Topical Chlorhexidine 0.2% versus Topical Natamycin 5% for the Treatment of Fungal Keratitis in Nepal: A Randomized Controlled Noninferiority Trial.

PURPOSE: To investigate if topical chlorhexidine 0.2%, which is low cost and easy to formulate, is noninferior to topical natamycin 5% for the treatment of filamentous fungal keratitis. DESIGN: Randomized controlled, single-masked, noninferiority clinical trial. PARTICIPANTS: Adults attending a tertiary-level ophthalmic hospital in Nepal with filamentous fungal infection confirmed on smear or confocal microscopy. METHODS: Participants were randomly allocated to receive topical chlorhexidine 0.2% or topical natamycin 5%. Primary analysis (intention-to-treat) was by linear regression, using baseline logarithm of the minimum angle of resolution (logMAR) best spectacle-corrected visual acuity (BSCVA) and treatment arm as prespecified covariates. Mixed fungal-bacterial infections were excluded from the primary analysis but included in secondary analyses and secondary safety-related outcomes. The noninferiority margin was 0.15 logMAR. This trial was registered with ISRCTN, number ISRCTN14332621. MAIN OUTCOME MEASURES: The primary outcome measure was BSCVA at 3 months. Secondary outcome measures included perforation or therapeutic penetrating keratoplasty by 90 days. RESULTS: Between June 3, 2019, and November 9, 2020, 354 eligible participants were enrolled and randomly assigned: 178 to chlorhexidine and 176 to natamycin. Primary outcome data were available for 153 and 151 of the chlorhexidine and natamycin groups, respectively. Of these, mixed bacterial-fungal infections were found in 20 cases (12/153 chlorhexidine, 8/151 natamycin) and excluded from the primary analysis. Therefore, 284 patients were assessed for the primary outcome (141 chlorhexidine, 143 natamycin). We did not find evidence to suggest chlorhexidine was noninferior to natamycin and in fact found strong evidence to suggest that natamycin-treated participants had significantly better 3-month BSCVA than chlorhexidine-treated participants, after adjusting for baseline BSCVA (regression coefficient, -0.30; 95% confidence interval [CI], -0.42 to -0.18; P < 0.001). There were more perforations and emergency corneal grafts in the chlorhexidine arm (24/175, 13.7%) than in the natamycin arm (10/173, 5.8%; P = 0.018, mixed infections included), whereas natamycin-treated cases were less likely to perforate or require an emergency corneal graft, after adjusting for baseline ulcer depth (odds ratio, 0.34; 95% CI, 0.15-0.79; P = 0.013). CONCLUSIONS: Treatment with natamycin is associated with significantly better visual acuity, with fewer adverse events, compared with treatment with chlorhexidine. Natamycin remains the preferred first-line monotherapy treatment for filamentous fungal keratitis.

Conjunctival Scarring, Corneal Pannus, and Herbert's Pits in Adolescent Children in Trachoma-endemic Populations of the Solomon Islands and Vanuatu.

BACKGROUND: In the Solomon Islands and Vanuatu, the sign trachomatous inflammation-follicular (TF) is common, but ocular infection with Chlamydia trachomatis is not. It is therefore debatable whether azithromycin mass drug administration (MDA), the recommended antibiotic treatment strategy for trachoma's elimination as a public health problem, is necessary in this setting. We set out to estimate what proportion of adolescents were at risk of progression of trachomatous scarring. METHODS: A cross-sectional survey was undertaken of all children aged 10-14 years resident in communities identified as high-TF clusters during previous population-based mapping. Graders examined children for clinical evidence of trachomatous scarring, pannus, and Herbert's pits (HPs) or limbal follicles in both eyes. A dried blood spot was collected from each child and tested for antibodies to C. trachomatis. RESULTS: A total of 492 children in 24 villages of the Solomon Islands and Vanuatu were examined. In total, 35/492 (7%) of children had limbal signs (pannus and/or HPs) plus any conjunctival scarring. And 9/492 (2%) had limbal signs and moderate or severe conjunctival scarring; 22% of children were anti-Pgp3 seropositive. CONCLUSIONS: Few adolescents here are at risk of future complications from trachoma, supporting the conclusion that further antibiotic MDA is not currently required for trachoma elimination purposes in these settings.

In vivo confocal microscopy and trachomatous conjunctival scarring: Predictors for clinical progression.

