[Experimental study on Pseudomonas keratitis in mice. 2. Clinical and histopathological investigation on experimental Pseudomonas keratitis in mice].
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OBJECTIVE: To investigate the incidence and features of bacterial, fungal and protozoal keratitis in Scotland. DESIGN: Prospective, population-based cohort study of all persons who developed culture proven microbial keratitis over an 8 month period. SETTING: West of Scotland, UK. SUBJECTS: Approximately 3,000,000 population. MAIN OUTCOME MEASURES: Incidence and risk factors for microbial keratitis. METHODS: All patients were included who had presumed microbial keratitis from which bacteria, fungi or Acanthamoeba was isolated from the corneal scraping by the hospital laboratory using a standardised protocol. In addition, contact lens wearing patients with pathognomonic features of Acanthamoeba keratitis, who yielded a negative culture result when referred on chlorhexidine therapy, were included if Acanthamoeba could be cultured from their lens storage case. RESULTS: The overall annual incidence of culture-proven microbial keratitis was 0.26 per 10,000 with a rate of 1.8 per 10,000 for contact lens wearers (all types, soft and rigid). Based on a previous pilot study of 'presumed' microbial keratitis in Glasgow, it was possible to estimate the incidence of expected 'presumed' microbial keratitis as 0.36 per 10,000 overall and 2.44 per 10,000 for contact lens wearers (all types). The incidence for Acanthamoeba keratitis was 1.49 per 10,000 soft contact lens wearers; this infection was not detected in the absence of contact lens wear nor with use of gas permeable or rigid contact lenses. CONCLUSIONS: 'Presumed' microbial keratitis from all causes, in the adult population, was approximately three times less common in the West of Scotland (0.36 per 10,000) than would be expected from a comparable retrospective study from Minnesota, USA for the years 1980-1988 (1.1 per 10,000). It was rare (approximately one case expected in 2 million per year) in the absence of pre-existing corneal disease, cosmetic contact lens wear or trauma. Ocular surface disease was the underlying cause predisposing to infection in 58% of cases, with an incidence of 'presumed' keratitis of 0.21 per 10,000 population; the highest incidence was found in the elderly population. Contact lens wear was responsible for 38% of cases, emphasising the importance of preventive hygiene and effective disinfection in this group. The estimated incidence of 'presumed' microbial keratitis in the West of Scotland associated with cosmetic wear (daily and extended use) of soft contact lenses was significantly less (P<0.05) than that expected from a prospective study in New England, America in 1985 (266 per 10,000, rather than 8.05 per 10,000). However, the estimated incidence for presumed microbial keratitis for the West of Scotland associated with wearing soft contact lenses for cosmetic purposes in the daily wear modality (266 per 10,000) was less, but not significantly less, than that found in the prospective American study (4.20 per 10,000). The daily wear mode for contact lenses is almost universal in the West of Scotland, where extended wear has never been recommended. Extended wear has been shown in the USA to be associated with an incidence of presumed microbial keratitis between five and ten times higher than that associated with daily wear. This explains the lower incidence we have observed and a difference with the US study for overall infection rates but not when associated with daily wear alone. The incidence of proven Acanthamoeba keratitis found in the Scottish study among wearers of soft contact lenses for daily wear cosmetic purposes was exceptionally high at 1.49 per 10,000.
PURPOSE: Herpetic keratitis is manifested in various corneal disorders, for example, dendritic keratitis, persistent epithelial defect, disciform keratitis, and endotheliitis. In this paper, we report on the quantity of herpes simplex virus (HSV) genome in tears from patients with various types of herpetic keratitis in an attempt to understand the role of HSV in these conditions. METHODS: We collected tear samples from both eyes of 56 consecutive patients with herpetic keratitis who visited Kinki University Hospital between June 2000 and May 2002. All patients had unilateral herpetic keratitis: epithelial keratitis in 27 eyes; persistent epithelial defect in 6; active disciform stromal keratitis in 14; silent stromal keratitis in 6; and endotheliitis in 3. We measured levels of HSV genome in these tear samples using a real-time polymerase chain reaction (PCR) method. RESULTS: In epithelial keratitis, HSV DNA was detected in all 27 samples from affected eyes (6.4 +/- 4.4 x 10(5) copies/sample). In persistent epithelial defect, HSV DNA was detected in all 6 samples from affected eyes (8.5 +/- 3.3 x 10(4) copies/sample). In active disciform stromal keratitis, HSV DNA was detected in 8 of the 14 affected eyes (1.4 +/- 1.1 x 10(5) copies/sample including zero values in negative samples). HSV DNA was not detected in samples from unaffected eyes or eyes affected by silent stromal keratitis or endotheliitis. CONCLUSION: Real-time PCR is a useful method for quantifying HSV DNA in tear samples from patients with herpetic keratitis. Using this method, we demonstrate that HSV reproduction occurs in persistent epithelial defect and disciform stromal keratitis.
