Age: 11.0
Sex: F
Vaccine: HPV4
Symptoms: Immunoglobulin therapy, Insomnia, Laboratory test normal, Migraine, Mouth ulceration
Clinical narrative: This literature marketed report has been received from the authors of a published article and refers to an 11-year-old patient. On an unknown date, the patient received her first dose of GARDASIL vaccine (dose, route of administration, lot# and expiration date were not reported) at a well-child visit. She had been healthy aside from sinus surgery and frequent infections. Prior immunology evaluation was negative, but there was a family history of autoimmune disease. Two days postvaccination, she developed headache and vomiting thought due to a viral illness. Her symptoms were progressive, however, and by 5 to 6 weeks postvaccination, there was abdominal pain, frequent vomiting, severe fatigue, pallor, daily syncope, chest pain, dyspnea, low-grade fevers, arthralgias, daily headache, memory loss, tinnitus, hearing loss, vertigo, unsteady gait, leg weakness, muscle twitches, paresthesias, and insomnia. By 7 weeks postvaccination, she had become bed-bound. She also developed moderate alopecia, Raynaud's phenomenon, recurrent oral ulcers, and nasal scabbing, suggesting the possibility of systemic autoimmunity. Eight months postvaccination, she was diagnosed with postural tachycardia syndrome (POTS) and neurocardiogenic syncope (NCS) by tilt table testing and autonomic reflex testing revealed abnormal blood pressure response to Valsalva and reduced baroreflex adrenergic sensitivity. Nonautoimmune causes for her symptoms were excluded with laboratory testing, echocardiogram, cardiac monitoring and brain magnetic resonance imaging. The autoimmune dysautonomia panel antibodies, NMDA (N-methyl-d-aspartate) receptor antibodies, thyroid antibodies, and celiac antibodies were all negative. Testing for Sjogren's syndrome (including the early Sjogren's antibodies), antiphospholipid syndrome (with primary and secondary antibodies) and lupus was also negative. However, autoantibodies against adrenergic and muscarinic receptors were detected (Anti-beta-1 adrenergic receptor antibodies: 21.7 units/ml (positive), anti-ßbeta-2 adrenergic receptor antibodies: 11.4 units/ml (indeterminate), anti-muscarinic cholinergic receptor-3 antibodies:13.5 units/ml (positive) and anti-muscarinic cholinergic receptor-4 antibodies: 24.9 units/ml (positive)). The patient did improve with conservative therapy, but she remained moderate to severely disabled by her illness. Small fiber neuropathy was suspected due to her cardiovascular and presumed gastrointestinal autonomic dysfunction as well as the presence of muscle twitches and paresthesias, and a skin biopsy was performed (from the lower legs as normative data were available) to evaluate for this possibility (biopsy results: Epidermal Nerve Fiber Density: left lower leg: 8.1/mm (normal), right lower leg: 8.6/mm (normal); Sweat Gland Nerve Fiber Density: left lower leg:16.7% (abnormal), right lower leg: 27.5% (abnormal). Given the patient's young age (13 years at the time of the biopsy), these results were consistent with a very severe autonomic neuropathy and likely a mild to moderate small fiber sensory neuropathy. Given evidence for autoimmune autonomic neuropathy, a trial of intravenous immunoglobulin therapy was initiated. After four months of therapy at a dose of 1 gm/kg monthly, the patient continues to gradually improve. Her COMPASS-31 score has improved from 46 to 29 and her estimated level of functioning has improved from 20% (mostly bedridden) to 60% (more good days than bad days). The earliest signs of improvement came after the second week of treatment. Her recurrent syncope and paresthesias have resolved. Her epigastric pain, migraines, insomnia, anxiety, fatigue, and cognitive ability have all moderately improved and she had been able to stop her biweekly saline infusions. She continued on monthly intravenous immunoglobulin. The outcome of autonomic neuropathy, syncope, small fibre neuropathy and autoimmune neuropathy was reported as recovered/resolved. The outcome of systemic immune activation and postural orthostatic tachycardia syndrome was reported as recovering/resolving. The authors considered postural orthostatic tachycardia syndrome, systemic immune activation, autoimmune neuropathy, small fibre neuropathy, autonomic neuropathy and syncope to be related to GARDASIL. All the events were considered to be disabling by the reporter. Upon internal review, the events of systemic immune activation, autoimmune neuropathy and autonomic neuropathy were considered to be medically significant.