Recognition and Investigation of the Contact Lens-Related Fusarium Outbreak

These 2 respective outbreaks of contact lens-related infectious keratitis have been well documented. Briefly, the outbreak of Fusarium keratitis was described first in Asia, in particular Singapore, beginning in March 2005 with concerns raised later that year by Hong Kong health officials. At that time, Khor and associates reported 68 eyes of 66 patients which developed Fusarium keratitis in Singapore, 98% of whom wore soft contact lenses. All but 4 of the patients (93.9%) reported using any Renu brand disinfection solution (Bausch & Lomb Inc, Rochester, New York, USA), with a remarkably high percentage (63.6%) reporting the use of Renu with MoistureLoc, only recently introduced into worldwide use in late 2004. Scattered cases also were reported in the United States during the same time frame after its introduction there in 2005. A case-control study of 164 United States cases by the Centers for Disease Control and Prevention (CDC) found similarly that 154 (93.9%) of 164 cases were soft contact lens wearers. Of the 116 patients reporting single solution use, 94 reported Renu with MoistureLoc use (57% of all cases). In all, only 13% did not report any use of Renu with MoistureLoc. Its use was strongly associated (odds ratio, 13.3; 95% confidence interval [CI], 3.1 to 119.5) with contact lens-related Fusarium keratitis. This resulted in a regional recall involving Singapore and Hong Kong of Renu with MoistureLoc in February 2006, followed by voluntary recalls in the United States in April 2006 and globally on May 15, 2006.

Recognition and Investigation of the Contact Lens-Related Acanthamoeba Outbreak

Less than a year later at the American Academy of Ophthalmology meeting in November 2005, an increasing number of Acanthamoeba keratitis cases (n = 19) identified over the prior year at the Wills Eye Institute were reported. We identified a statistically significant increase in cases at the University of Illinois Eye and Ear Infirmary dating back to June 2003 (relative risk, 6.67; 95% CI, 3.05 to 17.52) and published an exploratory analysis of the first 40 cases at our institution through November 2005. In this, we identified a unique geographic distribution of cases in which the population-based rate ratio was higher in peripheral collar counties of Chicago (relative risk, 3.59; 95% CI, 1.44 to 8.39), inconsistent with previously known risk factors. Consequently, we initiated a single-center case-control study to investigate the outbreak origins, designing the study to allow for analysis of both environmental and more common lens-related or hygiene risk factors. Through our ongoing discussions with the Illinois Department of Public Health and the CDC, the CDC eventually concluded from a survey of 10 United States ophthalmology centers conducted in early 2007 that an increase in culture-positive cases was evident beginning in 2004 nationally. In May 2007, both an interim analysis of our ongoing case-control study and an exploratory analysis by the CDC using historical Fusarium keratitis study controls identified the use of AMO Complete Moisture Plus (Abbot Medical Optics, Santa Ana, California, USA) as a statistically significant risk factor for the development of contact lens-related Acanthamoeba keratitis (odds ratio, 16.67; 95% CI, 2.11 to 162.63), leading to an immediate worldwide recall on May 29, 2007.

Recognition and Investigation of the Contact Lens-Related Acanthamoeba Outbreak

Less than a year later at the American Academy of Ophthalmology meeting in November 2005, an increasing number of Acanthamoeba keratitis cases (n = 19) identified over the prior year at the Wills Eye Institute were reported. We identified a statistically significant increase in cases at the University of Illinois Eye and Ear Infirmary dating back to June 2003 (relative risk, 6.67; 95% CI, 3.05 to 17.52) and published an exploratory analysis of the first 40 cases at our institution through November 2005. In this, we identified a unique geographic distribution of cases in which the population-based rate ratio was higher in peripheral collar counties of Chicago (relative risk, 3.59; 95% CI, 1.44 to 8.39), inconsistent with previously known risk factors. Consequently, we initiated a single-center case-control study to investigate the outbreak origins, designing the study to allow for analysis of both environmental and more common lens-related or hygiene risk factors. Through our ongoing discussions with the Illinois Department of Public Health and the CDC, the CDC eventually concluded from a survey of 10 United States ophthalmology centers conducted in early 2007 that an increase in culture-positive cases was evident beginning in 2004 nationally. In May 2007, both an interim analysis of our ongoing case-control study and an exploratory analysis by the CDC using historical Fusarium keratitis study controls identified the use of AMO Complete Moisture Plus (Abbot Medical Optics, Santa Ana, California, USA) as a statistically significant risk factor for the development of contact lens-related Acanthamoeba keratitis (odds ratio, 16.67; 95% CI, 2.11 to 162.63), leading to an immediate worldwide recall on May 29, 2007.