Varied manifestations of herpes simplex keratitis are postulated to be related to alterations or paucity of protective immune response to the virus. In this study lymphocyte subpopulations and macrophage inhibition factor (MIF) assay are investigated in herpes simplex keratitis. Active T-lymphocytes are detected to be significantly low in active keratitis as compared to the healed stage (P less than 0.001) and normal control subjects (P less than 0.01). Active T-cells are also lower in bilateral keratitis than in unilateral keratitis (P less than 0.01), and in stromal keratitis than in epithelial keratitis (P less than 0.05). Total E-rosette-forming cells and leucocyte migration inhibition factor (MIF) assay demonstrates significantly lower values in bilateral keratitis than in unilateral keratitis, and in stromal keratitis than in epithelial keratitis. On healing, total E-RFC, active T-cells and MIF values improved and are comparable to those found in normal subjects. Enumeration of absolute lymphocyte counts and EAC rosette-forming cells (B-lymphocyte cells) did not yield any differences. Our observations demonstrate paucity of cell-mediated immune response in stromal keratitis. More marked deficiency is demonstrable in bilateral keratitis. Manifestations of herpes simplex keratitis and their healing is observed to be relatable to the level of cell mediated immune response.
PURPOSE: Previous studies on fungal and bacterial keratitis were descriptive single case series analysis. We conducted a hospital-based retrospective study to evaluate fungal and bacterial keratitis using a case-control design to compare risk factors and clinical outcomes. METHODS: Twenty-nine cases of culture-positive fungal keratitis seen over a 5-year period were compared to 51 cases of culture-positive bacterial keratitis seen over a 21 months period. Using bacterial keratitis as the reference group, case-control odds ratios (OR) for predisposing factors and cohort relative risks (RR) for clinical outcomes associated with fungal keratitis were derived. Mantel-Haenszel adjustment procedures were used to examine the respective roles of confounding and intermediate variables. RESULTS: Compared to bacterial keratitis, fungal keratitis was significantly more likely to be associated with ocular trauma (OR = 2.69, 95% confidence interval [CI], 1.06-6.86) but significantly less likely to be associated with contact lens wear (OR = 0.16, 95% CI, 0.04-0.67) and preexisting ocular diseases (OR = 0.23, 95% CI, 0.07-0.72). Fungal keratitis was more likely to perforate than bacterial keratitis (RR = 5.28, 95% CI, 1.35-20.66) and to require penetrating keratoplasty (OR = 5.86, 95% CI, 2.06-16.69). CONCLUSIONS: Fungal keratitis appears more likely to result from ocular trauma, whereas bacterial keratitis is more likely to result from contact lens wear and pre-existing ocular diseases. Fungal keratitis is more likely than bacterial keratitis to result in perforation and require penetrating keratoplasty.
PURPOSE: To determine the surgical outcomes of therapeutic penetrating keratoplasty (PKP) and its role in the management of microbial keratitis. DESIGN: Interventional case series. METHODS: We retrospectively performed a chart review of the hospital records of all 151 patients undergoing therapeutic PKP for culture-proven microbial keratitis at the National Taiwan University Hospital during a 14 year-period (1987-2001). Patients were divided into three categories: (1) bacterial keratitis; (2) fungal keratitis; and (3) acanthamoebic keratitis. Each of the following criteria was evaluated: (1) graft clarity 1 month and 1 year postoperatively; (2) cure of the disease; and (3) anatomical success rate. RESULTS: A total of 108 therapeutic PKP met the criteria. Therapeutic PKP eradicated the infection in 37/41 of patients with bacterial keratitis, 36/52 of patients with fungal keratitis, and 13/15 of patients with acanthamoebic keratitis. 22/32 of grafts of bacterial keratitis, 20/39 of fungal keratitis, and 11/14 of acanthamoebic keratitis remained clear at 1 year postoperatively. A higher percentage of graft clarity at 1 year postoperatively was achieved in all three categories when grafts were 8.5 mm or less compared with larger grafts. All five patients with secondary endophthalmitis observed at the time of therapeutic PKP experienced a progression of infection despite aggressive surgical treatment, and had to be enucleated. CONCLUSIONS: Therapeutic PKP is valuable in the management of microbial keratitis that is unresponsive to medical therapy. A higher percentage of clear graft was found when grafts were smaller in all three categories. Surgical results are worse for patients with fungal keratitis, regardless of graft clarity, anatomical success, or infection eradication rate.
