Turning a blind eye: HTLV-1-associated uveitis in Indigenous adults from Central Australia

Abstract

Purpose:
We describe the first two cases of HTLV-1 associated uveitis to be associated with HTLV-1c subtype infection.

Methods:
Case report.

Results:
Uveitis was demonstrated in two Indigenous Australian men, both of whom had high HTLV-1c proviral loads in peripheral blood. Visual outcomes were poor in each case.

Conclusion:
Clinicians should be aware of HTLV-1c infection as a cause of uveitis in Australia, and HTLV-1 serology should be included in the basic uveitis work-up in HTLV-1-endemic areas.

Full text

CASE REPORT
Turning a blind eye: HTLV-1-associated uveitis
in Indigenous adults from Central Australia
Rusheng Chew .Timothy Henderson .Jaskirat Aujla .Eline Whist .
Lloyd Einsiedel
Received: 2 December 2016 / Accepted: 17 July 2017 / Published online: 28 July 2017
ÓSpringer Science+Business Media B.V. 2017
Abstract
Purpose We describe the first two cases of HTLV-1
associated uveitis to be associated with HTLV-1c
subtype infection.
Methods Case report.
Results Uveitis was demonstrated in two Indigenous
Australian men, both of whom had high HTLV-1c
proviral loads in peripheral blood. Visual outcomes
were poor in each case.
Conclusion Clinicians should be aware of HTLV-1c
infection as a cause of uveitis in Australia, and HTLV-
1 serology should be included in the basic uveitis
work-up in HTLV-1-endemic areas.
Keywords HTLV-1 Uveitis Central Australia 
Indigenous
Introduction
Central Australia is a vast region of over
1,000,000 km
2
(approximately 10% of the total Aus-
tralian landmass) that is sparsely populated by about
60,000 people, of whom approximately 40% are
Indigenous Australians [1]. Of the Indigenous popu-
lation, the majority reside in over 50 remote commu-
nities, with only a minority living in the principal town
of Alice Springs [2]. There is a well-documented
disparity in health and socio-economic status between
Indigenous and non-Indigenous populations [3].
Infection with the human T cell lymphotropic virus
type 1 (HTLV-1) has recently been recognised to be a
major contributor to morbidity among the Indigenous
inhabitants of Central Australia [4] and has been
extensively studied in other endemic regions, such as
Japan and South America. An inability to control the
number of infected cells in peripheral blood (the
HTLV-1 proviral load; pVL) is associated with an
inflammatory response that may affect diverse organs
including the spinal cord (HTLV-1-associated
myelopathy; HAM) and the eye (HTLV-1-associated
uveitis; HAU) [5,6]. Here we describe the first two
cases of uveitis to be associated with HTLV-1c
subtype infection.
R. Chew L. Einsiedel (&)
Department of Infectious Diseases, Alice Springs
Hospital, PO Box 2234, Alice Springs, NT 0871,
Australia
e-mail: Lloyd.einsiedel@nt.gov.au
R. Chew
Barwon Health, Geelong, VIC, Australia
R. Chew
Mayne Medical School, University of Queensland,
Brisbane, QLD, Australia
T. Henderson J. Aujla E. Whist
Department of Ophthalmology, Alice Springs Hospital,
Alice Springs, NT, Australia
L. Einsiedel
Baker IDI Heart and Diabetes Institute Central Australia,
Alice Springs, NT, Australia
123
Int Ophthalmol (2018) 38:2159–2162
https://doi.org/10.1007/s10792-017-0659-3(0123456789().,-volV)(0123456789().,-volV)

