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PostPosted: Fri May 08, 2015 9:59 am 
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Ebola Persistance in Ocular Fluid during Convalescence - NEJM

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1500306

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PostPosted: Fri May 08, 2015 10:04 am 
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Persistence of Ebola Virus in Ocular Fluid during Convalescence
Jay B. Varkey, M.D., Jessica G. Shantha, M.D., Ian Crozier, M.D., Colleen S. Kraft, M.D., G. Marshall Lyon, M.D., Aneesh K. Mehta, M.D., Gokul Kumar, M.D., Justine R. Smith, M.B., B.S., Ph.D., Markus H. Kainulainen, Ph.D., Shannon Whitmer, Ph.D., Ute Ströher, Ph.D., Timothy M. Uyeki, M.D., M.P.H., M.P.P., Bruce S. Ribner, M.D., M.P.H., and Steven Yeh, M.D.

From the Department of Medicine, Division of Infectious Diseases (J.B.V., C.S.K., G.M.L., A.K.M., B.S.R.), the Department of Ophthalmology (J.G.S., G.K., S.Y.), and the Department of Pathology and Laboratory Medicine (C.S.K.), Emory University School of Medicine, and the Centers for Disease Control and Prevention
(M.H.K., S.W., U.S., T.M.U.) — both in Atlanta; the Infectious Diseases Institute, Mulago Hospital Complex, Kampala, Uganda (I.C.); and Flinders University, Adelaide, SA, Australia (J.R.S.).

Address
reprint requests to Dr. Yeh at the Department of Ophthalmology, Emory University School of Medicine, 1365B Clifton Rd.NE, Atlanta, GA 30322, or at steven.yeh@emory.edu.
This article was published on May 7, 2015, at NEJM.org.
DOI: 10.1056/NEJMoa1500306

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PostPosted: Fri May 08, 2015 10:06 am 
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Summary
Among the survivors of Ebola virus disease (EVD), complications that include uveitis can develop during convalescence, although the incidence and pathogenesis of EVD-associated uveitis are unknown. We describe a patient who recovered from EVD and was subsequently found to have severe unilateral uveitis during convalescence. Viable Zaire ebolavirus (EBOV) was detected in aqueous humor 14 weeks after the onset of EVD and 9 weeks after the clearance of viremia.

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PostPosted: Fri May 08, 2015 10:07 am 
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The current outbreak of EVD is believed to have begun in December 2013.1
As of April 26, 2015, a total of 26,312 cases of EVD (including 10,899 deaths) had been reported in six countries in West Africa (i.e., Sierra Leone, Liberia, Guinea, Mali, Nigeria, and Senegal), the United States, the United
Kingdom, and Spain.2
The outbreak has also resulted in the largest number of EVD survivors in history.
Among survivors of EVD, late complications that include ocular disease can develop during convalescence.3,4 However, few systematic studies have been conducted on post-EVD sequelae, so the incidence and clinical manifestations of postEVD ocular complications are unclear. Here, we report the clinical course of a man
in whom severe, acute, unilateral uveitis developed during the convalescent phase of EVD. We also report the detection of viable EBOV in aqueous humor obtained from the inflamed eye 14 weeks after the onset of the initial symptoms of EVD and 9 weeks after the clearance of viremia.

