|Year : 2017 | Volume
| Issue : 1 | Page : 61-63
Hallucination in kidney transplant recipient: A rare complication of voriconazole
Manmeet Singh Jhawar1, Pratish George1, Jasmin Das1, Dinesh K Badyal2
1 Department of Nephrology, Christian Medical College and Hospital, Ludhiana, Punjab, India
2 Department of Pharmacology, Christian Medical College and Hospital, Ludhiana, Punjab, India
|Date of Web Publication||19-Dec-2016|
Manmeet Singh Jhawar
Department of Nephrology, Christian Medical College and Hospital, Ludhiana, Punjab
Source of Support: None, Conflict of Interest: None
Postkidney transplant recipients are more susceptible to opportunistic infections including fungal infections. Voriconazole is a broad-spectrum antifungal with a good safety profile even in patients with renal dysfunction. Hallucination is a rare and underreported complication of oral voriconazole therapy, especially in kidney transplant recipients. Two patients of postrenal transplant who developed hallucination following oral therapy with voriconazole have been highlighted here. Symptoms improved in both patients following a reduction in dosage or cessation of therapy. This case report highlights the fact that even though voriconazole-induced hallucinations are a rare complication, it is important to be aware of the same so as to be able to diagnose it and institute appropriate corrective measures.
Keywords: Hallucinations, kidney transplant, voriconazole
|How to cite this article:|
Jhawar MS, George P, Das J, Badyal DK. Hallucination in kidney transplant recipient: A rare complication of voriconazole. CHRISMED J Health Res 2017;4:61-3
|How to cite this URL:|
Jhawar MS, George P, Das J, Badyal DK. Hallucination in kidney transplant recipient: A rare complication of voriconazole. CHRISMED J Health Res [serial online] 2017 [cited 2019 Oct 19];4:61-3. Available from: http://www.cjhr.org/text.asp?2017/4/1/61/196071
| Introduction|| |
Antifungal therapy with voriconazole provides a good option, especially in patients with renal dysfunction. The most commonly observed adverse drug reactions (ADRs) with voriconazole are visual disturbances followed by skin rashes. Hallucinations are rare, especially when oral voriconazole therapy is being used, with the prevalence of visual hallucination around 5%.  These are often underreported complication of voriconazole therapy and can be misdiagnosed for neuropsychiatric disturbances, especially in critically ill patients. These cases highlight visual and auditory hallucination due to voriconazole in a postkidney transplant recipients in whom such complications have previously not been reported.
| Case reports|| |
A sixty-five-year-old male postkidney transplantation on treatment at an outside center (on prednisolone, tacrolimus, mycophenolate mofetil, and everolimus) on antituberculosis therapy (ATT) (isoniazid and pyrazinamide) for 6 months presented with fever, breathlessness, and decreased urine output. He had acute worsening of renal function (creatinine - 1.8 mg/dl), anemia (Hb - 9.8 g/dl), respiratory failure (pO 2 - 62.5) with metabolic acidosis (bicarbonate - 11.3), and normal liver function tests. A septic screen was done and he was initiated on meropenem, renal modified oral acyclovir (for oral herpetic lesions), trimethoprim, and continued on ATT. Computerized tomography (CT) of the chest showed multiple centrilobular nodules and ground glass opacities. He did not consent for bronchoscopy lavage and biopsy. Oral voriconazole (at a dose of 200 mg twice a day) was initiated in view of CT findings and sputum culture positive for candida nonalbicans, with close monitoring of tacrolimus targeting trough levels of 3-7 ng/ml. He improved after initiation of therapy and was afebrile. On the 3 rd day of treatment, he had visual (sense of children playing in the room, raindrops appearing on the wall) and auditory hallucinations (voices of children and adults talking with him), tremulousness, and headache. Clinically, there were no features of meningitis and patient refused imaging and cerebrospinal fluid. Voriconazole-induced hallucination was suspected. Serum drug levels of voriconazole could not be done due to nonavailability. Voriconazole dose was reduced by 50%, hallucination improved over the next 48 h and therapy was continued for a total of 8 days.
