\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Vogt-Koyanagi-Harada syndrome in the setting of COVID-19 infection}



\author[1]{Tiffany Eatz}%
\author[2]{Jude Charles}%
\affil[1]{University of Miami Miller School of Medicine}%
\affil[2]{University of Miami Hospital and Clinics}%


\vspace{-1em}



  
  \date{June 13, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
To report a case of Vogt-Koyanagi-Harada disease (VKH) in a 27-year-old
male two weeks proceeding COVID-19 infection onset. Severe complications
of VKH can be avoided by early diagnosis and adequate treatment with
corticosteroids and immunosuppressants. It is possible that COVID-19 was
a potential immunological trigger of VKH in our patient.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Vogt-Koyanagi-Harada (VKH) disease is a T-cell mediated multisystemic
autoimmune inflammatory disorder characterized by skin, ocular, auditory
and neurologic involvement. The T-cell mediated granulomatous
intraocular inflammation is responsible for vitritis, disk edema, serous
retinal detachments, and eventual sunset glow
fundus.\textsuperscript{1}T-cells target melanocytes, with an ensuing
cascade leading to four distinct disease phases as follows: prodromal,
uveitis, convalescent, and recurrent.\textsuperscript{2} VKH symptoms
include headache, meningismus, hearing loss, poliosis, alopecia, and
vitiligo.\textsuperscript{3} It is most prevalent in Asians, Native
Americans, Hispanics, and Middle Easterners. If promptly and adequately
treated, patients can experience good outcomes and avoid complications
including sunset glow fundus, cataracts, glaucoma, subretinal fibrosis,
and choroidal neovascularization. Some studies have reported the link
between some viral infections such as cytomegalovirus (CMV) and Epstein
Barr virus (EBV) and the development of VKH. It has been postulated that
similarity between peptides on melanocytes and some exogenous viral
peptides lead to adverse T-cells attacks on melanocytes-containing
tissues and lead to the symptoms seen in VKH.\textsuperscript{4} We
report a case of a VKH syndrome in a patient diagnosed with COVID-19.

\textbf{Case Report}

A 27-year-old male with no significant past medical history presented
with a two-week history of intermittent unilateral headache, bilateral
eye pain with photophobia, and phonophobia, followed by tinnitus and
blurry vision, which ultimately progressed to total bilateral vision
loss. His initial physical exam was unremarkable including vitals,
except for total bilateral visual loss with preserved light perception.
An ophthalmologic exam revealed normal intraocular pressure and
panuveitis with serous retinal detachments bilaterally.

The patient was admitted for further evaluation. Infectious work-up
revealed positive COVID-19 PCR. Other infectious and metabolic panels
were unremarkable. Cerebrospinal fluids studies (CSF), VDRL, FTA,
QuantiFERON gold, flow cytometry, cytology, and cultures were all
negative, except for moderate pleocytosis with lymphocytes predominance
and elevated CSF protein. Cytology was also negative for malignancy.
Computed tomography, B-scan, and magnetic resonance imaging (MRI) showed
bilateral retinal detachment with no optic nerve involvement (Figure 1).
Fundus Fluorescein angiography (FFA)/indocyanine green (ICG) of the
bilateral retinal vessels revealed mottled hyperfluorescence and
hypofluerescence as well as fundus auto fluorescence bilaterally
associated with retinal pigment epithelium detachment consistent with
VKH (Figure 2).

The patient was subsequently diagnosed with VKH. He was treated with
high dose prednisone and was then discharged on a prednisone taper and
methotrexate. Sixteen weeks later, the patient had a visual recovery to
20/60 on the left eye and 20/80 on the right eye, and his symptoms have
since resolved.

