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Acanthamoeba Keratitis: A New Normal
EDITORIALS Acanthamoeba Keratitis: A New Normal ELMER Y. TU
2014 MARKS ROUGHLY 10 YEARS SINCE THE START OF THE
outbreak of Acanthamoeba keratitis in the Chicago area,1 and I am still continually asked whether we’re ‘‘seeing cases’’. These hopeful questioners cover the spectrum of interested parties including those working in the contact lens industry, cornea specialists, and people who are simply interested in the story. At the University of Illinois Eye and Ear Infirmary, our hope, too, is that answer is no, but the disappointing answer is an unqualified yes. We have logged well over 150 cases in the past decade, with an increasing number of those patients losing the long, painful battle to avoid loss of their eye. The larger question that nobody has a definitive answer for is what can or should be done about it. As it stands now, what started out as 2 similar-appearing outbreaks of atypical contact lens-related keratitis in the mid 2000s could not have taken more divergent paths.2 The first outbreak of Fusarium keratitis related to contact lens wear was reported in Singapore and subsequently in the United States. In the span of 1 year, its association with Renu with Moistureloc (Bausch & Lomb, Rochester, New York, USA) was identified, the product was withdrawn from the worldwide market, and a follow-up study was performed confirming the expected sharp reduction in cases.3,4 Highly effective contact lens disinfectants even against fungal pathogens in vitro, Renu with Moistureloc’s failures were widely regarded freak occurrences, something that could not be anticipated by any reasonable means and unlikely to occur again. Case closed. Contemporaneously, a sharp increase in the number of Acanthamoeba keratitis cases was noted at both the Wills Eye Institute and the University of Illinois Eye and Ear Infirmary.1,5 Not unreasonably, a very similar study of risk factors was conducted by the Centers for Disease Control and Prevention, with many investigators expecting a similar solution or material-based association as was seen in the Fusarium outbreak. Both the Centers for Disease Control and Prevention study and an interim analysis of our ongoing study of potential environmental risk factors for Acanthamoeba identified the use of Complete See accompanying article on page 460. Accepted for publication Jun 13, 2014. From the Department of Ophthalmology and Visual Sciences, University of Illinois Eye and Ear Infirmary, Chicago, Illinois. Inquiries to Elmer Y. Tu, Department of Ophthalmology and Visual Sciences, University of Illinois Eye and Ear Infirmary, 1855 West Taylor Street (M/C 648), Room 3.164, Chicago, IL 60612; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2014.06.007
Ó
2014 BY
Moistureplus (Abbot Medical Optics, Santa Ana, California, USA [formerly known as Advanced Medical Optics]) as a significant risk factor.6,7 Detailed in our early publications, however, the geographic nature of our outbreak and the increase in cases with all contact lens disinfection systems were clear warning signs that this outbreak would be very different.1,7 Unfortunately, the recall of Complete Moistureplus did not have the desired result. A multicenter survey later confirmed that the number of cases of Acanthamoeba keratitis remained at historically high levels for the United States sites,8 consistent with the single-center experience at the University of Illinois Eye and Ear Infirmary. This prompted a second outbreak investigation, designed very similarly to the first and conducted by the Centers for Disease Control and Prevention in 2011, which, to date, has not identified any additional causative risk factors.9 Taken together, the abrupt, significant rise in the number of Acanthamoeba keratitis cases and the failure to identify definitively a dominant contact lens care-related cause strongly suggest that an exposure risk leading to Acanthamoeba keratitis has changed fundamentally. Because no remaining contact lens materials or disinfection systems have been identified as having a higher relative risk of developing Acanthamoeba keratitis, it also seems likely that they are all equally effective, or ineffective, as most in vitro studies suggest.10 Regardless of the source or your preferred test of efficacy against Acanthamoeba, current practices and materials, as a whole, are by definition insufficient to suppress the current outbreak. Until funding and effort are directed toward the goal of understanding its origin, it seems that contact lens wearers and corneal subspecialists are constrained to accept a new baseline incidence for Acanthamoeba keratitis, approximately 10 times higher than before 2004. Faced with this new level of unmodified risk, the only remaining options are to convert patients to a moderately more costly option of daily disposable contact lenses or to improve our ability to disinfect contact lenses. However, neither has been shown to eliminate the risk of Acanthamoeba keratitis completely. At the time—unlike during the Fusarium keratitis outbreak—the Food and Drug Administration pushed strongly to develop mandatory standardized disinfection standards against Acanthamoeba for contact lens disinfection systems where none had existed previously. Whatever the motivation, this proactive approach to the
ELSEVIER INC. ALL
RIGHTS RESERVED.
