The incidence of uveitis after vaccination is thought to be of the order of 10.5 in 100,000 person-years.1 Although a number of immunological factors have been implicated including immune complex deposition, adjuvant effects, and molecular mimicry, the precise mechanisms and antigens that underlie vaccine-induced uveitis remain unclear.2,3 We describe a patient who presented with bilateral panuveitis and exudative retinal detachments resembling Harada disease after vaccination against human papilloma virus (HPV).
A 20-year-old white woman presented with acute-onset blurred vision bilaterally 3 weeks after her second injection of quadrivalent HPV (HPV4) vaccine (Gardasil; Merck, Kenilworth, NJ). The first injection had been administered 7 months previously. The patient was myopic (spherical equivalent: −4). There was no history of headache, systemic or ocular disease, or ocular trauma; no neurological, auditory, or skin changes were evident. A recent pregnancy test result had been negative.
Best-corrected visual acuity (BCVA) was 20/60 in both eyes. Aqueous flare was noted with occasional inflammatory cells in the anterior chamber and vitreous. There were no keratitic precipitates. The patient had bilateral diffuse neurosensory retinal detachments at the posterior poles with yellowish subretinal exudation at the fovea (Figure 1). Fluorescein angiography revealed bilateral disc leakage, with staining of a peripheral retinal vessel in the left eye. Late pooling of fluorescein within the exudative retinal detachments was noted, and it was unclear whether any diffuse leakage at the level of the RPE contributed to sequestration of subretinal fluid. Midperipheral yellowish choroidal lesions, seen on color photography, correlated spatially with foci of hypofluorescence during the mid-phase of the angiogram (Figures 1C–D).
Fundus findings at presentation. (A) Color photographs of the posterior poles show exudative macular detachments. (B) Fluorescein angiography shows disc hyperfluorescence with leakage with late pooling of fluorescein into the right subretinal space. (C–D) Color photograph and fluorescein angiogram temporal to the macula (registered images) show yellowish choroidal lesions that correlate with hypofluorescent foci in the transit phase. (E–F) Enhanced-depth horizontal spectral-domain optical coherence tomography sections through the right and left foveae. The choroid is thickened at the posterior pole to beyond the depth range of the scan.
Spectral-domain optical coherence tomography (SD-OCT) with enhanced-depth imaging confirmed the presence of multiple elevations of the neurosensory retina with intervening areas of persistent retinal attachment; the subretinal fluid exhibited a degree of hyper-reflectivity (Figures 1E–F). The choroid was thickened at the posterior pole, especially below the fovea, beyond the depth range of the OCT device. Subfoveal choroidal thickness measured by ultrasound exceeded 1,000 µm (Figure 2).
Ultrasound B-scan of the left eye at presentation. Choroidal thickness measures 1,100 µm (yellow caliper points), and exudative macular detachment is noted (arrowhead).
Laboratory findings revealed a raised erythrocyte sedimentation rate (29 mm/h) and positive HLA-DRB1*0405 haplotype (Table). Chest X-ray findings were normal.
The patient was started on oral prednisolone 60 mg daily for 2 weeks, followed by a tapering regimen leading to discontinuation at 6 weeks due to rapid improvement.
One month after presentation, the anterior uveitis and exudative retinal detachments had resolved and visual acuity improved to 20/25 bilaterally. During follow-up, choroidal thickness reduced to 400 µm at 1 month and 300 µm at 3 months. At 5 months, choroidal thickness had stabilized at 300 µm, with BCVA of 20/20 and 20/25 in the right and left eyes, respectively (Figure 3).
Fundus findings at 5 months. Color photographs and enhanced-depth spectral-domain optical coherence tomography of both eyes. Choroidal thickness is approximately 400 µm.
Our patient presented with acute visual deterioration attributable to a panuveitis with exudative retinal detachment 3 weeks after receiving a second dose of HPV4 vaccine. She experienced a rapid response to oral prednisolone without recurrence after treatment was discontinued. The differential diagnosis essentially includes a vaccine-induced response or a coincidental episode of uveitis resembling Harada disease.
Uveitis has been reported as an adverse effect of various vaccines, including Bacille-Calmette-Guerin,3 measles-mumps-rubella,4 hepatitis B,2 and varicella zoster5 vaccines. Choroidopathy with “ampiginous” features has been reported as a complication of the HPV4 vaccine.6
Holt et al. have examined pooled reports from the National Registry of Drug-Induced Ocular Side Effects (Casey Eye Institute, Portland, OR), finding 24 cases of uveitis occurring after HPV4 vaccination, all in women and girls. They also described a 17-year-old girl with bilateral uveitis occurring 2 weeks after HPV4 vaccination, treated topically. Although the initial response was favorable and inflammation remained quiescent during a tapering regimen, anterior uveitis recurred after a second dose of HPV4.7
Vogt-Koyanagi-Harada (VKH) disease refers to a spectrum of idiopathic cell-mediated autoimmune disorders characterized by granulomatous panuveitis with serous retinal detachments. Neurological and integumentary features may develop, and cross-reactivity with melanocyte antigens is believed to account for the pattern of tissue involvement. Isolated ophthalmic disease is also recognized and referred to as Harada disease.8
VKH is more common in patients of Asian, Middle Eastern, Hispanic, and Native American descent. The target antigen is unknown, but certain HLA class 2 serotypes, such as HLA-DR4 (HLA-DRB1*04), HLA-DR53, and HLA-DQ, are associated with VKH in different ethnic groups.9 A recent meta-analysis concluded that HLA-DRB1*0405 and *0410 carry odds ratios of 10.3 and 6.5, respectively, for developing VKH, with the strongest associations in East Asians.10 It has also been hypothesized that persistence of Epstein-Barr virus and cytomegalovirus antigens may represent a chronic cross-reactive stimulus that accounts for the prolonged inflammation in VKH.11,12
Tao et al. have described two patients with VKH-like disease after vaccination against influenza H1N1, both of whom responded rapidly to corticosteroid treatment without subsequent recurrence.13 These cases featured fluorescein angiographic findings similar to those of our patient, but without the peripheral retinal leaking vessel that our patient exhibited.
