Inadvertent Provocative Oral Ondansetron use Leading to Toxic Epidermal Necrolysis in an HIV-infected Patient.

Toxic epidermal necrolysis (TEN) is a severe cutaneous adverse reaction to drugs, characterized by extensive detachment of epidermis and mucous membranes with a mortality of 30-40%. An increased occurrence of cutaneous drug reactions is seen in patients with human immunodeficiency virus (HIV) infection. We present this case of TEN caused by ondansetron in an HIV-infected patient. A 24-year-old HIV-1-infected man on antitubercular therapy and cotrimoxazole, presented with extensive and confluent erosions involving the face, trunk, extremities and mucous membranes following the intake of oral ondansetron, ofloxacin and ornidazole. All the drugs were withdrawn and he was treated with intravenous dexamethasone and antibiotics with consequent healing of the erosions. However, the lesions recurred on inadvertent intake of oral ondansetron. He was treated with intravenous antibiotics, fluid resuscitation and supportive care. The skin lesions healed completely over 2 months with postinflammatory depigmentation and scarring, and the eye lesions healed with corneal opacities. We would like to emphasize that the drug most frequently associated with adverse drug reactions may be innocent in a given patient and the physician dealing with a suspected drug reaction must always remain unbiased regarding the causative drug.

What was known?

1. Incidence of TEN is about 3 times higher in HIV-infected patients when compared to the general population.

2. Identification of the responsible drug is often very difficult because HIV-infected patients are often on multiple drugs.

3. Drug provocation testing is contraindicated in TEN.

Introduction

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are severe cutaneous adverse reactions (SCAR) to drugs, characterized by extensive detachment of epidermis and mucous membranes. Its impact on public health is significant because of the high mortality rate (30-40%), frequent lasting debility and reluctance of survivors and physicians to subsequent use of medications.[12] Therefore, accurate identification of the drug inducing the hypersensitivity reaction is paramount. Confirmation of a presumptive drug has been done in instances by drug provocation testing; however, it is contraindicated in life-threatening reactions such as TEN.[3] Hence, going by convention, a definitive association between a drug and an adverse reaction relies on improvement of the reaction after withdrawal from, and reappearance after rechallenge with the offending drug.[4]

Case Report

A 24-year-old known human immunodeficiency virus (HIV)-1-infected man presented to his general practitioner with an episode of acute gastroenteritis for which he was treated with oral ofloxacin, ornidazole, ondansetron and multivitamins. On the fifth day of treatment he developed redness followed by large blisters over the trunk which progressed to form erosions. He was admitted and treated at a private nursing home as a case of TEN. All his previous medications were discontinued. He was treated with intravenous dexamethasone and cefotaxime along with supportive management. He responded well and the lesions healed over the next 15 days. Five days after complete healing, patient took a single tablet of ondansetron 4 mg (self-administered, he did not take any other medication concurrently) for nausea following which he rapidly developed redness, blisters and erosions all over the body within 16-20 hours of intake including the eyes, oral cavity and genitals. He was then referred to us by his general practitioner for further management. On detailed drug inquiry, he gave history of treatment with antitubercular therapy comprising rifampicin, isoniazid, ethambutol and pyrazinamide for pulmonary tuberculosis and cotrimoxazole for Pneumocystis jiroveci pneumonia prophylaxis for the past 4 months; all of which were stopped after the first episode of TEN. His most recent CD4 count was 256/μL and there was no history of intake of antiretroviral drugs.

On examination, the general condition of the patient was poor. He was conscious and well-oriented. The temperature (oral) was 37.2°C, pulse 120/min, blood pressure 100/60 mmHg. Systemic examination was within normal limits. Cutaneous examination revealed multiple, widespread, confluent erosions with thick, necrotic, hemorrhagic crusts all over the body [Figure 1] with a body surface area involvement of 80% (Wallace's rule of nine). Nikolsky sign was positive. The palms and soles showed hemorrhagic blisters. The mucous membranes of the eyes, nose, oral cavity and genitals showed marked inflammation and erosions with crusts. Thus, on the basis of history and clinical findings a diagnosis of TEN most likely to ondansetron was made.

Figure 1

Confluent erosions with necrotic, hemorrhagic crusts

The patient was admitted and investigated. Hemoglobin was 15g%, total leucocyte count 2.4 × 109/L with neutrophils 69%, lymphocytes 31%; erythrocyte sedimentation rate 30 mm in first hour. Blood glucose levels, liver function tests, renal function tests and chest radiograph were within normal limits. SCORTEN value was 1 on the first and third day of admission corresponding to a predicted mortality of 3.2%.

He was treated initially with intravenous antibiotics like cefotaxime and metronidazole, and later with piperacillin-tazobactam and amikacin based on smear, culture and antibiotic sensitivity of skin swabs. Blood cultures were negative on multiple occasions. Supportive and symptomatic treatment was given with intravenous fluids based on central venous pressure monitoring and urine output; intravenous paracetamol and tramadol for pain relief; chest physiotherapy and nasogastric tube feeds. The wounds were dressed with autoclaved paraffin-impregnated gauze. Ophthalmic care included saline rinses, tobramycin and lubricating eye drops, glass rod passage in the fornices to prevent symblepharon and chloramphenicol ointment nightly. The lesions began to heal after 3 weeks with gradual re-epithelialization. Intravenous antibiotics were discontinued after the fifth week of therapy and supportive treatment was continued. The skin lesions healed completely after two months of admission with postinflammatory depigmentation and scarring [Figure 2] and sequelae such as bilateral corneal opacities.

