Amid the ongoing challenges of COVID-19, Optometry Tasmania (O-TAS) stepped up to welcome delegates to the annual Tasmanian Lifestyle Congress, a hybrid event held from 6–8 August at Hobart’s Wrest Point Hotel. Among a packed weekend of lectures were two presentations covered here – ocular manifestations of COVID-19 by Professor Nitin Verma and the latest on gene therapy by Professor Brendan Vote.
Delegates this year were fortunate to hear from the esteemed Professor Nitin Verma, who has practised as an ophthalmologist in Tasmania for the past 20 years and is the current President of the Royal Australian and New Zealand College of Ophthalmologists (RANZCO).
Congratulating the organisers in his opening remarks, Prof Verma said, “A congress like this, where there are people present, when you’re not talking to a screen, is very rare”.
With COVID in the background, Prof Verma advised optometrists to have a high index of suspicion for COVID when a patient presents with conjunctivitis
The original site for the Ophthalmic Gene Therapy Centre.
Despite the general fatigue of COVID-19, Prof Verma succeeded in engaging the attention of the audience, online and in the room, by bringing the focus of this insidious virus to its ocular manifestations.
Calling on all eye care professionals to work together and support each other through the pandemic, he said this virus, and particularly the Delta strain, is “serious business, it’s not a cold or flu anymore”.
The risk of death from COVID-19 in Australia is one in 35 (at the time of the presentation). Between 10 and 30% of people who contract COVID-19 will suffer long-term consequences.
The prevalence of ophthalmic manifestations among COVID-19 patients ranges from 2–32%. While their causal relationship with SARS-COV-2 is yet to be established with certainty, it is important to recognise manifestations and take appropriate action.
The most common ocular manifestation is conjunctivitis because we have ACE2 receptors on the surface of the eye, to which the SARS-COV-2 protein will bind. Viral keratoconjunctivtis, haemorrhagic and pseudomembranous conjunctivitis, episcleritis and Kawasaki disease-like syndrome in children have also been reported in patients with COVID-19.
With COVID in the background, Prof Verma advised optometrists to have a high index of suspicion for COVID when a patient presents with conjunctivitis, and if possible make sure they are the last patient seen on any day.
Additionally, he recommended undertaking a thorough ophthalmic examination, using all safety measures, to rule out more common causes like bacterial, chlamydial, adenoviral or microsporidial diseases. Patients with conjunctivitis should be specifically asked about COVID-19 related symptoms and advised to get tested if present.
Further studies are necessary to determine if conjunctiva can be a portal of entry and reservoir for the virus, however he advised to use protective shields, especially ones that concave towards yourself – particles can spread to up to two metres.
Other anterior manifestations include meibomian orifice abnormalities and lid margin hyperemia/telangiectasia, found in 38% of patients in an Italian study by Meduri et al. Blepharitis positively correlated with the COVID-19 disease duration, and Prof Verma said this may develop as a late manifestation of the disease. The incidence is also expected to rise in the post-pandemic era, especially in patients with pre-existing ocular surface alterations.
With COVID in the background, Prof Verma advised optometrists to have a high index of suspicion for COVID when a patient presents with conjunctivitis
A number of posterior segment manifestations of COVID-19 have been reported, and these typically take place 12 or so days after onset of symptoms. There are ACE2 receptors in the retina and we know the virus has been detected in the retina in post-mortem enucleated eyes.
Patterns of posterior segment involvement reported in COVD-19 infections include occlusion of the central retinal artery, or central and branch retinal vein; acute macular neuroretinopathy, paracentral acute middle maculopathy (PAMM), vitritis, acute retinal necrosis, and serpiginous choroiditis.
Neuro-ophthalmic manifestations may include papillophlebitis, optic neuritis, Adies Tonic pupil, Miller Fisher syndrome and cranial N palsy, neurogenic ptosis, and cerebrovascular accidents.
Orbital manifestations could include dacryoadenitis, retroorbital pain, orbital cellulitis and sinusitis, mucormycosis and orbital histiocytic lesion.
Ophthalmic Gene Therapy Centre, at completion stage.
Mucormycosis (Black Fungus), in particular needs to be recognised urgently. Not uncommon in India prior to COVID-19, cases reported have since sky-rocketed in that country, perhaps because people in the community are sharing respiratory equipment, usually only accessible in hospitals, and doing so without sterilisation.
Prof Verma said mucormycosis, which has been described quite extensively in the media, is sight-threatening and, if you miss it, your patient will die. Fast referral is critical.
Mucormycosis occurs later in the course of the infection, and is caused by three different types of angio-invasive fungi: mucormycosis, aspergillus and scedosporium. These fungi get into the blood vessels, enabling them to travel from the sinuses, to the orbital apex, the eye, the cavernous sinus and the brain.
Risk factors are considered to include poorly controlled diabetes, insulin resistance, injudicious corticosteroid use, hematological malignancies, bone marrow and organ transplantation, being immunocompromised, neutropenia and contamination of respirators and ventilators from non-sterile water and gases.
Treatment requires neurosurgery, ear nose and throat, and ophthalmology specialists. Intravenous anti-fungals are the key.
When summarising these ocular manifestations reported in COVID-19 patients, Prof Verma said, whether any or all of these conditions are the result of a pre-existing systemic condition, whether the virus has, in fact, aggravated the underlying condition, whether the virus causes direct damage to the nerves, vessels, and other structures or whether it is ultimately the body’s own immune system responsible for the pathology, are some of the unanswered questions which would take larger population based studies with standardised methods of examination, investigations and data collection to resolve. While the viral RNA has been identified in different parts of the eye, its replication and infectivity is not established.