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PostPosted: Fri May 08, 2015 10:09 am 
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Case Report
A previously healthy 43-year-old male physician received a diagnosis of EVD on
September 6, 2014, while he was working in an Ebola treatment unit in Kenema,
Sierra Leone. He was transferred to Emory University Hospital in Atlanta and arrived
4 days after the onset of symptoms. He was treated with an experimental
small interfering RNA antiviral agent (TKM-100802, Tekmira Pharmaceuticals),
convalescent plasma, and aggressive supportive care.5
The hospital course was complicated by multiorgan system failure requiring
mechanical ventilation for 12 days and hemodialysis for 24 days.6
After extubation,
the patient had altered mental status, difficulty walking related to severe proximal
weakness and deconditioning, and extreme fatigue.
On day 44 of the illness, hemodialysis was
no longer required and his mental status had
markedly improved, with some residual mild
word-finding difficulty. Ambulation was limited
to short distances because of exertional fatigue.
Blood and urine tested negative for EBOV on
quantitative reverse-transcriptase–polymerasechain-reaction
(RT-PCR) assay on serial specimens,
and he was discharged home. A semen
sample obtained on the day of discharge was
positive for EBOV RNA on quantitative RT-PCR
assay, and EBOV was isolated from semen by
means of culture at the Centers for Disease Control
and Prevention (CDC).7
The patient was advised
to abstain from sex or to use condoms for
at least 3 months.8
Longitudinal monitoring of
semen specimens for EBOV is ongoing.
After discharge, 10 weeks after the onset of
EVD symptoms, the patient’s word-finding difficulty
and exercise tolerance were markedly
improved, but he had new symptoms, including
low back pain involving the right lumbar and
sacroiliac region, bilateral enthesitis of the
Achilles’ tendon, and paresthesias involving the
distal lower limbs. Ophthalmic symptoms, which
began shortly after discharge from the hospital,
included occasional bilateral ocular burning,
foreign-body sensation, and photophobia. He
required an adjustment in his prescription for
reading glasses, which suggested an accommodative
change. His ocular history was clinically
significant only for myopia. He was referred to
the Emory Eye Center for further evaluation.
On initial evaluation in November 2014, the
patient’s visual acuity was 20/15 bilaterally while
wearing eyeglasses. Intraocular pressure, pupils,
ocular motility, and confrontational visual fields
were normal. The examination of the anterior
eye by means of slit lamp was normal. The examination
of the dilated posterior eye revealed
previously undocumented multiple, peripheral
chorioretinal scars with hypopigmented halos in
both eyes and a small intraretinal hemorrhage
adjacent to one scar in the left eye (Fig. 1). He
received the diagnosis of posterior uveitis (i.e.,
chorioretinitis), a likely sequela of EVD. Close
clinical follow-up was planned.
One month later, 14 weeks after the diagnosis
of EVD, he presented with an acute onset of redness,
blurred vision with halos, pain, and photophobia
in the left eye. Visual acuity was measured
at 20/15 in the right eye and 20/20 in the
left eye. The left intraocular pressure was highly
elevated at 44 mm Hg (normal value, 10 to 21).
Slit-lamp examination of the left eye showed
conjunctival injection, mild corneal edema, rare
nongranulomatous keratic precipitates, and grade
1+ leukocytes and protein (flare) in the anterior
chamber (Fig. 2). Examination of the anterior
chamber with gonioscopy indicated no signs of
angle closure. Dilated funduscopic examination
showed stable chorioretinal scars in both eyes
with no other signs of ocular inflammation. He
received a diagnosis of anterior uveitis and ocular
hypertension in the left eye. Treatment was
started with eyedrops containing 1% prednisolone
acetate four times daily and with ocular
hypotensive agents including acetazolamide (at a
dose of 500 mg orally twice daily), eyedrops
containing 0.2% brimonidine twice daily, and
eyedrops containing 2% dorzolamide and 0.5%
timolol twice daily. Results of laboratory testing,
including measurement of the erythrocyte sedimentation
rate and C-reactive protein, were
normal; rapid plasma reagin testing and serologic
analysis for Toxoplasma gondii were negative.
Because of escalating anterior-chamber inflammation
and worsening symptoms during
the subsequent 48 hours, the frequency of administration
of prednisolone acetate was increased
to every 2 hours, and eyedrops containing
1% atropine twice daily were added. After
another 24 hours of increasing inflammation
and concern about an infectious cause, paracentesis
of the anterior chamber was performed,
with aspiration of 170 μl of aqueous humor
through a sterile 30-gauge needle while the practitioner
was wearing gloves and a surgical mask.
The specimen was double-bagged and delivered
to a dedicated laboratory at Emory University
Hospital for testing samples from patients with
EVD. Testing was performed by clinical laboratory
technologists who were trained in the safe
handling of infectious pathogens and with the
use of the standard institutional operating protocols.9
The aqueous humor tested positive for
EBOV RNA on quantitative RT-PCR assay, with a
cycle threshold value of 18.7. EBOV was isolated
from this specimen by means of a viral culture
performed at the CDC.7
A conjunctival swab obtained
before the procedure and tear-film specimens
collected before the procedure and 24 hours
after the procedure tested negative for EBOV RNA
on quantitative RT-PCR assay. In addition, a
specimen of peripheral blood tested negative for
EBOV RNA on quantitative RT-PCR assay. Preliminary
analyses of EBOV sequenced from blood
during the patient’s hospitalization for symptomatic
EVD, as compared with EBOV sequenced
from ocular fluid, identified a single nonsynonymous
mutation, as well as two silent mutations
and two mutations in noncoding regions. The
significance of these mutations is unknown.
However, these findings are in contrast to results
that showed no changes in viral consensus
sequences acquired over several days from a
single patient.10 All personal protective equipment
and materials that were used during paracentesis
and laboratory testing were sterilized by
means of autoclaving before disposal.11
The uveitis continued to progress; by 5 days
after the onset of symptoms, visual acuity in the
left eye was decreased to 20/60. Anterior-segment
examination revealed scleritis and persistent
anterior uveitis. Intermediate uveitis (i.e.,
vitritis, with grade 0.5+ haze) was noted on examination
of the dilated posterior segment. Oral
prednisone (at a dose of 1 mg per kilogram of
body weight per day) was started. Ophthalmic
drops of 1% prednisolone acetate every 2 hours,
0.5% timolol twice daily, and 1% atropine twice
daily were continued in the left eye.
During the subsequent 72 hours, the patient’s
condition improved, with resolution of the scleritis
and a decrease in the anterior uveitis. Despite
this improvement in the anterior-segment
inflammation, the vitritis worsened, resulting in
a decrease in visual acuity to 20/400 in the left
eye at 1 week (Fig. 3). On examination 3 months
after presentation with uveitis, the vitritis was
resolving and left visual acuity had recovered to
20/15. Follow-up ophthalmic evaluations are ongoing.