\textbf{Discussion}

Since VKH syndrome was firstly described, the need for diagnostic
criteria became evident because of the complexity and the variety of
symptoms associated with the disease. The American Uveitis Society (AUS)
created the initial diagnostic criteria.\textsuperscript{1} However, its
lack of specificity and sensitivity led to the development of the
Revised Diagnostic Criteria (RDC) for VKH disease created by Read et al.
in 2001, which is the standard in current
practice.\textsuperscript{5,6}It includes five criteria: (1) the
exclusion criteria for sympathetic ophthalmia, (2) the exclusion of
other uveitis entities, (3) the ocular manifestations of the early and
late stages, (4) the neurological/auditory findings, and (5) the
integumentary findings.\textsuperscript{7} Based on the presence of all
5 criteria or less, VKH can be categorized as complete, incomplete, and
probable.\textsuperscript{1} Some other attempts to optimize the
criteria were made in China. Although the new study showed higher
sensitivity compared to RDC, its external validity was limited, given it
included only Chinese patients.\textsuperscript{8} Our patient presented
with all the RDC criteria findings except for integumentary. However,
integumentary findings are less common; therefore, the patient was
diagnosed with VKH.

Some authors argue that the diagnosis of VKH can be established through
clinical and imaging findings alone without the need for other ancillary
tests, such as CSF analysis, and ultimately question their
utility.\textsuperscript{9} However, when performed, CSF studies reveal
a lymphocyte predominant pleocytosis in 75\% of
patients.\textsuperscript{1,10} Our patient's CSF study also
demonstrated this finding. It is important to note that CSF analysis
contributes more to ruling out other infectious/inflammatory conditions
than ruling in the diagnosis of VKH,\textsuperscript{11} especially
because the differential diagnoses for VKH-associated uveitis/meningitis
are numerous.\textsuperscript{12} Those differentials include, but not
limited to, other viral meningitis, uveitis, scleritis, syphilis,
carcinoma. Our patient's CSF, meningoencephalitis panel, syphilis
testing, and cytology were negative, and thus, a diagnosis of VKH was
favored.\textsuperscript{13}

Imaging study has been reported to be positive in 75 to 100\% of the
patients.\textsuperscript{1,5,6,12,14} Yang et al. reported retinal
detachment in 87\% in a series of 261 patients on optical coherence
tomography and hypo and hyperfluorescence on ICG and FFA in 91\% of the
patients.\textsuperscript{8} All of those findings were seen in our
patient. Leptomeningeal enhancement is reported in the
literature\textsuperscript{15} and was also observed in our patient.

There is no definitive etiological mechanism to explain the instigation
of the pathogenesis of VKH. Over time, accumulating evidence has shown
that genetic factors, including VKH disease-specific risk factors
(HLA-DR4) and general risk factors for immune-mediated diseases (IL-23R)
play a role in the development of VKH disease. However, dysfunction of
the immunological response of both the innate and adaptive immune
system, independent of congenital mutations, is involved as well,
triggered by environmental and microbiological factors. These
microbiological factors majorly consist of viruses, which have been
discovered in patients with VKH disease. Symptoms of such viruses may
even be observed in the VKH prodromal phase. Cellular and molecular
mimicry is thought to be the triggering factor for VKH. For instance,
tyrosinase enzyme is found mostly in melanocytes and has a similar
peptide sequence as one of the proteins seen in CMV. Therefore,
antibodies against CMV cross react with this enzyme and lead to VKH
symptoms.\textsuperscript{1,4} Patients with VKH had been reported to
have positive CSF for EBV and CMV, though the pathogenesis is
unclear.\textsuperscript{2,12,16}

Although COVID-19 PCR tests are positive for about 5-8 days after
symptom onset, patients may continue to test positive for up to 3 months
after their infection.\textsuperscript{17,18} Therefore, it is possible
that the immunological trigger for VKH in our patient was COVID-19 if
COVID infection onset was prior to the 2-week history of VKH symptom
onset, or during the prodromal VKH phase. Santamaria et al. reported one
of multiple possible associations between COVID-19 and
VKH.\textsuperscript{19} Their patient presented six weeks after acute
respiratory infection and was found to have positive COVID-19 viral PCR
in addition to typical VKH findings.\textsuperscript{19}