Other Implications
Other ocular implications of COVID-19 have included a seven-fold increase in conjunctival and corneal injury among children, caused by alcohol-based sanitisers compared to 2019.
A large study comparing myopia progression in 123,535 children in China (Feiching) in 2020 against children five years ago, found a three times shift in those under six-years-of-age; two times greater in sevenyear- olds and 1.4 times greater in eight-year olds. This is expected to be due to increased screen time and decreased outdoor time.
There has been extensive discussion about the use of CRISPRCas-9 for gene therapy, but do we really know what it means?
In Australia, there have been reports of cerebro-spinal fluid leakages as a result of over-exuberant swabbing during COVID-19 tests (if a patient presents post-test with a headache and leaking fluid, send them straight to hospital).
Summarising his presentation, Prof Verma said the key to getting COVID-19 under control is vaccinations and he emphasised the extremely low risk profile of the vaccines available. He said unified messaging is also key and that’s where all eye care professionals come in: understand COVID; understand the COVID guidelines (and follow them); have a plan in place for the practice including guidelines for use of PPE, and be able to contact trace.
“Get vaccinated, encourage patients to get vaccinated, give the correct advice, get tested if you have symptoms,” he said.
Just as importantly, he implored the audience to support each other in these stressful times.
GENE THERAPY COMING
Professor Brendan Vote, who established the Tasmanian Eye Institute in 2008, was excited to announce that Hobart’s much anticipated Ophthalmic Gene Therapy Centre has been built and, subject to Therapeutic Goods Administration certification and approval, should be ready to open its doors later this year.
“For more than 20 years, we’ve heard the promise of genetics. This is the future of our treatments,” he told the audience.
With a long-held interest in the promise of genetics and spurred on by colleague Professor Alex Hewitt, Prof Vote has been phenotyping patients and coding their clinical diagnosis for many years.
Phenotype, from the Greek phainen (to show) and tupos (type), refers to the set of observable characteristics of an individual resulting from the interaction of its genotype with the environment; thus they reflect the nature and the nurture of the organism (Wanscher 1975; Mayr 1982; Henig 2001, Jewell 2001).
The phenotypes Dr Vote has collected from 500 patients have contributed to international research and significant findings about disease pathways that may lead to new therapies.
Examples include findings: strengthening the notion that complement dysregulation (C4A) plays a crucial role in age-related macular degeneration (AMD) etiology; finding of a positive genetic correlation between primary open angle glaucoma and AMD (not previously described); and identification of the first genetic association signal specific to wet AMD, near Matrixmetalloproteinase 9 (MMP9).
Rare or Not so Rare
Gene therapies, which effectively edit genetic sequences, have progressed rapidly, from being studied in test-tubes just nine years ago to being used to treat patients. This means the future for diseases like retinitis pigmentosa and Best’s disease is bright. However, there are many challenges for gene therapy:
- We need to identify the gene (the problem),
- We need to make the gene (the solution),
- We need to deliver the gene to the right place and switch it on (or off) without eliciting a host immune response,
- We need to ensure the gene doesn’t disrupt other gene functions (off target effects), and
- We need treatments that are cost effective.
The many rare (or orphan) genetic diseases we see require an individualised approach (personalised) and genetic sequencing (diagnosis) alone has, in the past been prohibitive. Dr Vote explained that while the first gene sequencing cost over AU$1million, that cost has been reduced dramatically and gene sequencing is now possible for $100, which makes genotyping (diagnosis) more feasible.
CRISPR-Cas-9
There has been extensive discussion about the use of CRISPR-Cas-9 for gene therapy, but do we really know what it means?
Dr Vote explained that CRISPR-Cas-9 – or clustered regularly interspaced short palindromic repeat – was first identified in the 1980s.
The repeated palindromic (mirrored) patterns in DNA are part of an ancient bacterial immune response to a virus. When a bacteria gets infected and survives a virus, it puts the DNA data code of the virus in between the DNA palindrome repeats. Then, whenever a virus comes along, the bacteria is able to recognise (using CRISPR) the viral DNA as foreign and cuts it out (disables it).
Cas-9 is the protein that disables the virus, and researchers identified that Cas-9 can also be used to remove and replace mutated DNA.
“CRISPR is a personalised medicine, it’s a bit like pathology, pharmacy and the medicine all rolled in to one – you have to diagnose the pathology of the specific defect and that’s where phenotyping comes in; then we have to develop the specific genetic therapy in a sterile environment, and then we have to deliver that cure,” explained Dr Vote.
While there are challenges associated with this, he said CRISPR is coming to Australia within the next year.
Ophthalmic Gene Therapy Centre
It was back in 2016, with CRISPR on the near horizon, that Prof Hewitt came up with the idea of developing Australia’s first Ophthalmic Gene Therapy Centre in Hobart. Dr Vote jumped on board and has gone to extraordinary lengths to raise awareness, support and funds – including bleaching, dying and shaving his hair.
“We needed a sterile, TGA approved centre and we thought, why not Hobart where Prof Hewitt is based?” Dr Vote said.
The centre has now been built and, once it receives TGA certification – which should be later this year – Dr Vote says the work to cure patients can begin.
“Alex has cures ready to go – the instant we’re ready and open with certifications, we’re ready to go with patients and cures.”
To find out more or provide support, visit www.tasmanianeye.org. Tasmanian Eye Institute is a fully registered charity with ACNC with deductible gift recipient (DGR) status, so all donations are fully tax deductible and philanthropic funds are eligible to provide donations/support.