A sixty-nine-year-old male postkidney transplantation (on prednisolone, tacrolimus, and mycophenolate mofetil) chronic allograft nephropathy presented with fever in Type I respiratory failure (pO 2 - 58), anemia (Hb - 7.4 g/dl), and creatinine (5.8 mg/dl). High-resolution CT chest was suggestive of ground glass appearance with the presence of nodules. A possibility of fungal pneumonia was kept; bronchoscopy could not be done in view of concurrent atrial fibrillation. Oral voriconazole therapy (at a dose of 200 mg twice a day) was started, with tacrolimus trough levels 4.24 ng/dl during therapy. On the 3 rd day of therapy, he developed visual hallucination (sense of his bed going on the road with people sitting next to him) which persisted over the next 2 days. Voriconazole was discontinued on day 6 and changed over to caspofungin. His hallucination subsided on the next day. A possibility of voriconazole-induced hallucination was suspected. Serum drug levels of voriconazole could not be done due to nonavailability.
| Discussion|| |
Posttransplant patients are at a high risk for opportunistic infections including fungal infections. Treatment of multiple opportunistic fungal infections with voriconazole, a broad spectrum second generation azole antifungal agent, has shown to result in favorable outcomes. 
Visual disturbances, in the form of altered color discrimination, blurred vision, and photopsia, are the most common side effect of voriconazole with skin rashes being the second most common side effect. Elevation of liver enzymes occurs as with other azole group of drugs.  Visual hallucination is a less common side effect noted with voriconazole at a rate of 5% and is clearly different from photopsia.  Adverse neurological events are associated with elevated serum voriconazole levels, and its measurement can improve the drug safety profile. 
Hallucination is a rare complication of voriconazole therapy and is often overlooked or misdiagnosed. Visual and auditory hallucinations are significantly more frequent (32%) at voriconazole concentrations of >5 mg/L as compared to ≤5 mg/L (P < 0.01).  Analysis of a retrospective pharmacovigilance database showed 13.3% patients on voriconazole had a visual hallucination; however, the hallucinations were not distinguished from visual changes.  A prospective natural cohort study of 72 patients showed 12 patients who experienced hallucination while on voriconazole therapy. Hallucinations occurred mainly after intravenous (IV) formulations though they were also seen with oral formulations. Symptoms disappeared when IV is switched over to oral treatment; hence, it was advisable to continue with oral therapy in critically ill conditions. 
Our case 1 had a serious ADR with visual and auditory hallucination following administration of voriconazole with Naranjo index score of seven (probable adverse reaction) and case 2 had serious visual hallucinations with Naranjo index score of eight (probable adverse reaction).  Case 1 was on isoniazid which results in increased serum level or effect of voriconazole by affecting hepatic enzyme CYP2C19 metabolism. It is possible that due to the above interaction, his levels of voriconazole were high, which may have returned to therapeutic levels following dose reduction. However, in the absence of drug levels, this cannot be absolutely ascertained. In case 2 due to severe debilitation due to visual hallucination, voriconazole was switched over to caspofungin following which his symptoms subsided. Major metabolic pathway for voriconazole, CYP2C19, is highly dependent on genetic polymorphism. Low CYP2C19 activity is seen in 15%-20% of Asian descent, resulting in four times higher voriconazole levels than in those with normal metabolism.  Saturation of voriconazole metabolism leads to nonlinear pharmacokinetics and substantial intersubject variability in serum concentrations.  It is possible that due to the above genetic polymorphism, our case 2 had increased voriconazole drug levels leading to hallucinations.
| Conclusions|| |
Voriconazole-induced hallucination in postkidney transplant recipient patient, especially with oral medication, is a rare and underreported complication. Interactions with other medications which patient is receiving or genetic polymorphism may result in these rare adverse effects. It is important to be aware of the same, so as to diagnose it correctly and institute appropriate corrective measures.
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Conflicts of interest
There are no conflicts of interest.
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