Many other ocular manifestations of COVID-19 infection have been
reported in a systematic review by Aggarwal.\textsuperscript{20} He
reported that ocular manifestations are found in 8\% to 15\% of COVID-19
infected patients. Such manifestations include, but not limited to,
follicular conjunctivitis, eye redness, ocular pain and
discharges.\textsuperscript{20} Panuveitis and unilateral optic neuritis
were also reported.\textsuperscript{21}

COVID-19 has viral endovascular, neurological, and ophthalmological
manifestations. The novel SARS-CoV-2 virus may cause atypical
neurological impairment via ischemic and immunological alteration due to
megakaryocyte infiltration.\textsuperscript{22} COVID-19 has been
demonstrated to cause not only both hemorrhagic and thrombotic stroke,
venous sinus thrombosis, endotheliosis, but also dysfunction of smell
and taste, muscle injury, Guillain-Barre syndrome, and encephalopathy,
most likely mediated by neurotoxins and dysfunctional immunological
response.\textsuperscript{23--25} Demonstrated by ophthalmological
research, clinical observation, and analysis of social media
posts,\textsuperscript{26} SARS-CoV-2 has also been found to instigate
conjunctivitis, anterior uveitis, retinitis, and optic neuritis in
patients.\textsuperscript{27--29} It is not beyond reason that given
COVID-19's immunological, neurological, and ophthalmological
manifestations, it was the possible inducing microbiological trigger in
the development of VKH disease in our patient.

Although the definitive underlying mechanism by which COVID-19 can
trigger VKH has yet to be elucidated, decreased immune tolerance,
increased antigenicity, spike protein toxicity, and molecular mimicry
are plausible. VKH has even been reported in patients after COVID-19
vaccines in various instances.\textsuperscript{30,31} Nevertheless, we
also acknowledge that due to a high rate of COVID-19 infection, the
association between COVID-19 and VKH could be fortuitous.

\textbf{Conclusions}

VKH is a rare and potentially debilitating disorder in which severe
complications can be avoided by early diagnosis and adequate treatment.
It is imperative to keep up with advancing radiological and
technological advancements to enable optimization of the rate of VKH
diagnosis. Corticosteroids and immunosuppressants remain the mainstay of
treatment for VKH. COVID-19 would be a potential immunological trigger
of VKH in our patient if COVID-19 infection onset was prior to the
2-week history of VKH symptom onset or during VKH prodromal phase.
Further investigation is necessary to establish whether this hypothesis
is valid.

\textbf{Keywords:} VKH, COVID-19, comorbid, rare, infectious disease,

\textbf{Patient Consent}

Consent to publish the case report was not obtained. This report does
not contain any personal information that could lead to the
identification of the patient.

\textbf{Funding}

None

\textbf{Conflicts of Interest}

The following authors have no financial disclosures or personal
conflicts of interest: JC, TAE.

\textbf{Authorship}

All authors attest that they meet the current ICMJE criteria for
Authorship.

\textbf{Acknowledgments/Disclosures}

All procedures performed in this study involving a human participant
adhered to the 1964 Declaration of Helsinki and its later amendments.
Collection of information in this report complied with the Health
Insurance Portability and Accountability Act of 1996.

References

1. O'Keefe GAD, Rao NA. Vogt-Koyanagi-Harada disease. \emph{Surv
Ophthalmol} . 2017;62(1):1-25. doi:10.1016/j.survophthal.2016.05.002

2. Du L, Kijlstra A, Yang P. Vogt-Koyanagi-Harada disease: Novel
insights into pathophysiology, diagnosis and treatment. \emph{Prog Retin
Eye Res} . 2016;52(1):84-111. doi:10.1016/j.preteyeres.2016.02.002

3. Patil Y, Garg R, Rajguru J, et al. Vogt--Koyanagi--Harada (VKH)
syndrome: A new perspective for healthcare professionals. \emph{J Fam
Med Prim Care} . 2020;9(1). doi:10.4103/jfmpc.jfmpc\_787\_19

