Age: 47.0
Sex: M
Vaccine: FLU3
Symptoms: Hyponatraemia, Immunoglobulins normal, Influenza A virus test negative, Influenza B virus test, Influenza virus test negative
Clinical narrative: This case was reported in a literature article and described the occurrence of herpes simplex encephalitis in a 47-year-old male patient who received FLUARIX. The patient's past medical history included cold sores (as child). Concurrent medical conditions included dyslipidemia, insulin-dependent diabetes mellitus and hypertension. On an unknown date, the patient received FLUARIX at an unknown dose. On an unknown date, less than a month after receiving FLUARIX, the patient experienced herpes simplex encephalitis (serious criteria hospitalization and GSK medically significant), sepsis (serious criteria hospitalization and GSK medically significant), dehydration (serious criteria hospitalization), fever (serious criteria hospitalization), aphasia (serious criteria hospitalization), weakness (serious criteria hospitalization), malaise (serious criteria hospitalization), hiccups (serious criteria hospitalization), tachycardia (serious criteria hospitalization), leukocytosis (serious criteria hospitalization), hyponatremia (serious criteria hospitalization), hypochloremia (serious criteria hospitalization) and hyperglycemia (serious criteria hospitalization). The patient was treated with acyclovir and foscarnet. On an unknown date, the outcome of the herpes simplex encephalitis, sepsis, dehydration, fever, aphasia, weakness, malaise, hiccups, tachycardia, leukocytosis, hyponatremia, hypochloremia and hyperglycemia were recovered/resolved. The reporter considered the herpes simplex encephalitis, sepsis, dehydration, fever, aphasia, weakness, malaise, hiccups, tachycardia, leukocytosis, hyponatremia, hypochloremia and hyperglycemia to be related to FLUARIX. Additional information was provided. This case was reported in a literature article and described the occurrence Herpes simplex virus 1 herpesvirus encephalitis (HSV-1 HSE) in a 47-year-old male patient who was vaccinated with FLUARIX (GlaxoSmithKline). The patient had insulin-dependent diabetes mellitus, hypertension and dyslipidaemia. The patient's medical history was notable for cold sores as a child. The patient did not have a recent history of orolabial herpetic infection, nor did he suffer from frequent colds or other viral illnesses to suggest a generalized immunologic deficiency. No information on patient's family history or concomitant medication was provided. On an unspecified date in 2012, the patient received FLUARIX (administration route and site unspecified; dosages unknown; batch number not provided). On an unspecified date in November 2012, 10 days after the vaccination, the patient presented to an outside hospital with acute fever, aphasia and dysnomia as well as with several day history of weakness, malaise and hiccups. The patient was tachycardic. Laboratory evaluation revealed a leukocytosis (12,400/mm3) without bandemia as well as hyponatremia (129 meq/L), hypochloremia (93 meq/L) and hyperglycemia (270 mg/dL) (normal range not provided for all). The patient was admitted to the intensive care unit (ICU) for sepsis and dehydration. The patient's lumbar puncture revealed clear fluid with elevated white blood cells (WBC) (7), red blood cells (RBC) (271) and glucose (188), normal protein (normal range not provided for all) and no organisms. A magnetic resonance imaging (MRI) of brain revealed oedema of the left temporal lobe and pre-insular cortices without enhancement. The patient's electroencephalogram demonstrated bilateral temporal lobe slowing without epileptiform changes, prompting treatment with intravenous acyclovir for presumed HSV encephalitis. The patient's cerebrospinal fluid-polymerase chain reaction (CSF-PCR) was positive for HSV-1 DNA at 100 copies/mL and negative for HSV-2. 2 weeks later, a repeated MRI showed enhancement of the left temporal lobe and bilateral insular cortices. The patient's anti-herpetic therapy was transitioned to foscarnet 6 g IV BID and his condition improved. The patient tested negative for influenza A or B. His absolute lymphocyte counts were consistently low throughout his hospitalisation, between 400 and 800/mm3. After 1 month, the patient was discharged to a rehabilitation facility and experienced a good recovery. 