OBJECTIVE: To assess the incidence and clinical characteristics of herpes simplex keratitis in France. DESIGN: National multicenter prospective study on herpetic keratitis. PARTICIPANTS: During a 3-month study period (September-December 2002), all cases of herpes simplex keratitis were prospectively reported by a randomly selected sample of 412 ophthalmologists representative of the 5471 French ophthalmologists in terms of gender, geographic distribution, and clinical practice. METHODS: The following set of assumptions were made to calculate the incidence of herpectic keratitis: (1) the participating (self-selected) ophthalmologists in the study could adequately represent French ophthalmologists, (2) estimates based on the 3-month study period could be used to calculate the annual incidence (i.e., no significant seasonal variations), and (3) all patients suffering from herpetic corneal lesions consult or are referred to an ophthalmologist. We calculated the incidence of herpetic keratitis by (1) estimating the average number of incident cases per ophthalmologist per year, (2) multiplying the average number of incident cases by the total number of French ophthalmologists (n = 5471), and (3) dividing the result by the French population. RESULTS: Four hundred twelve ophthalmologists reported 357 cases of herpes keratitis. We estimated that the overall incidence of herpetic keratitis during the study period was 31.5 per 100,000 person-years (95% confidence interval [CI], 25.5-37.5), and incidences were 13.2 per 100,000 person-years for new cases (95% CI, 10.4-15.9) and 18.3 per 100,000 person-years for recurrences (95% CI, 14.6-22.1). The most frequent types were dendritic keratitis (56.3%, n = 153), stromal keratitis (29.5%, n = 81), and geographic keratitis (9.8%, n = 27). Other ocular lesions were associated with keratitis in 35.0% (n = 125) of cases; the most frequent were conjunctivitis (18.8%, n = 67), uveitis (11.8%, n = 42), and/or lid involvement (8.6%, n = 31). CONCLUSIONS: This prospective epidemiological study provides an estimate of the incidence of herpes keratitis in France. Herpetic keratitis remains an epidemiologically important eye disease that justifies the need to pursue health care and research programs aimed at improving the outcome of ocular herpetic disease.
PURPOSE: To compare the clinical efficacy of itraconazole 1% eyedrops with a standard therapy regimen (natamycin 5% eyedrops) for topical monotherapy of fungal keratitis. METHODS: Patients presenting with suspected uniocular microbial keratitis over a period of 12 months (January to December 2002) underwent detailed clinical examination and microbiological investigation. One hundred consecutive patients with direct smear- and/or culture-proven fungal keratitis were enrolled in the study after obtaining informed consent. The ulcers were categorized as severe or nonsevere. The first 50 consecutive patients received primary therapy with topical natamycin hourly, and the next 50 consecutive patients received topical itraconazole hourly. The primary efficacy criteria were the physician's judgment of clinical success, cure rate, and the rate of treatment failure. RESULTS: The diagnosis of fungal keratitis was established by positive microscopy and culture findings in 88 patients and by positive microscopy alone in 12 patients. Species of Fusarium, Aspergillus, and Curvularia were the principal isolates. Thirty-six (72%) of 50 patients (28 of 37 with nonsevere keratitis and 8 of 13 with severe keratitis) showed a favorable response to primary natamycin therapy (mean duration, 20.5 days), while 30 (60%) of 150 patients (25 of 38 with nonsevere keratitis and 5 of 12 with severe keratitis) exhibited a favorable response to primary itraconazole therapy (mean duration, 23.1 days). In keratitis due to Fusarium spp, 19 (79%) of 24 patients showed a favorable response to natamycin, which was significantly greater than the 8 (44%) of 18 patients who showed a favorable response to itraconazole (P < 0.02). However, no such difference was evident in keratitis due to Aspergillus spp or Curvularia spp; in keratitis due to Aspergillus spp, favorable responses were noted in 6 (54.5%) of 11 patients receiving natamycin and 5 (50%) of 10 patients receiving itraconazole, while in keratitis due to Curvurlaria spp, such responses occurred in both patients receiving natamycin and in 8 (89%) of 9 patients receiving itraconazole. Both antifungal formulations were generally well tolerated with no obvious adverse effects. CONCLUSIONS: Topical natamycin should continue to be considered as the treatment of choice for filamentous fungal keratitis; when natamycin is unavailable, topical itraconazole therapy could be used, particularly if the infections are due to Aspergillus or Curvularia spp.