4. 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. \emph{Int
Ophthalmol} . 2007;27(2-3):87-95. doi:10.1007/s10792-006-9020-y

5. Read RW, Holland GN, Rao NA, et al. Revised diagnostic criteria for
Vogt-Koyanagi-Harada disease: Report of an international committee on
nomenclature. \emph{Am J Ophthalmol} . 2001;131(5):647-652.
doi:10.1016/S0002-9394(01)00925-4

6. Rao NA, Sukavatcharin S, Tsai JH. Vogt-Koyanagi-Harada disease
diagnostic criteria. \emph{Int Ophthalmol} . 2007;27(2-3):195-199.
doi:10.1007/s10792-006-9021-x

7. Depeursinge A, Racoceanu D, Iavindrasana J, et al. Fusing Visual and
Clinical Information for Lung Tissue Classification in HRCT
Data.\emph{Artif Intell Med} . Published online 2010:ARTMED1118.
doi:10.1016/j

8. Yang P, Zhong Y, Du L, et al. Development and evaluation of
diagnostic criteria for vogt-koyanagi-harada disease. \emph{JAMA
Ophthalmol} . 2018;136(9):1025-1031.
doi:10.1001/jamaophthalmol.2018.2664

9. Tsai JH, Sukavatcharin S, Rao NA. Utility of lumbar puncture in
diagnosis of Vogt-Koyanagi-Harada disease. \emph{Int Ophthalmol} .
2007;27(2-3):189-194. doi:10.1007/s10792-007-9044-y

10. Kitaichi N, Matoba H, Ohno S. The positive role of lumbar puncture
in the diagnosis of Vogt-Koyanagi-Harada disease: Lymphocyte subsets in
the aqueous humor and cerebrospinal fluid. \emph{Int Ophthalmol} .
2007;27(2-3):97-103. doi:10.1007/s10792-006-9016-7

11. Norose K, Yano A, Aosai F, Segawa K. Immunologic analysis of
cerebrospinal fluid lymphocytes in Vogt-Koyanagi-Harada
disease.\emph{Investig Ophthalmol Vis Sci} . 1990;31(7):1210-1216.

12. Damico FM, Kiss S, Young LH. Vogt-Koyanagi-Harada
disease.\emph{Semin Ophthalmol} . 2005;20(3):183-190.
doi:10.1080/08820530500232126

13. Kato Y, Kurimura M, Yahata Y, Tajima K, Kato T.
Vogt-Koyanagi-Harada's disease presenting polymorphonuclear pleocytosis
in the cerebrospinal fluid at the early active stage. \emph{Intern Med}
. 2006;45(12):779-781. doi:10.2169/internalmedicine.45.1669

14. El Sanharawi M, Sandali O, Naudet F. Ultrasound biomicroscopy of the
ciliary body in ocular/oculodermal melanocytosis. \emph{Am J Ophthalmol}
. 2013;156(3):627-628. doi:10.1016/j.ajo.2013.05.030

15. Lohman BD, Gustafson CA, McKinney AM, Sarikaya B, Silbert SC. MR
imaging of Vogt-Koyanagi-Harada syndrome with leptomeningeal
enhancement. \emph{Am J Neuroradiol} . 2011;32(9):169-171.
doi:10.3174/ajnr.A2279

16. Hayasaka Y, Hayasaka S. Almost simultaneous onset of
Vogt-Koyanagi-Harada syndrome in co-workers, friends, and
neighbors.\emph{Graefe's Arch Clin Exp Ophthalmol} .
2004;242(7):611-613. doi:10.1007/s00417-004-0888-9

17. Vargas-Ferrer J, Zamora-Mostacero V. Re-Detectable Positive RT-PCR
Test Results in Recovered COVID-19 Patients: The Potential Role of
ACE2.\emph{Disaster Med Public Health Prep} . 2020;14(4):E36-E37.
doi:10.1017/dmp.2020.276