Our patient presented with features similar to those of VKH, but without any prodromal illness or extraocular features. The history was negative for any factors predisposing to VKH or Harada disease, as traditionally described. Although our patient carries the HLA-DRB1*0405 suballele, her rapid and apparently definitive recovery, after a relatively short course of corticosteroids, is atypical of Harada disease, which usually requires at least 3 to 6 months of treatment, often with steroid-sparing immunosuppressants.14 In this respect, her clinical course more closely resembles vaccine-induced uveitis, and the temporal correlation of her disease onset with the second vaccine dose is suggestive of a causal rather than coincidental relationship.13 Moreover, if virus-related hypotheses for VKH are to be considered, the non-replicating nature of vaccine antigen may account for the abbreviated clinical course; and if this is the case, it is plausible that our patient might have developed a more chronic or severe manifestation had she not been vaccinated and had instead acquired HPV infection. We postulate that in her case, the first dose of HPV4 sensitized the immune system, and that the second dose triggered an autoimmune uveitis.
Although uveitis and choroidopathy have been reported after administration of HPV4, we have not uncovered any previous reports of Harada-like manifestations. Vaccine-induced immunological sequelae can be difficult to distinguish from coincidental autoimmune disease. It is therefore important for ophthalmologists to be aware of the possible association between vaccination and a Harada-like reaction and to ask appropriately directed questions when obtaining history from young patients with uveitis.
- Klein NP, Ray P, Carpenter D, et al. Rates of autoimmune diseases in Kaiser Permanente for use in vaccine adverse event safety studies. Vaccine. 2010;28(4):1062–1068. doi:10.1016/j.vaccine.2009.10.115 [CrossRef]
- Fraunfelder FW, Suhler EB, Fraunfelder FT. Hepatitis B vaccine and uveitis: an emerging hypothesis suggested by review of 32 case reports. Cutan Ocul Toxicol. 2010;29(1):26–29. doi:10.3109/15569520903427717 [CrossRef]
- Spratt A, Key T, Vivian AJ. Chronic anterior uveitis following bacille Calmette-Guerin vaccination: molecular mimicry in action?J Pediatr Ophthalmol Strabismus. 2008;45(4):252–253. doi:10.3928/01913913-20080701-15 [CrossRef]
- Islam SM, El-Sheikh HF, Tabbara KF. Anterior uveitis following combined vaccination for measles, mumps and rubella (MMR): a report of two cases. Acta Ophthalmol Scand. 2000;78(5):590–592. doi:10.1034/j.1600-0420.2000.078005590.x [CrossRef]
- Naseri A, Good WV, Cunningham ET Jr, . Herpes zoster virus sclerokeratitis and anterior uveitis in a child following varicella vaccination. Am J Ophthalmol. 2003;135(3):415–417. doi:10.1016/S0002-9394(02)01957-8 [CrossRef]
- Khalifa YM, Monahan PM, Acharya NR. Ampiginous choroiditis following quadrivalent human papilloma virus vaccine. Br J Ophthalmol. 2010;94(1):137–139. doi:10.1136/bjo.2009.159293 [CrossRef]
- Holt HD, Hinkle DM, Falk NS, Fraunfelder FT, Fraunfelder FW. Human papilloma virus vaccine associated uveitis. Curr Drug Saf. 2014;9(1):65–68. doi:10.2174/15748863113086660062 [CrossRef]
- Read RW, Holland GN, Rao NA, et al. Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an international committee on nomenclature. Am J Ophthalmol. 2001;131(5):647–652. doi:10.1016/S0002-9394(01)00925-4 [CrossRef]
- Islam SM, Numaga J, Fujino Y, et al. HLA class II genes in Vogt-Koyanagi-Harada disease. Invest Ophthalmol Vis Sci. 1994;35(11):3890–3896.
- Shi T, Lv W, Zhang L, Chen J, Chen H. Association of HLA-DR4/ HLA-DRB1*04 with Vogt-Koyanagi-Harada disease: a systematic review and meta-analysis. Sci Rep. 2014;4:6887. doi:10.1038/srep06887 [CrossRef]
- Minoda H, Sakai J, Sugiura M, Imai S, Osato T, Usui M. [High inducibility of Epstein-Barr virus replication in B lymphocytes in Vogt-Koyanagi-Harada disease]. Nippon Ganka Gakkai Zasshi. 1999;103(4):289–296.
- Sugita S, Takase H, Kawaguchi T, Taguchi C, Mochizuki M. Cross-reaction between tyrosinase peptides and cytomegalovirus antigen by T cells from patients with Vogt-Koyanagi-Harada disease. Int Ophthalmol. 2007;27(2–3):87–95. doi:10.1007/s10792-006-9020-y [CrossRef]
- Tao Y, Chang LB, Zhao M, Li XX. Two cases of exudative retina detachment and uveitis following H1N1 influenza vaccination. Chin Med J (Engl). 2011;124(22):3838–3840.
- Attia S, Khochtali S, Kahloun R, Zaouali S, Khairallah M. Vogt-Koyanagi-Harada Disease. Exp Rev Ophthalmol. 2012;7(6):565–585. doi:10.1586/eop.12.63 [CrossRef]
Laboratory Investigations at Presentation
|Complete blood count||WNL|
Laboratory Investigations at Presentation