Case 1
A 48-year-old Indigenous man from a remote Abo-
riginal community was referred by an optometrist to
the Alice Springs Hospital Ophthalmology clinic with
reduced visual acuity in the right eye. He had been
symptomatic for at least 2 months and, 2 years prior,
had undergone cataract extraction and intraocular lens
insertion, with a good post-operative result.
Visual acuity (VA) unaided was 6/19 on the right
(pinholes to 6/12) and 6/15 on the left. The right
intraocular pressure was elevated to 55 mmHg. On
examination, ciliary injection was seen in the right
eye. There were small pigmented keratic precipitates,
the corneal stroma was clear, and there were periph-
eral anterior synechiae present, some of which were
heavily pigmented. 2?cells were noted in the anterior
chamber. The vitreous was clear and the retinal vessels
were normal, with no vasculitis or chorioretinitis seen;
however, the view was suboptimal. Examination of
the left eye was unremarkable.
He was otherwise asymptomatic; in particular, he
denied cough or joint pain. An autoimmune screen
returned negative results for anti-cyclic citrullinated
peptide, anti-neutrophil cytoplasmic antibodies,
angiotensin-converting enzyme and HLA-B27. His
syphilis serology was non-reactive, and IFN-crelease
assay for tuberculosis was negative. Serology for
HTLV-1 was positive (HTLV-1 Western blot positive,
National Serological Reference Laboratory (NRL),
Melbourne, Australia), and the HTLV-1 pVL was high
at 2285.41 copies 910
5
peripheral blood leucocytes
(PBL). A diagnosis of glaucoma secondary to uveitis
was made, and treatment was commenced with
prednisolone/phenylephrine eye drops two-hourly,
latanoprost eye drops at night, timolol 0.5% eye drops
twice daily and oral acetazolamide 250 mg thrice
daily. This resulted in a decrease in symptom severity,
indicating a satisfactory initial response to treatment.
After 2 months, his unaided right VA declined to
6/48 (pinhole still 6/12). The cornea was mildly
oedematous, and 1?cells were seen in the anterior
chamber. Retinal examination revealed small pale
areas, with patchy areas of abnormal retinal reflex,
oedema and vasculitis. This indicated posterior seg-
ment involvement, and a tapering course of pred-
nisolone 60 mg daily was commenced. Compliance
with therapy and attendance for review was limited,
and 3 months after initial presentation the intraocular
pressure remained high at 40 mmHg. At 4 months, he
lost vision in the right eye completely and declined
further treatment.
Case 2
A 39-year-old Indigenous man from a remote Abo-
riginal community was referred to the Alice Springs
Hospital Ophthalmology clinic by an optometrist after
complaining of decreased visual acuity in the right eye
for the preceding 5 years. The right eye was not red
and he denied any significant irritation or photophobia.
He had undergone right cataract extraction with
intraocular lens insertion 7 years previously.
When reviewed in the ophthalmology clinic, his
best-corrected VA on the right was 6/24 and on the left
was 6/6. Slit lamp examination showed extensive fine
keratic precipitates in the right eye, and there were 2?
cells in the anterior chamber. There were no signs of
iris transillumination or anterior segment neovascu-
larisation. The vitreous was hazy (2 to 3?vitritis),
making examination of the fundus difficult. The left
eye also had diffuse keratic precipitates, but exami-
nation was otherwise normal, without evidence of
significant active intraocular inflammation. His
intraocular pressures were 20 mmHg on the right
and 10 mmHg on the left. An outreach optometrist had
previously noted significant keratic precipitates in the
right eye.
His medical history was significant for poorly
controlled type 2 diabetes and hypercholesterolaemia.
He had also been exposed to tuberculosis, but did not
have active disease. Serology for HTLV-1 was
positive (HTLV-1 Western blot positive, NRL, Mel-
bourne, Australia), and the HTLV-1 pVL was again
very high (12934.88 910
5
PBL). Tests for autoim-
mune conditions and tuberculosis were not performed.
A diagnosis of right eye uveitis was made, and
corticosteroid-based treatment was initiated. Unfortu-
nately, he was unable to attend follow-up appoint-
ments and was found to have become blind in the right
eye when he presented to hospital for an unrelated
issue 2 years later.
Discussion
HTLV-1 is a human retrovirus that predominantly
infects CD4?T cells. Worldwide, 10–20 million
2160 Int Ophthalmol (2018) 38:2159–2162
123