Case Ascertainment and Aggregation of Infectious Outbreaks

The initial reports of Fusarium and Acanthamoeba keratitis were remarkably similar in that both were identified first at tertiary care ophthalmology centers: Singapore National Eye Center, in addition to the University of Illinois Eye and Ear Infirmary and the Wills Eye Institute, respectively. The reasons are for this are both obvious and important, with several factors driving these 2 diseases in particular toward tertiary care facilities and ultimately facilitating outbreak identification. First, the standard treatment for each infection involves medications not widely available. Although a commercial preparation of natamycin 5% is widely available for the treatment of fungal keratitis, the rate of clinical resistance for Fusarium species, specifically, is significant. Similarly, standard therapy for Acanthamoeba keratitis consists of either commercial medications unavailable in the United States or compounded biguanides, or both. Second, the infections are known to masquerade as other either infectious or noninfectious conditions, often requiring the expertise of clinicians and microbiologic facilities familiar with their diagnosis. Third, these infections often are highly symptomatic, with poor outcomes if not treated promptly and appropriately; 17% of the University of Illinois Eye and Ear Infirmary Acanthamoeba keratitis patients and 34% of United States Fusarium keratitis patients required corneal transplantation.

Finally, the rarity of each disease, before the outbreaks, facilitated more rapid recognition. Although Fusarium keratitis is the most common filamentous fungal infection in non–contact lens users, previously, it was uncommon with contact lens use. Further, although Acanthamoeba keratitis is primarily restricted to contact lens users, the previous annual United States incidence estimates, based on the outbreak of the late 1980s and roughly our preoutbreak experience, was approximately 2 cases per 1 million contact lens users. These infections have remained rare even in the midst of the outbreaks. The annual Fusarium keratitis incidence in Singapore was estimated at 2.4 cases per 10 000 contact lens wearers, and although no comparable Acanthamoeba keratitis incidence rates have been calculated, our gross estimates from the Chicago outbreak approach 20 annual cases per 1 million contact lens users. Hence, it is unlikely that a single ophthalmologist, or even cornea subspecialist, would be able to detect an outbreak acutely, thus, the importance of tertiary care centers in large metropolitan areas to provide case aggregation and the perspective of a more population-based comparison of disease trends with time.

Taken together, these 4 factors made possible a relatively complete case ascertainment at the tertiary care facilities that led to the identification of each outbreak. Without a structured surveillance system for contact lens-related keratitis, or any microbial keratitis, the absence of any of the above characteristics would mask or significantly delay the detection of outbreaks of (1) milder, more easily diagnosed disease; (2) diseases with widely available, effective therapy; or (3) diseases that are significantly more common than these. The historical recognition that extended wear use of contact lenses was significantly associated with bacterial infectious keratitis, for example, might have been delayed if efficacious antibiotics were available in the community at the time, obviating the need for fortified antibiotics compounded at specialty hospitals where case aggregation would occur. Looking to the future, we likely will have no ability to identify a substantial outbreak of a more common, fluoroquinolone-sensitive, contact lens-related microbial keratitis because of the successful nature of community-based empiric antibiotic treatment as well as the nonspecificity of the use patterns for these drugs, which have a wide range of both nontherapeutic and noncorneal indications.