18. Esteve C, Catherine FX, Chavanet P, Blot M, Piroth L. How should a
positive PCR test result for COVID-19 in an asymptomatic individual be
interpreted and managed? \emph{Med Mal Infect} . 2020;50(8):633-638.
doi:10.1016/j.medmal.2020.09.014

19. Santamaria A, Chang J, Savarain C. SARS-CoV-2 among the Potential
Viral Triggers for Vogt-Konayagi-Harada Disease: First Case Report and
Literature Review. \emph{Ocul Immunol Inflamm} . 2021;00(00):1-7.
doi:10.1080/09273948.2021.1966052

20. Aggarwal K, Agarwal A, Jaiswal N, et al. Ocular surface
manifestations of coronavirus disease 2019 (COVID-19): A systematic
review and meta-analysis. \emph{PLoS One} . 2020;15(11 11):1-20.
doi:10.1371/journal.pone.0241661

21. Benito-Pascual B, Geg\selectlanguage{ngerman}úndez JA, Díaz-Valle D, et al. Panuveitis and
Optic Neuritis as a Possible Initial Presentation of the Novel
Coronavirus Disease 2019 (COVID-19). \emph{Ocul Immunol Inflamm} .
2020;28(6):922-925. doi:10.1080/09273948.2020.1792512

22. Nauen DW, Hooper JE, Stewart CM, Solomon IH. Assessing Brain
Capillaries in Coronavirus Disease 2019. \emph{JAMA Neurol} .
2021;78(6). doi:10.1001/jamaneurol.2021.0225

23. Yu H, Sun T, Feng J. Complications and Pathophysiology of COVID-19
in the Nervous System. \emph{Front Neurol} . 2020;11.
doi:10.3389/fneur.2020.573421

24. Koralnik IJ, Tyler KL. COVID-19: A Global Threat to the Nervous
System. \emph{Ann Neurol} . 2020;88(1). doi:10.1002/ana.25807

25. Koralnik IJ, Tyler KL. COVID-19: a global threat to the nervous
system Running head: Neurologic manifestations of COVID-19. \emph{Wiley
Online Libr} . 2020;88(1).

26. Eatz T, Al-Khersan H, Tanenbaum R, Sridhar J. Does social media have
a place in ophthalmology practice? \emph{Expert Rev Ophthalmol} .
2021;16(5). doi:10.1080/17469899.2021.1941877

27. Seah I, Agrawal R. Can the Coronavirus Disease 2019 (COVID-19)
Affect the Eyes? A Review of Coronaviruses and Ocular Implications in
Humans and Animals. \emph{Ocul Immunol Inflamm} . 2020;28(3).
doi:10.1080/09273948.2020.1738501

28. Pascarella G, Strumia A, Piliego C, et al. COVID-19 diagnosis and
management: a comprehensive review. \emph{J Intern Med} . 2020;288(2).
doi:10.1111/joim.13091

29. Bettach E, Zadok D, Weill Y, Brosh K, Hanhart J. Bilateral anterior
uveitis as a part of a multisystem inflammatory syndrome secondary to
COVID-19 infection. \emph{J Med Virol} . 2021;93(1).
doi:10.1002/jmv.26229

30. Saraceno JJF, Souza GM, dos Santos Finamor LP, Nascimento HM,
Belfort R. Vogt-Koyanagi-Harada Syndrome following COVID-19 and ChAdOx1
nCoV-19 (AZD1222) vaccine. \emph{Int J Retin Vitr} . 2021;7(1).
doi:10.1186/s40942-021-00319-3

31. Papasavvas I, Herbort CP. Reactivation of Vogt-Koyanagi-Harada
disease under control for more than 6 years, following anti-SARS-CoV-2
vaccination. \emph{J Ophthalmic Inflamm Infect} . 2021;11(1).
doi:10.1186/s12348-021-00251-5

\textbf{Hosted file}

\verb`VKH Figures.docx`  available at \url{https://authorea.com/users/486084/articles/571213-vogt-koyanagi-harada-syndrome-in-the-setting-of-covid-19-infection}

\selectlanguage{english}
\FloatBarrier
\end{document}