417
Acanthamoeba keratitis outbreak seems almost prescient now in anticipating the persistence of the Acanthamoeba keratitis outbreak 1 decade later. Although these new standards are being developed and tested on many parallel tracks both at the Food and Drug Administration and within the contact lens industry,11 it seems unlikely that many of the contact lens disinfection systems currently in common use would comply with these new standards. This would be a result consistent with the clinical experience, because Acanthamoeba keratitis infections continue to be seen in users of all of these disinfection systems, including 1-step hydrogen peroxide systems. Developing new standards and new disinfection systems is a long, difficult process challenged primarily to balance efficacy and toxicity. In this month’s issue of the Journal, Lonnen and associates report the preliminary results of a novel ultraviolet disinfection system that seems to largely satisfy these needs in a simple, rapid manner effecting a 3log unit reduction of Acanthamoeba cysts with minimal, if any, change to the shape characteristics or biocompatibility of the contact lenses themselves.12 The authors appropriately acknowledge that several challenges remain, not the least of which is that the level of disinfection against Acanthamoeba to reduce the risk of keratitis significantly is completely unknown. Some authors have suggested that complete, terminal sterilization may be needed. The unit apparently can achieve this with higher exposure times, but not without altering the lenses, a limitation commonly seen with chemical disinfectant systems where Acanthamoeba disinfection cannot be achieved without compounds or concentrations that result in alteration of the biocompatibility, toxicity or shape characteristics of the lenses. Its efficacy in the presence of other organisms, proteins, and biofilm remains unknown, but overall, it is still a promising first step among many others at this point in development.
The authors refer to the next step, after some continued study and optimization, as human trials most probably to answer the question of safety, but they will not answer the question of efficacy against clinical infection. Although a devastating disease, Acanthamoeba keratitis is still a rare one, affecting only approximately 20 patients in 1 million contact lens wearers in a given year, making a prospective study impractical. Providing a means of effective sterilization is only a small part of preventing infection. It is also highly dependent on patient compliance with the regimen and storage recommendations, which may be reflected in the significantly higher rate of general microbial keratitis in online or mail order contact lens wearers where reinforcement of these practices may be more lacking.13 The test of efficacy likely will be consumer use with all of these variables where, for Acanthamoeba keratitis at least, aggregation of cases may be possible, and a postmarket validation of both the standards and any the systems it spawns is of vital importance.14 The risk of Acanthamoeba keratitis in the United States has changed fundamentally, and absent any further effort to identify its underlying cause, the risk is likely to remain the same or to increase over time. Repeating studies of current contact lens materials, disinfectant solutions, and hygiene factors is unlikely provide any simple, actionable answers. Although expending limited resources to identify the source of the increase of such a rare disease is certainly debatable, evidence that other contact lens infections also may have risen significantly and the potential negative general health impact of hypothesized changes in environmental risk factors should be considered in the calculation.1,15 For the foreseeable future, we will be charged to accept this new level of risk constrained only to managing its consequences and have the more agonizing task of adjusting our patients to a new normal.
THE AUTHOR HAS COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and the following was reported. The author is a consultant to Seattle Genetics.
REFERENCES 1. Joslin CE, Tu EY, McMahon TT, Passaro DJ, Stayner LT, Sugar J. Epidemiological characteristics of a Chicago-area Acanthamoeba keratitis outbreak. Am J Ophthalmol 2006; 142(2):212–217. 2. Acharya NR, Lietman TM, Margolis TP. Parasites on the rise: a new epidemic of Acanthamoeba keratitis. Am J Ophthalmol 2007;144(2):292–293. 3. Chang DC, Grant GB, O’Donnell K, et al. Multistate outbreak of Fusarium keratitis associated with use of a contact lens solution. JAMA 2006;296(8):953–963. 4. Grant GB, Fridkin S, Chang DC, Park BJ. Postrecall surveillance following a multistate fusarium keratitis outbreak, 2004 through 2006. JAMA 2007;298(24): 2867–2868.