Unique Epidemiologic Factors of the Individual Outbreaks

Despite these similarities, there are distinct differences in the epidemiologic factors of each outbreak that offer important lessons in their respective outbreak study design and implementation. In a rare disease such as microbial keratitis, the case-control study design is preferred because it is highly efficient; however, appropriate selection of controls is critical to maintain study validity and to prevent the introduction of systemic error, biasing results. Because of the rarity of Fusarium keratitis among contact lens users, baseline incidence and historical risk factors generally were unknown. However, a simple evaluation of the percentage of cases using the recalled solution, as well as a comparison against market share, strongly implicated the role of a single solution. As such, a case-control study designed to investigate contact lens solutions, as well as the potential role of general lens-related keratitis risk factors, including lens hygiene, was launched. Controls were selected to allow for analysis of these factors: controls were matched to the neighborhood of cases restricted to contact lens users older than 17 years. Results identified the strong association of Renu with MoistureLoc with Fusarium keratitis as well as the relatively smaller contribution of topping off, or solution reuse. This strong association contributed to a worldwide recall, with an immediate reduction in Fusarium keratitis cases identified through both active and passive surveillance techniques.

The independent investigations (CDC and the University of Illinois Eye and Ear Infirmary) of the Acanthamoeba keratitis outbreak provide further insight. Our initial publication identified a unique geographic distribution of cases in Chicago, suggesting the need for a case-control study design that allowed for an analysis of factors that can vary by geography, with solutions potentially less relevant in this outbreak. More reliable Acanthamoeba keratitis incidence estimates further suggested a problem beyond just a single solution: despite a potential signal, no single solution accounted for a strong majority of cases, indicating as much as a 5-fold increase in disease regardless of type of solution used (arm-chair epidemiology: 2 vs 20 to 30 annual cases in Chicago, 40% of cases without AMO Complete MoisturePlus use, hence now 8 to 10 annual cases with all solutions, so up to a ×5 increase). Further, Acanthamoeba species are found commonly in water and soil, but are considered largely a waterborne pathogen in humans. Although many forms of infectious keratitis have been linked to temperature and climate, only Acanthamoeba keratitis has been linked consistently to alterations in the quality of the domestic water supply. Because our initial analysis identified a unique geographic distribution of cases hypothesized as related to the water supply, we selected a case-control study design in which controls were clinic based and matched for age and date of visit to be able to analyze the effect of geography and the potential effects of water supply, which is inherently impossible when controls are matched by neighborhood. To our benefit, our single-center study design not only allowed for analysis of typical lens-related risk factors, but also restricted potential confounding factors (ie, Miami weather is more conducive in the winter than Chicago to water-related activities that increase the risk of infection).

In comparison, the CDC investigation closely mirrored the study design conducted for the Fusarium keratitis outbreak. The initial Morbidity and Mortality Weekly Report alert in May 2007, in which 46 culture-positive (39 soft contact lens wearers) Acanthamoeba cases were identified, was based on control data collected during the Fusarium keratitis outbreak the year prior. The potential pitfall is that solution market share changes with time and may not reflect contemporary use, especially given the interim recall of Renu with MoistureLoc solution. Their subsequent outbreak investigation that recruited new controls retained the same study design as the Fusarium keratitis study, with the recruitment of controls who were matched by neighborhood to identified cases.

Nevertheless, both independent studies confirmed the significant association of the use of AMO Complete MoisturePlus with Acanthamoeba keratitis (odds ratio, 16.67; 95% CI, 2.11 to 162.63). Not surprising, given the high frequency of cases that reported use of solutions other than the recalled solution, the number of Acanthamoeba keratitis cases in Chicago and nationally has not returned to baseline, unlike the Fusarium keratitis outbreak that occurred 1 year prior serving serendipitously as an excellent baseline comparison for the Acanthamoeba keratitis outbreak. This indicates the contribution of other, as yet unidentified risk factors of the Acanthamoeba keratitis outbreak.