Figure 2

Healing of erosions with postinflammatory depigmentation and scarring

Discussion

TEN is characterized by extensive sheet-like skin erosions (greater than 30% body surface area) with widespread purpuric macules or flat atypical target lesions, accompanied by severe involvement of conjunctival, corneal, buccal, labial and genital mucous membranes.[2] A cause can be attributed to drugs [Table 1] in 90% of cases. Other causes are infections such as Mycoplasma pneumoniae, vaccinations such as mumps, measles, rubella and graft-versus-host disease.[56]

Table 1

Drugs commonly incriminated in toxic epidermal necrolysis[25]

The Naranjo Adverse Drug Reaction (ADR) probability scale is an internationally accepted scoring system used to objectively assess whether an adverse reaction can be attributed a drug. Naranjo ADR probability scale score was highest for ondansetron (score of 7), hence it was a ‘probable’ cause of the reaction.[7]

Identification of the responsible drug is often difficult because patients frequently take multiple medications. The time between initiation of the drug and onset of the skin eruption is a key element in identifying the offending drug because most immunologically mediated drug reactions occur within 8-21 days after initiation of a new medication.[8] Recurrence within 48 hours on administration of a drug previously having caused a similar reaction is highly suggestive. A given drug is unlikely to be responsible for TEN if it was first given 24 hours previously, or if the duration of treatment exceeds three weeks.[2] In our case, it was unlikely that cotrimoxazole or the antitubercular drugs were responsible for the reaction as the patient received them for 4 months continuously before presentation. The eventuality of recurrence of lesions after consumption of ondansetron rules out ofloxacin or ornidazole as the causative agent.

An increased incidence of cutaneous drug reactions is seen in patients with HIV infection, the incidence increasing with increasing stage and CD4+ T-cell counts below 200/ μl. Drugs commonly responsible include cotrimoxazole, aminopenicillins, isoniazid, rifampicin, anti-epileptics and antiretrovirals (notably nevirapine and abacavir). Most common reaction patterns are morbilliform rash, urticaria, erythema multiforme and fixed drug eruption (FDE). Occasionally, SJS and TEN, hepatitis and interstitial pneumonitis may occur. In particular, the incidence of TEN in HIV-infected is three times higher than that of the general population. Various theories have been proposed to explain this phenomenon as follows:

Increased burden of medications taken by these patients.

Increased incidence of viral infections especially Ebstein-Barr virus (EBV) and Cytomegalovirus (CMV).

Switch from a Th1 to Th2 type of cytokine pattern leading to B-cell proliferation, IgE and IgA hyperimmunoglobulinemia and hypereosinophilia.

Dysregulation of immune balance by drugs and their metabolites.

Decrease in reactive oxygen species (ROS) scavengers such as glutathione.[5910]

One or more of the above factors may have been operational in producing a severe reaction to the usually safe drug ondansetron.

The drug most frequently associated with adverse drug reactions may be innocent in a particular patient and the physician dealing with a suspected drug reaction must always remain open minded, moreover in patients infected with HIV.

A number of in vitro tests have been designed to help determine whether an adverse skin reaction in an individual is due to a specific drug. They include the migration inhibition factor test, lymphocyte toxicity assay, lymphocyte transformation test, and basophil degranulation test. However, their sensitivity and specificity have not been assessed reliably with relevant controls and they are not readily available; hence they are of little help in clinical settings. Cutaneous patch tests with the offending agent are frequently positive after recovery of acute generalised exanthematous pustulosis (80% of patients) and FDE, but are positive in only a minority of cases of SJS or TEN. Furthermore, the recurrence is not 100% with rechallenge (e.g., there are refractory periods) and a negative result may give an erroneous sense of security.[8]

Ondansetron, a carbazole compound is a highly selective competitive antagonist at the 5-HT3 serotonin receptor in the gastrointestinal tract and the chemoreceptor trigger zone, thereby preventing or reducing emesis. It can be administered orally, intravenously or intramuscularly. It has a plasma elimination half-life of 3.5-4.5 hours and is metabolized by the liver. It has a wide therapeutic index and is well-tolerated. Adverse reactions seen commonly with its use are constipation, headache, asymptomatic increases in liver transaminases, diarrhoea, fever, malaise and rarely, an anaphylactic or anaphylactoid reaction.[1112] We are not aware of any case of TEN having been reported with the use of ondansetron after a search in the PUBMED and MEDLINE indexes. Similar adverse effect profile has been seen with other serotonin receptor antagonists like granisetron, tropisetron, dolasetron and palonosetron; however, no reports of TEN has been reported with the use of these agents.[11]

To summarize, TEN was triggered in our case by ondansetron based on the temporal relation, improvement after withdrawal, and explosive recurrence after inadvertent re-exposure. Ondansetron is a safe, commonly prescribed drug for nausea and vomiting and this case report of TEN should not discourage its clinical use. To reiterate, the treating physician should always have an open-minded outlook while dealing with a suspected drug reaction, because at times seemingly innocuous drugs can be the culprit. This is more applicable in the setting of use of newer drugs where there is a paucity of literature related to drug reactions; and in HIV-infected patients who are predisposed to drug reactions.

What is new?

1. The drug most frequently associated with an adverse drug reaction may be innocent in a particular patient.

2. The treating physician must always remain unbiased regarding the causative agent.

3. This is the first case report of ondansetron causing TEN

4. Provocative drug testing is contraindicated in a patient with a life threatening reaction. However, in our case the offending drug was taken inadvertently.