418
5. Thebpatiphat N, Hammersmith KM, Rocha FN, et al. Acanthamoeba keratitis: a parasite on the rise. Cornea 2007; 26(6):701–706. 6. Acanthamoeba keratitis multiple states, 2005–2007. MMWR Morb Mortal Wkly Rep 2007;56(21):532–534. 7. Joslin CE, Tu EY, Shoff ME, et al. The association of contact lens solution use and Acanthamoeba keratitis. Am J Ophthalmol 2007;144(2):169–180. 8. Yoder JS, Verani J, Heidman N, et al. Acanthamoeba keratitis: the persistence of cases following a multistate outbreak. Ophthalmic Epidemiol 2012;19(4):221–225. 9. Ross J, Roy SL, Mathers WD, et al. Clinical characteristics of Acanthamoeba keratitis infections in 28 states, 2008 to 2011. Cornea 2014;33(2):161–168. 10. Shoff ME, Joslin CE, Tu EY, Kubatko L, Fuerst PA. Efficacy of contact lens systems against recent clinical
AMERICAN JOURNAL OF OPHTHALMOLOGY
SEPTEMBER 2014
and tap water Acanthamoeba isolates. Cornea 2008;27(6): 713–719. 11. Shoff ME, Eydelman MB. Strategies to optimize conditions for testing multipurpose contact lens solution efficacy against Acanthamoeba. Eye Contact Lens 2012;38(6):363–367. 12. Lonnen J, Putt KS, Kernick ER, Lakkis C, May L, Pugh RB. The efficacy of Acanthamoeba cyst kill and effects upon contact lenses of a novel ultraviolet lens disinfection system. Am J Ophthalmol 2014;158(3):460–468.
VOL. 158, NO. 3
13. Stapleton F, Keay L, Edwards K, et al. The incidence of contact lens-related microbial keratitis in Australia. Ophthalmology 2008;115(10):1655–1662. 14. Tu EY, Joslin CE. Recent outbreaks of atypical contact lens-related keratitis: what have we learned? Am J Ophthalmol 2010;150(5):602–608.e602. 15. Jeng BH, Gritz DC, Kumar AB, et al. Epidemiology of ulcerative keratitis in Northern California. Arch Ophthalmol 2010;128(8):1022–1028.
EDITORIAL
419
2014 MARKS ROUGHLY 10 YEARS SINCE THE START OF THE
outbreak of Acanthamoeba keratitis in the Chicago area,1 and I am still continually asked whether we’re ‘‘seeing cases’’. These hopeful questioners cover the spectrum of interested parties including those working in the contact lens industry, cornea specialists, and people who are simply interested in the story. At the University of Illinois Eye and Ear Infirmary, our hope, too, is that answer is no, but the disappointing answer is an unqualified yes. We have logged well over 150 cases in the past decade, with an increasing number of those patients losing the long, painful battle to avoid loss of their eye. The larger question that nobody has a definitive answer for is what can or should be done about it. As it stands now, what started out as 2 similar-appearing outbreaks of atypical contact lens-related keratitis in the mid 2000s could not have taken more divergent paths.2 The first outbreak of Fusarium keratitis related to contact lens wear was reported in Singapore and subsequently in the United States. In the span of 1 year, its association with Renu with Moistureloc (Bausch & Lomb, Rochester, New York, USA) was identified, the product was withdrawn from the worldwide market, and a follow-up study was performed confirming the expected sharp reduction in cases.3,4 Highly effective contact lens disinfectants even against fungal pathogens in vitro, Renu with Moistureloc’s failures were widely regarded freak occurrences, something that could not be anticipated by any reasonable means and unlikely to occur again. Case closed. Contemporaneously, a sharp increase in the number of Acanthamoeba keratitis cases was noted at both the Wills Eye Institute and the University of Illinois Eye and Ear Infirmary.1,5 Not unreasonably, a very similar study of risk factors was conducted by the Centers for Disease Control and Prevention, with many investigators expecting a similar solution or material-based association as was seen in the Fusarium outbreak. Both the Centers for Disease Control and Prevention study and an interim analysis of our ongoing study of potential environmental risk factors for Acanthamoeba identified the use of Complete See accompanying article on page 460. Accepted for publication Jun 13, 2014. From the Department of Ophthalmology and Visual Sciences, University of Illinois Eye and Ear Infirmary, Chicago, Illinois. Inquiries to Elmer Y. Tu, Department of Ophthalmology and Visual Sciences, University of Illinois Eye and Ear Infirmary, 1855 West Taylor Street (M/C 648), Room 3.164, Chicago, IL 60612; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2014.06.007
Ó
2014 BY
