEN occurrence can be associated even with the least suspected cutaneous manifestations by a few days typically. Early on in the , such as rifaximin that is widely used in most patient of disease common sites of cutaneous involvement include presternal decompensated cirrhosis for treatment of hepatic encephalopathy region of the trunk and the face, and also the palms and soles. and hepatopulmonary syndrome. Recently, a severity of illness Involvement (erythema and erosions) of the buccal, genital and/ score for TEN was published, which combined seven independent or ocular mucosa occurs in >90% of patients. Ocular involvement risk factors for mortality (age ≥ 40, heart rate ≥ 120/min, history is frequent, and present variably, including acute conjunctivitis, of cancer or hematologic malignancies, involved body surface eyelid edema, erythema, crusts, and ocular discharge, to conjunctival area > 10%, serum level > 10 mmol/L, serum bicarbonate membrane or pseudomembrane formation or corneal erosion, level < 20 mmol/L and serum glucose level > 14 mmol/L). Scoring cicatrizing lesions, symblepharon, fornix foreshortening and corneal one point for each item, the predicted mortality was 3.2%, 12.1%, ulceration.[10,11] In our patient, there was early involvement of 5.3%, 58.3%, and 90.0% for 0–1, 2, 3, 4, and ≥ 5 points respectively. eyes with diffuse cutaneous lesions typical of SJS with not >10% An energy intake of 120% of the predicted basal metabolic rate of body surface involvement. A second phase of this disease and intake of 3 g/kg protein result in adequate wound healing as is characterized by large areas of epidermal denudation. In the shown by expert studies.[13] The negative prognostic factors for absence of denudation, exerting tangential mechanical pressure mortality in SJS‑TEN include the hypernatremia, increased blood on several erythematous zones (Nikolsky sign) can produce urea nitrogen (BUN), neutropenia, thrombocytopenia, visceral desquamation (but is not specific for TEN or SJS). Even though involvement, and delayed presentation.[14‑16] Our patient had a raised histological examination including direct immunofluorescence BUN after the start of cutaneous illness and thrombocytopenia was analysis of affected skin biopsy specimens is important to rule out evident even at admission in the presence of ACLF. In the presence differential diagnoses such as autoimmune blistering diseases, bullous of severe TEN with impending organ failures, the use of intravenous fixed , and acute generalized exanthematic pustulosis, immunoglobulins or corticosteroids is advocated even though large this was not done in this case in view of underlying coagulopathy and studies failed to show any improvement in mortality as compared to also in the wake of strong clinical diagnosis of SJS. The extent of supportive measures only. In our patient, the presence of SJS that did skin involvement is a major prognostic factor. Necrotic skin, which not progress to TEN was a sign of wellness and eventual recovery is already detached or detachable skin, should only be included in with aggressive management even in the presence of a serious illness the evaluation of the extent of skin involvement. Drug exposure such as ACLF was seen. The importance of management of SJS and resulting hypersensitivity reaction [Table 1] is the cause of a or TEN in the wake of ACLF is to prevent organ failures. Timely large majority of cases of SJS/TEN. Allopurinol was the most therapeutic intervention, quick diagnosis and immediate removal common cause of SJS/TEN in studies done in Europe and Israel. of the offending agent resulted in the patient not having unwanted The highest risk of induction of SJS‑TEN was found to be more events during the hospital stay. Severe cutaneous adverse reactions during the first 2 months of treatment. Interestingly, the long‑term in liver disease patients, in the presence of a widely used drug like use of gluco‑corticosteroids for a variety of diseases does not change rifaximin is a remote possibility, which when tackled well, can lead the incidence of the occurrence of SJS‑TEN for the incriminated to life salvage. drugs, but it does lengthen the interval between the beginning of the intake of the drug and onset of SJS‑TEN.[12] Photo‑induced REFERENCES

