Age: 47.0
Sex: M
Vaccine: FLUX
Symptoms: CSF glucose increased, CSF protein normal, CSF red blood cell count positive, CSF white blood cell count increased, Choroidal effusion
Clinical narrative: Case number PHHY2016US155800 is an initial literature report received on 06 Nov 2016. The author presented the case of a patient who suffered three consecutive yearly Herpes Simplex Virus (HSV)-1 central nervous system (CNS) episodes (encephalitis, seizure and retinitis), each within days of his influenza vaccination. This report refers to a 47 year old male patient. His medical history was notable for cold sores as a child. He had insulin dependent diabetes mellitus, hypertension and dyslipidemia. He was vaccinated with FLUARIX (other manufacturer, batch number: not reported) on an unknown date. Ten days after vaccination, he presented to an outside hospital in Nov 2012 with acute fever, aphasia and dysnomia as well as a several day history of weakness, malaise and hiccups. He was tachycardic and 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). He was admitted to the intensive care unit (ICU) for sepsis and dehydration. His lumbar puncture revealed a clear fluid with elevated white blood cell (WBC): 7, red blood cell (RBC): 271 and glucose (188), normal protein and no organisms. A magnetic resonance imaging (MRI) of his brain revealed edema of the left temporal lobe and pre-insular cortices without enhancement. His electroencephalogram (EEG) demonstrated bilateral temporal lobe slowing without epileptiform changes, prompting treatment with intravenous acyclovir for presumed HSV encephalitis (HSE). His cerebrospinal fluid (CSF) polymerase chain reaction (PCR) was positive for HSV-1 DNA  at 100 copies/ml and negative for HSV-2. An MRI, repeated two weeks later, showed enhancement of the left temporal lobe and bilateral insular cortices. His anti-herpetic therapy was transitioned to foscarnet 6 g intravenous (IV) twice daily (BID) and his condition improved. He was discharged to a rehabilitation facility after one month and experienced a good recovery. He tested negative for influenza A or B. His absolute lymphocyte counts were consistently low throughout his hospitalization, between 400 and 800/mm3. The patient was vaccinated with AGRIFLU (batch number: not reported) on an unknown date. The patient presented eleven months later with aphasia and dysnomia three days after receiving vaccination. He was afebrile with a normal total leukocyte count, however his lymphocyte count was again low at 1100/mm3. His 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 he was started on KEPPRA at 500 mg BID. The seriousness of the events were not reported, but the events encephalomalacia and seizure were upgraded as medically significant based on the information available in the NVS-IME list and that of aphasia and HSV reactivation was upgraded as medically significant based on the information available in the source documents. One year later, he FLUZONE (other manufacturer, batch number: not reported) on an unknown date. One day after vaccination, he developed eye received pain, tearing and loss of vision in the left eye. On presentation two days later, his vision was limited to hand motion and he had left afferent pupillary defect, conjunctival hyperemia, optic nerve and retinal edema and scattered retinal hemorrhages. He was referred to the retina service the following day, at which time his vision had deteriorated to light perception only. His fundus exam 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 (ARN) with intravitreal foscarnet (2.4 mg/0.1 ml), sub-Tenon'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). Four days later, his visual acuity was still light perception although improvement was noted in his retinitis and vitritis. He was additionally treated with a 5 day course of 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. His vision improved to hand motion in the temporal field at one year, however his retina remains ischemic with a chronic inferotemporal detachment still under silicone oil tamponade. His exam also showed pallor of the optic nerve and severe vascular attenuation. He 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 CD4 cells at 461/mm3, despite overall normal total leukocyte counts. His immunoglobulin subset levels were normal and demonstrated good reactivity to influenza, tetanus and Varicella zoster. The author stated that in this patient there was a reproducible temporal relationship between sequential influenza vaccinations and HSV reactivation. He first presented with encephalitis just days after vaccination. The following year, he presented with similar, albeit milder symptoms. While HSV was not detected in his CSF at the second presentation, it might have represented transient viral reactivation. His final vaccination preceded HSV infection at a second neurologic site, the retina. Given the widespread safe and efficacious use of influenza vaccinations even in persons with significant immune compromise, there were likely multiple host and viral factors that contributed to this patient's disease. This 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. His immune studies demonstrated normal humoral immunity. He does, however, appeared to have 25 to 75% fewer circulating CD4T cells than normal during these episodes and this could translate to a relative paucity in immune surveillance within the CNS. The author stated that a subtle immunologic deficiency in this patient might have lowered the threshold for clinically significant HSV reactivation in the CNS. Subsequently vaccination might 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 might have triggered viral reactivation directly, or indirectly via neurotoxicity or loss of neurotropic support. The author concluded the article stating that 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.