PURPOSE: Epithelial keratitis is the most common presentation of ocular infection by herpes simplex virus (HSV). Quantitative assessment of available therapy is needed to guide evidence-based ophthalmology. This study aimed to compare the efficacy of various treatments for dendritic or geographic HSV epithelial keratitis and to evaluate the role of various clinical characteristics on epithelial healing. METHODS: Following a systematic review of the literature, information from clinical trials of HSV dendritic or geographic epithelial keratitis was extracted, and the methodological quality of each study was scored. Methods of epithelial cauterization and curettage were grouped as relatively equivalent physicochemical therapy, and solution and ointment formulations of a given topical antiviral agent were combined. The proportion healed with 1 week of therapy, a scheduled follow-up day that approximated the average time of resolution with antiviral therapy, was selected as the primary outcome based on a masked evaluation of maximum treatment differences in published healing curves. The proportion healed at 14 days was recorded as supplemental information. Fixed-effects and random-effects meta-analysis models were used to obtain summary estimates by pooling results from comparative treatment trials. Hypotheses about which prognostic factors might affect epithelial healing during antiviral therapy were developed by multivariate analysis of the Herpetic Eye Disease Study dataset. RESULTS: After excluding 48 duplicate reports, 14 nonrandomized studies, 15 studies with outdated or similar treatments, and 29 trials lacking sufficient data on healing or accessibility, 76 primary reports were identified. These reports involved 4,251 patients allocated to 93 treatment comparisons of dendritic epithelial keratitis in 28 categories and 9 comparisons of geographic epithelial keratitis in 6 categories. For dendritic keratitis, idoxuridine was better than placebo at 7 days (combined odds ratio [OR], 3.59; 95% confidence interval [CI], 1.92-6.70), and at 14 days (OR, 4.17; 95% CI, 1.33-13.04), but pooling was limited by lack of homogeneity and low study quality. Direct comparisons at 1 week of treatment showed that trifluridine or acyclovir was significantly better than idoxuridine (OR, 3.12 and 4.56; 95% CI, 1.55-6.29 and 2.76-7.52, respectively), and indirect comparisons were also consistent with a clinically significant benefit. Vidarabine was not significantly better than idoxuridine in pooled treatment comparisons at 1 week (OR, 1.20; 95% CI, 0.72-2.00) but was better in 2 indirect comparisons (OR, 4.22 and 4.78; 95% CI, 1.69-10.54 and 2.15-10.65, respectively). At 14 days, trifluridine (OR, 6.05; 95% CI, 2.50-14.66), acyclovir (OR, 2.88; 95% CI, 1.39-4.78), and vidarabine (OR, 1.24; 95% CI, 0.65-2.37) were each better than idoxuridine. Trials of geographic epithelial keratitis also suggested that trifluridine, acyclovir, and vidarabine were more effective that idoxuridine. Other topical antiviral agents, such as bromovinyldeoxuridine, ganciclovir, and foscarnet, appeared equivalent to trifluridine or acyclovir. Oral acyclovir was equivalent to topical antiviral therapy and did not hasten healing when used in combination with topical treatment. Antiviral agents did not increase the speed of healing when compared to debridement but reduced the risk of recrudescent epithelial keratitis. The combination of physicochemical treatment with an antiviral agent seemed to be better than either physicochemical or antiviral treatment alone, but the heterogeneous cauterization and curettage techniques and the various treatment combinations limited valid quantitative summary effect measures. The combination of topical interferon with an antiviral agent was significantly better than antiviral therapy at 7 days (OR, 13.49; 95% CI, 7.39-24.61) but not at 14 days (OR, 2.36; 95% CI, 0.82-6.79). Finding apparent heterogeneity for some pooled estimates suggested that dissimilarities in patients, interventions, outcomes, or other logistical aspects of clinical trials occur across studies. CONCLUSIONS: The available evidence on the acute treatment of presumed HSV epithelial keratitis demonstrates the effectiveness of antiviral treatment and shows the log-logistic healing curve of treated dendritic epithelial keratitis. Topical trifluridine, acyclovir, and vidarabine were significantly more effective than idoxuridine but similar in relative effectiveness for dendritic epithelial keratitis. Physicochemical methods of removing infected corneal epithelium are effective, but adjunctive virucidal agents are needed to avert recrudescent epithelial keratitis. Whether debridement in combination with antiviral therapy is more beneficial than antiviral chemotherapy alone appears likely but remains inconclusive. The combination of topical interferon with an antiviral agent significantly speeds epithelial healing. Future trials of the acute treatment of HSV epithelial keratitis must aim to achieve adequate statistical power for assessing the primary outcome and should consider the effect of lesion size and other characteristics on treatment response.