Moistureplus (Abbot Medical Optics, Santa Ana, California, USA [formerly known as Advanced Medical Optics]) as a significant risk factor.6,7 Detailed in our early publications, however, the geographic nature of our outbreak and the increase in cases with all contact lens disinfection systems were clear warning signs that this outbreak would be very different.1,7 Unfortunately, the recall of Complete Moistureplus did not have the desired result. A multicenter survey later confirmed that the number of cases of Acanthamoeba keratitis remained at historically high levels for the United States sites,8 consistent with the single-center experience at the University of Illinois Eye and Ear Infirmary. This prompted a second outbreak investigation, designed very similarly to the first and conducted by the Centers for Disease Control and Prevention in 2011, which, to date, has not identified any additional causative risk factors.9 Taken together, the abrupt, significant rise in the number of Acanthamoeba keratitis cases and the failure to identify definitively a dominant contact lens care-related cause strongly suggest that an exposure risk leading to Acanthamoeba keratitis has changed fundamentally. Because no remaining contact lens materials or disinfection systems have been identified as having a higher relative risk of developing Acanthamoeba keratitis, it also seems likely that they are all equally effective, or ineffective, as most in vitro studies suggest.10 Regardless of the source or your preferred test of efficacy against Acanthamoeba, current practices and materials, as a whole, are by definition insufficient to suppress the current outbreak. Until funding and effort are directed toward the goal of understanding its origin, it seems that contact lens wearers and corneal subspecialists are constrained to accept a new baseline incidence for Acanthamoeba keratitis, approximately 10 times higher than before 2004. Faced with this new level of unmodified risk, the only remaining options are to convert patients to a moderately more costly option of daily disposable contact lenses or to improve our ability to disinfect contact lenses. However, neither has been shown to eliminate the risk of Acanthamoeba keratitis completely. At the time—unlike during the Fusarium keratitis outbreak—the Food and Drug Administration pushed strongly to develop mandatory standardized disinfection standards against Acanthamoeba for contact lens disinfection systems where none had existed previously. Whatever the motivation, this proactive approach to the
ELSEVIER INC. ALL
RIGHTS RESERVED.
417
Acanthamoeba keratitis outbreak seems almost prescient now in anticipating the persistence of the Acanthamoeba keratitis outbreak 1 decade later. Although these new standards are being developed and tested on many parallel tracks both at the Food and Drug Administration and within the contact lens industry,11 it seems unlikely that many of the contact lens disinfection systems currently in common use would comply with these new standards. This would be a result consistent with the clinical experience, because Acanthamoeba keratitis infections continue to be seen in users of all of these disinfection systems, including 1-step hydrogen peroxide systems. Developing new standards and new disinfection systems is a long, difficult process challenged primarily to balance efficacy and toxicity. In this month’s issue of the Journal, Lonnen and associates report the preliminary results of a novel ultraviolet disinfection system that seems to largely satisfy these needs in a simple, rapid manner effecting a 3log unit reduction of Acanthamoeba cysts with minimal, if any, change to the shape characteristics or biocompatibility of the contact lenses themselves.12 The authors appropriately acknowledge that several challenges remain, not the least of which is that the level of disinfection against Acanthamoeba to reduce the risk of keratitis significantly is completely unknown. Some authors have suggested that complete, terminal sterilization may be needed. The unit apparently can achieve this with higher exposure times, but not without altering the lenses, a limitation commonly seen with chemical disinfectant systems where Acanthamoeba disinfection cannot be achieved without compounds or concentrations that result in alteration of the biocompatibility, toxicity or shape characteristics of the lenses. Its efficacy in the presence of other organisms, proteins, and biofilm remains unknown, but overall, it is still a promising first step among many others at this point in development.
