Fluoxetine as antiviral therapy

Jacqueline Gofshteyn, Ana María Cárdenas and David Bearden.  Treatment of chronic enterovirus encephalitis with fluoxetine in a patient with X-linked agammaglobulinemia.  Pediatric Neurology, in press.

In patients with X-linked agammaglobulinemia (XLA), enteroviral infections more commonly lead to a chronic meningoencephalitis due to a specific vulnerability to enteroviral infections in agammaglobulinemic patients…

Chronic Enterovirus Meningoencephalitis in Agammaglobulinemia (CEMA) typically presents with slowly progressive developmental regression eventually leading to spastic quadriparesis. There are currently no approved antiviral therapeutics, although several drugs are currently in clinical trials. Treatment currently consists of supportive care as well as high dose intravenous immunoglobulin (IVIG), sometimes followed by intraventricular immunoglobulin . Prognosis is extremely poor with most patients experiencing death or severe disability . Prior large scale screening efforts of potentially novel compounds with antiviral efficacy against enteroviruses identified fluoxetine as a potential treatment agent. In vitro studies indicate that the antidepressant drug fluoxetine may be an effective anti-enteroviral compound. Given the lack of available treatment agents, the in vitro data supporting antiviral activity and the limited safety concerns with treatment, fluoxetine was trialed as a therapeutic agent for chronic enterovirus encephalitis.

Here we report a case of a patient with XLA and chronic enterovirus encephalitis who failed standard therapies but was successfully treated with fluoxetine. This case is illustrative of a new paradigm in antiviral drug discovery in which screening existing compounds for antiviral activity may be an effective alternative to traditional drug development...

He was diagnosed with XLA at age 1 when a routine complete blood count (CBC) revealed neutropenia, and follow up testing revealed low serum IgG. Genetic testing at that time revealed a BTK gene mutation c.1185G>A, a novel nonsense mutation that had not been previously described in the literature. He had no known family history of primary immunodeficiency, autoimmune disease, unexplained deaths or miscarriages. He was initially started on intravenous immunoglobulin (IVIG) but later was switched to subcutaneous immunoglobulin replacement (Hizentra) for chronic therapy.

At age 3 he was running, climbing and speaking in complete sentences. In February 2014, at the age of 3 ½ he started having increasing difficulty with balance. Over the course of the next few months he continued to regress such that in May 2014 he would speak only single words and would take only a few steps independently. There were no associated fevers or preceding viral symptoms noted with the onset of regression. Magnetic Resonance Imaging (MRI) of the brain was obtained and found symmetric white matter changes, prompting initial evaluation for acute disseminated encephalitis (ADEM). However, his slow steady regression across all developmental domains continued and ultimately he no longer had any verbal communication and developed spastic quadraparesis. His family transferred care to Children’s Hospital of Philadelphia (CHOP)…

Infectious workup including serum studies and lumbar puncture which were negative for HTLV, enterovirus and echovirus polymerase chain reaction (PCR), Lyme, and mycoplasma which were tested in both serum and CSF. He was admitted to CHOP in June 2015 where another lumbar puncture was performed and revealed CSF protein of 90, glucose of 56, 2 red blood cells, and 2 white blood cells per high powered field.  Enterovirus RT-PCR was negative in the CSF as were JC virus, rotavirus, fungal cultures and bacterial cultures and gram stain. Repeat MRI of the brain showed progressive diffuse atrophy and large symmetric T2 hyperintensities predominantly affecting white matter, as well as large bilateral subdural collections. The pattern of bilateral subdurals in addition to white matter lesion in a child with agammaglobulinemia raised suspicion for enterovirus encephalitis, as these imaging findings have been previously described.  A brain biopsy was done in which samples of the meninges, dura, and parenchyma was taken to confirm the diagnosis. Direct tissue sample RT-PCR testing for enterovirus RNA returned positive. Pathology findings showed morphological features of a severe, non-necrotizing, chronic meningoencephalitis and are in keeping with chronic enteroviral meningoencephalitis. Immunohistochemistry staining of biopsy samples for enterovirus was used to confirm the diagnosis. The samples were sent to the Center for Disease Control for further typing via amplification of the nucleotide acid levels and results were consistent with group B human coxsackie virus…

After confirmation from the brain biopsy of enterovirus encephalitis, IVIG was reinitiated at 1g/kg/day for 7 days with a goal of maintaining serum IgG levels above 2000, a serum level which is thought to be high enough to have CSF penetration. IVIG levels over the course of the next 9 months ranged from 1530-6960 mg/dL. Antiviral medications Pleconaril and Pocapavir, thought to prevent enteroviral replication, were sought, but were not available for clinical use at that time…

The patient was started on fluoxetine given recent reports suggesting efficacy of fluoxetine in inhibiting enterovirus replication in vitro. Fluoxetine was considered in the absence of other available treatment agents at that time because it is well known, generally safe, well tolerated, and inexpensive therapy. Fluoxetine was initiated as an adjuvant to IVIG at 0.5mg/kg/day and was slowly titrated up to 2.7 mg/kg/day…

His initial course was remarkable for a halting of clinical regression within 1 week of the initiation of fluoxetine therapy. On examination he had improvements in mental status and once again, became able to track visual stimuli, and make some vocalizations. Two months after initiating treatment, the patient was stable for discharge home with his family. At nine month follow-up after initiation of therapy he had no further loss of skills. He was re-enrolled in school due to noted improvements in attentiveness and response to external stimuli. Tremors and opisthotonic movements, which were previously noted to be persistent, had almost completely ceased. Continued loss of gross and fine motor skills was halted though there was no noted recovery of lost skills…

Zuo et al screened more than 1100 compounds in the Prestwick Chemical Library to identify potentially novel compounds with antiviral efficacy against enteroviruses, and identified fluoxetine hydrochloride    as a candidate drug. They found that fluoxetine and norfluoxetine inhibit enterovirus replication at established therapeutic concentrations using standard therapeutic doses for depression. This process was replicated by Ulferts and colleagues…

In the absence of available and effective anti-enteroviral therapy, fluoxetine deserves further study in this population. The antiviral mechanism of action of fluoxetine is not well understood. However it is proposed that its antiviral activity may be a result of direct interaction with the highly conserved enteroviral 2C protein. This protein is thought to be essential for viral replication through regulation of viral RNA synthesis, though the mechanism is not completely understood. It is also thought that fluoxetine has additional anti-inflammatory effects through inhibition of cytokine release modulated by Toll-like receptor stimulation