TEN or SJS are only reported in very rare cases. The occurrence of 1. Levi N, Bastuji‑Garin S, Mockenhaupt M, Roujeau JC, Flahault A, SJS‑TEN with use of rifaximin has been reported only once before. Kelly JP, et al. Medications as risk factors of Stevens‑Johnson syndrome Our case represents the continuum of that report which proves that and toxic epidermal necrolysis in children: A pooled analysis. Pediatrics 2009;123:e297‑304. 2. Bastuji‑Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Table 1: List of common drugs that are of high, Clinical classification of cases of toxic epidermal necrolysis, moderate and low risk for SJS‑TEN Stevens‑Johnson syndrome, and erythema multiforme. Arch Dermatol 1993;129:92‑6. High risk Moderate risk No or low‑risk 3. Hebra FV. Acute rashes and skin diseases. In: Virchow R, Editor. Guide to Allopurinol Cephalosporines β‑blockers the Special Pathology. 3rd ed Erlangen: Ferdinand Enke : 1860. Carbamazepine Macrolides ACE inhibitors 4. Rosenberg L, Rosenberg J. Erythema exsudativum multiforme with cotrimoxazole Quinolones Calcium channel blockers conjunctivitis and stomatitis. Arch Derm Syphilol 1940;41:1066. (and other 5. Rzany B, Mockenhaupt M, Baur S, Schröder W, Stocker U, Mueller J, sulfonamides and et al. Epidemiology of erythema exsudativum multiforme majus, (with sulfonamide structure) ) NSAIDs Stevens‑Johnson syndrome, and toxic epidermal necrolysis in antidiabetics ( type; Germany (1990‑1992): Structure and results of a population‑based (with sulfonamide structure) diclofenac) registry. J Clin Epidemiol 1996;49:769‑73. Nevirapine Insulin 6. Fritsch PO, Sidoroff A. Drug‑induced Stevens‑Johnson syndrome/toxic NSAIDs (oxicam NSAIDs (propionic acid epidermal necrolysis. Am J Clin Dermatol 2000;1:349‑60. type) type; ibuprofen) 7. 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. NSAIDs: anti‑inflammatory drugs, SJS: Stevens–Johnson syndrome, 8. Jalan R, Stadlbauer V, Sen S, Mookerjee RP, Davies N, Hodges S, et al. Natural TEN: Toxic epidermal necrolysis, ACE: Angiotensin‑converting‑enzyme 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. 13. Cartotto R, Mayich M, Nickerson D, Gomez M. SCORTEN accurately Hepatology 2006;44 Suppl 1:371A‑2. predicts mortality among toxic epidermal necrolysis patients treated in a 9. Sarin SK, Kumar A, Almeida JA, Chawla YK, Fan ST, Garg H, et al. burn center. J Burn Care Res 2008;29:141‑6. Acute‑on‑chronic liver failure: Consensus recommendations of the 14. Namdar T, von Wild T, Siemers F, Stollwerck PL, Stang FH, Mailänder P, Asian Pacific Association for the study of the liver (APASL). Hepatol Int et al. Does hypernatremia impact mortality in Toxic Epidermal Necrolysis? 2009;3:269‑82. Ger Med Sci 2010;8:Doc30. 10. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. 15. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and N Engl J Med 1994;331:1272‑85. Stevens‑Johnson syndrome: A review. Crit Care Med 2011;39:1521‑32. 11. Ducic I, Shalom A, Rising W, Nagamoto K, Munster AM. Outcome 16. Mockenhaupt M. The current understanding of Stevens‑Johnson syndrome of patients with toxic epidermal necrolysis syndrome revisited. Plast and toxic epidermal necrolysis. Expert Rev Clin Immunol 2011;7:803‑13. Reconstr Surg 2002;110:768‑73. 12. Schneck J, Fagot JP, Sekula P, Sassolas B, Roujeau JC, Mockenhaupt M. How to cite this article: Philips CA, Kalal CR, Sahney A, Kumar Effects of treatments on the mortality of Stevens‑Johnson syndrome KC. Rifaximin induced Stevens-Johnson syndrome in a patient and toxic epidermal necrolysis: A retrospective study on patients of acute on chronic liver failure. Onc Gas Hep Rep 2015;4:110-3. included in the prospective EuroSCAR Study. J Am Acad Dermatol Source of Support: Nil, Conflict of Interest: None declared. 2008;58:33‑40.

113 Oncology, Gastroenterology and Hepatology Reports| Jul-Dec 2015 | Vol 4 | Issue 2