Swimming Against the Current
The trials and tribulations of developing a cure for infectious corneal disease
John Dart | | Longer Read
At a Glance
- A systematic study of Acanthamoeba keratitis (AK) has identified risks associated with contact lens hygiene, contaminated water, and swimming or showering while wearing contact lenses
- Introducing polyhexanide therapy has had a dramatic effect on patient outcomes
- Research into AK has had a profound impact on developing new guidelines and regulations for contact lenses and developing new standards of care around the world.
Acanthamoeba keratitis (AK) is a rare infectious corneal disease. But although incidence is low (1 in 100,000 in the EU), it has potentially devastating consequences. In the UK keratoplasty is required in 25 percent of affected eyes (1), blindness (<3/60 acuity) results in 25 percent of eyes and no light perception or enucleation in 2 percent (2). Six to seven percent of UK contact lens users have bilateral infection (1, 3). In countries with a high prevalence of contact lens use, over 85 percent of cases of AK infection stem from wearing contacts, but it can also occur after corneal trauma, particularly in rural environments. AK is on the rise in developing economies and there is no approved drug to treat this disease. Through the systematic study of AK at Moorfields and the UCL Institute of Ophthalmology, including laboratory, epidemiological and clinical research, we have identified avoidable risk factors, developed better techniques for diagnosis, and introduced and developed a class of disinfectants – the biguanides – as topical anti-amoebic therapy.
Hygiene above all
We first established that an epidemic of cases of AK had developed in the UK in contact lens users in the 1990s. Users of the then newly-introduced monthly disposable contact lenses were at particular risk due to the association of these lenses with (subsequently withdrawn) chlorine-based disinfection systems (4). We subsequently showed in two national surveys of AK that the disease was up to 20 times more common in the UK than has been reported elsewhere, and that the incidence was increased in hard water areas; a previous clinical study had shown that limescale build up on domestic taps in hard water areas, harbored Acanthamoeba, probably by providing the mixed microbial microenvironment that the organism favors (3). We then demonstrated that genetically identical organisms, present in their contaminated domestic roof tank supplied water, had infected a high proportion of AK patients (5). We have shown that good contact lens hygiene practice is critical to the prevention of AK, including regular disinfection of lenses and lens case hygiene, or the use of daily disposable lenses, which eliminates the need for lens disinfection and contact lens case use. In addition to hygiene, we have identified the risks of exposure to contaminated water by showering and swimming while wearing contact lenses (3, 6). In 2018, we published an incidence and case control study which has identified a current UK outbreak and some new risk factors, including a contact lens solution containing Oxipol, which was consequently withdrawn as a result of our findings (6). This solution was the only readily modifiable risk factor identified and, since its withdrawal, the numbers of AK cases treated at Moorfields has substantially reduced.
Additionally, our research has demonstrated that diagnosis and treatment within three weeks of onset improves outcomes (7). We were also the first to investigate the value of the identification of Acanthamoeba DNA by PCR as the most sensitive and specific method for the diagnosis of AK, since confirmed by several other independent studies (8). We have also investigated the use of confocal microscopy, another widely used imaging technique for diagnosis, particularly in the USA. We performed a masked multi-observer study and measured the sensitivity and predictive value of this technique and the resulting potential for misdiagnosis (9).
Cleaning the pool
Acanthamoeba is notoriously difficult to treat; the cerebral disease has a high mortality rate. In the eye, disease persists because the cysts are resistant to most antimicrobials. When we recognized the epidemic of cases in the UK, there was little in terms of really effective treatment apart from the use of a diamidine – but resistance was high. As a result, patients needed therapeutic corneal transplant surgery but outcomes were poor with high morbidity. Responding to this serious issue, we collaborated with a protozoologist Simon Kilvington, who suggested polyhexamethylene biguanide (PHMB) – also known as polyhexanide – a swimming pool disinfectant to which the encysted form of Acanthamoeba was susceptible. In 1992, we first described the use of topical PHMB as therapy (10) and then followed this up with clinical studies that showed a dramatic and beneficial effect on outcomes (11). PHMB was rapidly taken up worldwide and is currently recommended as first line treatment by the Centers for Disease Control and Prevention in the USA and the Royal College of Ophthalmologists in the UK (12, 13).
The success of polyhexanide as a therapy was also recognized by the award of an EU grant of more than €4 million to the Orphan Drug for Acanthamoeba Keratitis (ODAK) project in 2012 which was designed to carry out the laboratory and clinical studies required to license PHMB as a medicine. Another biguanide, chlorhexidine, has also been introduced, building on our early work. There are no other anti-amoebics available that are consistently effective against the encysted from of the organism.
The ODAK Acanthamoeba keratitis randomized controlled treatment trial, the last package in the ODAK program of work, started at the end of 2017 and there are six sites in Europe (three in the UK, two in Italy and one in Poland). We have recruited over 100 of the 130 subjects required by the study and expect to complete recruitment at the end of 2019.