The authors refer to the next step, after some continued study and optimization, as human trials most probably to answer the question of safety, but they will not answer the question of efficacy against clinical infection. Although a devastating disease, Acanthamoeba keratitis is still a rare one, affecting only approximately 20 patients in 1 million contact lens wearers in a given year, making a prospective study impractical. Providing a means of effective sterilization is only a small part of preventing infection. It is also highly dependent on patient compliance with the regimen and storage recommendations, which may be reflected in the significantly higher rate of general microbial keratitis in online or mail order contact lens wearers where reinforcement of these practices may be more lacking.13 The test of efficacy likely will be consumer use with all of these variables where, for Acanthamoeba keratitis at least, aggregation of cases may be possible, and a postmarket validation of both the standards and any the systems it spawns is of vital importance.14 The risk of Acanthamoeba keratitis in the United States has changed fundamentally, and absent any further effort to identify its underlying cause, the risk is likely to remain the same or to increase over time. Repeating studies of current contact lens materials, disinfectant solutions, and hygiene factors is unlikely provide any simple, actionable answers. Although expending limited resources to identify the source of the increase of such a rare disease is certainly debatable, evidence that other contact lens infections also may have risen significantly and the potential negative general health impact of hypothesized changes in environmental risk factors should be considered in the calculation.1,15 For the foreseeable future, we will be charged to accept this new level of risk constrained only to managing its consequences and have the more agonizing task of adjusting our patients to a new normal.
THE AUTHOR HAS COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and the following was reported. The author is a consultant to Seattle Genetics.
REFERENCES 1. Joslin CE, Tu EY, McMahon TT, Passaro DJ, Stayner LT, Sugar J. Epidemiological characteristics of a Chicago-area Acanthamoeba keratitis outbreak. Am J Ophthalmol 2006; 142(2):212–217. 2. Acharya NR, Lietman TM, Margolis TP. Parasites on the rise: a new epidemic of Acanthamoeba keratitis. Am J Ophthalmol 2007;144(2):292–293. 3. Chang DC, Grant GB, O’Donnell K, et al. Multistate outbreak of Fusarium keratitis associated with use of a contact lens solution. JAMA 2006;296(8):953–963. 4. Grant GB, Fridkin S, Chang DC, Park BJ. Postrecall surveillance following a multistate fusarium keratitis outbreak, 2004 through 2006. JAMA 2007;298(24): 2867–2868.
418
5. Thebpatiphat N, Hammersmith KM, Rocha FN, et al. Acanthamoeba keratitis: a parasite on the rise. Cornea 2007; 26(6):701–706. 6. Acanthamoeba keratitis multiple states, 2005–2007. MMWR Morb Mortal Wkly Rep 2007;56(21):532–534. 7. Joslin CE, Tu EY, Shoff ME, et al. The association of contact lens solution use and Acanthamoeba keratitis. Am J Ophthalmol 2007;144(2):169–180. 8. Yoder JS, Verani J, Heidman N, et al. Acanthamoeba keratitis: the persistence of cases following a multistate outbreak. Ophthalmic Epidemiol 2012;19(4):221–225. 9. Ross J, Roy SL, Mathers WD, et al. Clinical characteristics of Acanthamoeba keratitis infections in 28 states, 2008 to 2011. Cornea 2014;33(2):161–168. 10. Shoff ME, Joslin CE, Tu EY, Kubatko L, Fuerst PA. Efficacy of contact lens systems against recent clinical
AMERICAN JOURNAL OF OPHTHALMOLOGY
SEPTEMBER 2014
and tap water Acanthamoeba isolates. Cornea 2008;27(6): 713–719. 11. Shoff ME, Eydelman MB. Strategies to optimize conditions for testing multipurpose contact lens solution efficacy against Acanthamoeba. Eye Contact Lens 2012;38(6):363–367. 12. Lonnen J, Putt KS, Kernick ER, Lakkis C, May L, Pugh RB. The efficacy of Acanthamoeba cyst kill and effects upon contact lenses of a novel ultraviolet lens disinfection system. Am J Ophthalmol 2014;158(3):460–468.
VOL. 158, NO. 3
13. Stapleton F, Keay L, Edwards K, et al. The incidence of contact lens-related microbial keratitis in Australia. Ophthalmology 2008;115(10):1655–1662. 14. Tu EY, Joslin CE. Recent outbreaks of atypical contact lens-related keratitis: what have we learned? Am J Ophthalmol 2010;150(5):602–608.e602. 15. Jeng BH, Gritz DC, Kumar AB, et al. Epidemiology of ulcerative keratitis in Northern California. Arch Ophthalmol 2010;128(8):1022–1028.
EDITORIAL
419