people are estimated to be infected. The largest
endemic foci are found in Japan (prevalence
10–37%) [7], the Caribbean (1.2–8.4%) [8], Africa
(3–5%) [9,10] and South America (1–5.7%) [9,10].
In endemic areas, the virus is generally transmitted
to infants through breast-feeding or horizontally
among adults by sexual contact [11]. The HTLV-
1c subtype is highly endemic to Central Australia
where seropositivity rates exceed 35% for hospi-
talised Indigenous adults from some regions [4], and
actual prevalence was found to exceed 40% for
Indigenous adults in one remote community [12]. In
vivo, each infected T cell generally contains one
provirus; hence, the proviral load correlates with the
percentage of infected T cells [5]. A HTLV-1 pVL
[1% PBL is associated with an increased risk of
inflammatory disease [13].
As many as 10% of people infected with HTLV-1
develop complications, and each of the major inflam-
matory and non-inflammatory sequelae of HTLV-1
infection, with the exception of HAU, has been
reported in Central Australia [13]. These include adult
T cell leukaemia/lymphoma, HAM, infective dermati-
tis and pulmonary disease [4,14,15]. An impaired
immune response to other pathogens, such as Strongy-
loides stercoralis, also contributes to morbidity and
mortality in this setting of social disadvantage [4].
Although HAU has not been reported previously in
Central Australia, it has been documented in HTLV-1-
infected individuals in Japan [15,16], the Caribbean
[17] and South America [18].
In Japan, where HAU has been best described, the
prevalence of HTLV-1 infection is highest in the
southwest of the country. The association between
HTLV-1 infection and uveitis was clearly demon-
strated in a single-centre study from this region by
Mochizuki et al., which showed that the seropreva-
lence of HTLV-1 infection was significantly higher in
patients with uveitis where no other cause was found
(35%), compared with controls with aetiology-defined
uveitis (10%) or non-uveitic ocular disease (16%)
[15]. A later retrospective study at the same centre
examining the aetiology of uveitis from 1975-2007
revealed HTLV-1 to be the commonest cause of
uveitis, causing 17% of the 1338 cases [16]. HAU
typically affects adults aged less than 50 years and
may be unilateral or bilateral. Iritis (97%), vitreous
opacities (92%) and retinal vasculitis (62%) are the
most common clinical features [15]. The age of our
patients and their clinical findings were therefore
consistent with the diagnosis of HAU.
While the gold standard for the diagnosis of HAU is
detection of HTLV-1 proviral DNA or anti-HTLV-1
antibodies in the aqueous humour, such sampling is
invasive and infrequently done. The diagnosis of
HAU, therefore, relies on positive serology for HTLV-
1 and the exclusion of other causes of uveitis [19].
The pathogenesis of HAU, as with other HTLV-1-
associated inflammatory diseases, is thought to be
related to lymphocyte-driven inflammation mediated
by infected CD4
?
T cells. Indeed, previous studies
have demonstrated a preponderance of these cells in
the aqueous humour, which produce inflammatory
cytokines such as IL-1a, IL-2, IL-3, IL-6, IL-8, IL-10,
TNF-a, IFN-cand GM-CSF [19,20]. Levels of
soluble IL-2 receptors and the proportion of infected
CD4?T cells were also increased in serum and
peripheral blood, respectively [20]. Given the inflam-
matory nature of the HAU, corticosteroid therapy is
effective because it suppresses cytokine production by
the infected T cells [19]. While visual outcomes are
generally good with adherence to treatment, recur-
rence is common and may occur in as many as 60% of
cases [20].
Although it was not possible to obtain humoral
aspirates to confirm the presence of anti-HTLV-1
antibodies or HTLV-1 proviral DNA, the uveitis in our
two cases is very likely to be HTLV-1 associated.
Consistent with cases in other populations, the HTLV-
1 pVL for both cases exceeded 1% PBL. Elsewhere,
HTLV-1 pVL for patients with HAU is substantially
higher than those of asymptomatic carriers [16].
Alternative causes of uveitis were excluded in the
first case, and while we acknowledge that a thorough
screen for many of the other causes of uveitis was not
done in the second case, the HTLV-1 pVL exceeded
10% PBL in that patient. Additionally, the patient in
the second case, despite being diabetic, did not have
anterior segment neovascularisation or other signs of
diabetic eye disease although, as mentioned, exami-
nation of the fundus was difficult.
That the condition has not been reported previously
from Central Australia is likely to reflect the limited
health literacy of remote community residents and
barriers to accessing specialised medical care in this
setting. Significantly, one patient reported progressive
deterioration in vision over a period of 5 years and the
second for several months. Neither was able to adhere
Int Ophthalmol (2018) 38:2159–2162 2161
123

to a complicated medical regimen or attend follow-up.
This may account for the poor outcomes for our two
cases when compared to that reported in the literature.
The two cases presented here in which blindness
resulted in both affected eyes reveal another serious
complication of HTLV-1 infection. Clinicians should
be aware of HTLV-1 infection as a cause of uveitis in
Australia and HTLV-1 serology should be included as
part of the basic uveitis work-up in HTLV-1-endemic
areas. This will allow a more accurate definition of this
clinical entity, its incidence rates and outcomes.
Notwithstanding the morbidity and mortality associ-
ated with HTLV-1 infection in this population, there
remains no coordinated strategy to control the trans-
mission of HTLV-1 among Indigenous Australians
who are generally not informed of the risks associated
with this infection. Improving health literacy in this
context therefore remains a considerable challenge.
Acknowledgements RC wrote the manuscript. LE, TH, JA
and EW revised the manuscript critically. All authors have
approved the final submitted version of the manuscript.
Compliance with ethical standards
Conflicts of interest All authors declare that they have no
conflict of interest.
Ethical approval This article does not contain any research
studies with human participants or animals performed by any of
the authors.
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