11 months later, the patient presented with aphasia and dysnomia 3 days after receiving AGRIFLU (Novartis). The patient was afebrile with a normal total leukocyte count, however his lymphocyte count was again low at 1100/mm3. The patient's symptoms resolved within hours without anti-viral treatment and a non-contrast MRI demonstrated only left temporal lobe encephalomalacia which was felt to be sequelae of his prior HSE. EEG demonstrated bilateral temporal slowing without epileptiform discharges. This episode was diagnosed as a temporal lobe seizure related to structural compromise and the patient was started on prophylactic KEPPRA at 500 mg BID. 1 year later, the patient developed eye pain, tearing and loss of vision in the left eye 1 day after receiving FLUZONE (Sanofi Pasteur). 2 days later on presentation, the patient's vision was limited to hand motion and he had a left afferent pupillary defect, conjunctival hyperaemia, optic nerve and retinal oedema and scattered retinal haemorrhages. The following day, the patient was referred to the retina service, at which time his vision had deteriorated to light perception only. The patient's fundus examination revealed mild vitritis, retinal whitening, vascular sheathing and peripheral choroidal effusions. Fluorescein angiography demonstrated occlusive vasculitis. An aqueous fluid sample was sent for PCR and the patient was empirically treated for viral retinitis (acute retinal necrosis) with intravitreal foscarnet (2.4 mg/0.1 mL), subtenon's triamcinolone (40 mg) and oral valacyclovir (1000 mg BID). The aqueous fluid PCR was positive for HSV-1 (150,000 copies/mL) and negative for HSV-2, varicella-zoster virus (VZV) and cytomegalovirus (CMV). 4 days later, the patient's visual acuity was still light perception although improvement was noted in his retinitis and vitritis. The patient was additionally treated with a 5-day course or oral prednisone at 60 mg daily. Over the ensuing weeks severe retinal atrophy progressed with the development of several atrophic holes and the retina became totally detached. The patient underwent a pars plana vitrectomy, air-fluid exchange, endolaser and silicone oil fill. At 1 year, the patient's vision improved to hand motion in the temporal field; however his retina remains ischemic with a chronic inferotemporal detachment still under silicone oil tamponade. The patient's examination also showed pallor of the optic nerve and severe vascular attenuation. The patient was being maintained on valacyclovir (500 mg daily) for life and had been advised to avoid future influenza vaccination. Laboratory studies at this time, again revealed decreased total lymphocytes 1200/mm3 as well as CD4T cells at 461/mm3, despite overall normal total leukocyte counts. The patient's immunoglobulin subset levels were normal and demonstrated good reactivity to influenza, tetanus and varicella zoster. The patient's immune studies demonstrated normal humoral immunity. He does, however, appeared to have 25-75% fewer circulating CD4T cells than normal during the episodes. This case was considered serious due to hospitalisation. The authors considered the event of HSV-1 HSE related to the FLUARIX. The authors stated that "in our patient, there was a reproducible temporal relationship between sequential influenza vaccinations and HSV reactivation. He first presented with encephalitis just days after vaccination." The authors concluded that "A subtle immunologic deficiency in our patient may have lowered the threshold for clinically significant HSV reactivation in the CNS. Subsequently, vaccination may have drawn the T cells normally involved in CNS immune surveillance toward the vaccine response, allowing viral reactivation to proceed unchecked. Additionally, vaccine-induced inflammatory cytokines may have triggered viral reactivation directly or indirectly via neurotoxicity or loss of neurotrophic support. The current influenza vaccines are extraordinarily safe and efficacious, even in patients with severe immune deficiencies and pre-existing CNS disease, with the reported neurologic sequelae existing at the level of case reports. This case divulges, not the perils of influenza vaccination, but the complexity of the HSV-1-host interface, and begs for greater understanding, and therapeutic manipulation, of the forces that govern it." The article is not available for regulatory submission due to copyright restriction.