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PostPosted: Fri May 08, 2015 10:10 am 
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Discussion
We describe the detection of viable EBOV in the
aqueous humor of the eye in a patient in recovery
from EVD with acute panuveitis (a combination
of anterior, intermediate, and posterior
uveitis). In a previous EVD outbreak, EBOV RNA
was detected on RT-PCR assay in a conjunctival
sample obtained from a 25-year-old patient 22
days after the onset of symptoms and 10 days
after viremia had cleared. In that patient, 45 days
after the onset of EVD symptoms, posterior uveitis
developed; the patient did not undergo any
additional testing of ocular tissue.4
Marburg virus,
a filovirus like EBOV, has also been associated
with uveitis during convalescence. In 1975,
Marburg virus was cultured from the aqueous
humor of a patient with acute anterior uveitis
that developed nearly 3 months after the onset
of acute illness.12 Viral culture of the patient’s
aqueous humor that was sampled 2 weeks later
was negative.13
Although the pathogenesis of EVD-associated
uveitis is unknown, we believe that the severe,
acute panuveitis that developed in our patient
was a direct cytopathic effect of active replication
of EBOV persisting in an immune-privileged
organ. The acute onset of symptoms, unilateral
location, and extreme elevation of intraocular
pressure that were seen in our patient are clinical
findings similar to infectious uveitis syn- dromes caused by herpesviruses, in which the
pathogenesis is known to be a direct consequence
of active viral replication.14,15 Although
the relative contribution of lytic viral infection,
as compared with immunologic reaction to
EBOV, in the pathogenesis of our patient’s aggressive
panuveitis is unclear, the low cycle
threshold on quantitative RT-PCR assay shows
that a high burden of viable EBOV was present
at the time that the patient’s ocular symptoms
were worsening. Further studies to investigate
the mechanisms responsible for the ocular persistence
of EBOV and the possible presence of
the virus in other immune-privileged sites (e.g.,
in the central nervous system, gonads, and articular
cartilage) are warranted.
Few systematic studies have examined postEVD
sequelae, so the incidence and clinical
manifestations of post-EVD ocular complications
are uncertain. Of 71 EVD survivors from
the 1995 Ebola outbreak in the Democratic Republic
of Congo, 20 were enrolled in a small,
retrospective study.4
Three of the 20 survivors in
this limited sample were found to have evidence
of uveitis (anterior, posterior, or panuveitis) that
occurred 42 to 72 days after the onset of EVD.
Data on the incidence of ocular complications
among survivors of the current West African
EVD outbreak are also limited. Although 40% of
participants in a recent survey of 85 EVD survivors
in Sierra Leone reported having “eye problems,”
the incidence of uveitis in this cohort is
unknown.16
In conclusion, our patient’s recovery from
EVD was complicated by acute anterior uveitis,
which rapidly evolved into a sight-threatening
panuveitis with detection of persistent EBOV
within the eye. This case highlights an important
complication of EVD with major implications for
both individual and public health that are immediately
relevant to the ongoing West African
outbreak. It is reassuring that samples of conjunctivae
and tears tested negative for EBOV, a
finding that supports previous studies suggesting
that patients who recover from EVD pose no
risk of spreading the infection through casual
contact.3,17 Further studies are needed to assess
the persistence of EBOV during convalescence,
to elucidate the mechanisms underlying this
persistence in ocular and other immune-privileged
tissue sites, and to develop strategies for
the clinical management of EVD complications.

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PostPosted: Fri May 08, 2015 10:11 am 
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The findings and conclusions in this report are those of the
authors and do not necessarily represent the official position of
the CDC.
Supported by a grant from the National Center for Advancing
Translational Sciences of the National Institutes of Health
(UL1TR000454, to the Atlanta Clinical and Translational Science
Institute), an unrestricted grant from Research to Prevent
Blindness and a grant from the National Eye Institute (P30-
EY06360, to the Department of Ophthalmology, Emory University
School of Medicine), and a fellowship grant from the Australian
Research Council (FT130101648, to Dr. Smith).
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Alison Boess and the family of Dr. Ian Crozier; staff
members at the Biotechnology Core Facility Branch of the CDC
for their assistance in generating viral sequences; Dr. William
Bornstein, Dr. Bryce Gartland, Crystal Evans, Maureen Lindsey,
Brian Frislie, Emily Beck, Connie Wilbanks, Paula DesRoches,
and all the investigators at the Emory Serious Communicable
Diseases Unit; Kimberly Lovitt, Rhonda Waldron, Debora Jordan,
Jannah Dobbs, Matthew Raeber, and the staff at the Department
of Ophthalmology at Emory University; and Dr. Monica Farley
and the staff at the Division of Infectious Diseases at Emory
University.

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PostPosted: Fri May 08, 2015 10:12 am 
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Suppl 1:S28-S35.

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