The British Contact Lens Association’s Guide for Practitioners now makes several references to our research on risk factors in relation to swimming, extended-wear contact lenses and hygiene related to contact lens cases. Our work has been incorporated into contact lens packaging and led to disposable contact lens cases being supplied with bottles of contact lens solution. Our demonstration that chlorine-based solutions are not effective against AK has led to such solutions being removed from the market – both in the UK and US. PCR for diagnosis of AK is becoming widely used in routine diagnostic laboratories (14). The sensitivity of this technique is between 85 and 95 percent (culture is up to 60 percent), with 100 percent specificity. Our clinical studies have identified the importance of early diagnosis and introduction of appropriate therapy (within three weeks of onset) as the major predictor of disease outcomes, since corroborated by independent studies (15).
Biguanides (PHMB and chlorhexidine) with or without a diamidine (propamidine or hexamidine) have become the standard of care for this condition around the world (16). We have also formulated the only available guidelines both for the management of persistently culture positive cases (about 5 percent of our series) (17) and for the management of the severe scleral inflammation that is associated with the disease, but unrelated to direct invasion of organisms – the major reason for enucleation at our center. Here, the treatment involves the use of systemic immunosuppressive therapy and effective topical anti-amoebic therapy (18).
I am proud to say that our work over the years has had a profound impact on the prevention, diagnosis and treatment of AK today – and into the future.
- D Robaei et al., “Therapeutic and optical keratoplasty in the management of Acanthamoeba keratitis: risk factors, outcomes, and summary of the literature”, Ophthalmology, 122, 17 (2015). PMID: 25262318.
- V Papa et al., “Acanthamoeba keratitis therapy: time to cure and visual outcome analysis for different anti-amoebic therapies in 227 cases”, British J. Ophthalmol [Epub date ahead of print 12.8.2019].
- CF Radford et al., “Acanthamoeba keratitis in England and Wales: incidence, outcome, and risk factors”, Br J Ophthalmol, 86, 536 (2002). PMID: 11973250.
- CF Radford et al., “Risk factors for acanthamoeba keratitis in contact lens users: a case-control study”, Br Med J, 310, 1567 (1995). PMID: 7787645.
- S Kilvington et al., “Acanthamoeba keratitis: the role of domestic tap water contamination in the United Kingdom”, Invest Ophthalmol Vis Sci, 45, 165 (2004). PMID: 14691169.
- N Carnt et al., “Acanthamoeba keratitis: confirmation of the UK outbreak and a prospective case-control study identifying contributing risk factors”, Br J Ophthalmol, 102, 1621 (2018). PMID: 30232172.
- AS Bacon et al., “Acanthamoeba keratitis. The value of early diagnosis”, Ophthalmology, 100, 1238 (1993). PMID: 8341508.
- OJ Lehmann et al., “Polymerase chain reaction analysis of corneal epithelial and tear samples in the diagnosis of Acanthamoeba keratitis”, Invest Ophthalmol Vis Sci, 39, 1261 (1998). PMID: 9620088.
- SC Hau et al. “Diagnostic accuracy of microbial keratitis with in vivo scanning laser confocal microscopy”, Br J Ophthalmol, 94, 982 (2010). PMID: 20538659.
- DF Larkin et al., “Treatment of Acanthamoeba keratitis with polyhexamethylene biguanide”, Ophthalmology, 99, 185 (1992). PMID: 1553206.
- IG Duguid et al., “Outcome of Acanthamoeba keratitis treated with polyhexamethyl biguanide and propamidine”, Ophthalmology, 104, 1587 (1997). PMID: 9331195.
- Centers for Disease Control and Prevention in the USA, “Parasites – Acanthamoeba – Granulomatous Amebic Encephalitis (GAE); Keratitis” (2017). Available at: https://bit.ly/2S7YWLg. Accessed July 11, 2019.
- The Royal College of Ophthalmologists, “Focus: Microbial keratitis” (2013). Available at: https://bit.ly/2YM4qhj. Accessed July 11, 2019.
- B Clarke et al., “Advances in the diagnosis and treatment of acanthamoeba keratitis”, J Ophthalmol (2012). PMID: 23304449.
- DV Patel et al., “Resurgence of Acanthamoeba keratitis in Auckland, New Zealand: a 7-year review of presentation and outcomes”, Clin Experiment Ophthalmol, 38, 15 (2010). PMID: 20447096.
- Medscape, “Acanthmoeba Infection Treatment & Management” (2017). Available at: https://bit.ly/2XJyt7I. Accessed July 11, 2019.
- JJ Pérez-Santonja et al., “Persistently culture positive acanthamoeba keratitis: in vivo resistance and in vitro sensitivity”. Ophthalmology, 110, 1593 (2003). PMID: 12917179.
- A Iovieno, “Acanthamoeba sclerokeratitis: epidemiology, clinical features, and treatment outcomes”, Ophthalmology, 121, 2340 (2014). PMID: 25097155.