IMPORTANCE: In vivo confocal microscopy (IVCM) provides high-resolution images of the ocular surface and has been validated in trachomatous conjunctival scarring. BACKGROUND: This study used IVCM to identify parameters associated with clinical scarring progression. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 800 participants in Northern Tanzania with trachomatous scarring. METHODS: Participants underwent clinical examination, photography and IVCM at baseline and 24-months. Clinical progression of scarring was defined by comparing baseline and 24-month photographs. Masked grading of IVCM images was used to identify scarring at both time points. Multivariable logistic regression was used to assess factors associated with clinical progression. MAIN OUTCOME MEASURES: Risk factors associated with clinical scarring progression. RESULTS: Clinical and IVCM assessment of 800 participants were performed at baseline, with 617 (77.1%) seen at 24-months. Of these, 438 of 617 (71.0%) had gradable IVCM images at both time points and 342 of 438 (78.1%) of these could be graded as showing definite clinical progression or no progression on image comparison. Clinical progression was found to occur in 79 of 342 (23.1%). After adjusting for age and sex, clinical scarring progression was strongly associated with a high IVCM connective tissue organization score at both baseline (odds ratio [OR] = 1.84 for each increase in scarring category; P = .002) and 24-months (OR = 1.60; P = .02). Dendritiform cells present at 24-months were strongly associated with clinical scarring progression after adjustment (OR = 2.62; P = .03). CONCLUSIONS AND RELEVANCE: Quantitative IVCM parameters, including connective tissue organization score and the presence of dendritiform cells, are associated with disease progression and may be useful markers in trachoma and other conjunctival fibrotic diseases.

Diagnosing ocular surface squamous neoplasia in East Africa: case-control study of clinical and in vivo confocal microscopy assessment.

OBJECTIVE: To examine the reliability of clinical examination and in vivo confocal microscopy (IVCM) in distinguishing ocular surface squamous neoplasia (OSSN) from benign conjunctival lesions. DESIGN: Case-control study. PARTICIPANTS: Sixty individuals with conjunctival lesions (OSSN and benign) and 60 age-matched controls with normal conjunctiva presenting to Kilimanjaro Christian Medical Centre, Moshi, Tanzania. METHODS: Participants were examined and photographed, and IVCM was performed. Patients with conjunctival lesions were offered excisional biopsy with histopathology and a human immunodeficiency virus (HIV) test. The IVCM images were read masked to the clinical appearance and pathology results. Images were graded for several specific features and given an overall categorization (normal, benign, or malignant). A group of 8 ophthalmologists were shown photographs of conjunctival lesions and asked to independently classify as OSSN or benign. MAIN OUTCOME MEASURES: Comparison of the histopathology diagnosis with the clinical and IVCM diagnosis. RESULTS: Fifty-two cases underwent excisional biopsy with histopathology; 34 were on the OSSN spectrum, 17 were benign, and 1 was lymphoma. The cases and controls had comparable demographic profiles. Human immunodeficiency syndrome infection was more common in OSSN compared with benign cases (58.8% vs. 5.6%; odds ratio, 24.3, 95% confidence interval [CI], 2.8-204; P = 0.003). Clinically, OSSN lesions more frequently exhibited feeder vessels and tended to have more leukoplakia and a gelatinous appearance. Overall, the ophthalmologists showed moderate agreement with the histology result (average kappa = 0.51; 95% CI, 0.36-0.64). The masked grading of IVCM images reliably distinguished normal conjunctiva. However, IVCM was unable to reliably distinguish between benign lesions and OSSN because of an overlap in their appearance (kappa = 0.44; 95% CI, 0.32-0.57). No single feature was significantly more frequent in OSSN compared with benign lesions. The sensitivity and specificity of IVCM for distinguishing OSSN from benign conjunctival lesions were 38.5% and 66.7%, respectively. CONCLUSIONS: In East Africa, conjunctival pathology is relatively common and can present significant diagnostic challenges for the clinician. In this study, neither clinical examination nor IVCM was found to reliably distinguish OSSN from benign conjunctival pathology because of an overlap in the features of these groups. Therefore, IVCM cannot currently replace histopathology, and management decisions should continue to rely on careful clinical assessment supported by histopathology as indicated.

Portable devices for diagnosis and monitoring of glaucoma: a scoping review protocol.

INTRODUCTION: Glaucoma is the leading cause of irreversible blindness in the world. The need to diagnose glaucoma early in its natural history before extensive sight loss occurs cannot be overemphasised. However, glaucoma is largely asymptomatic in the early stages of the disease making it complex to diagnose clinically and requires the support of technology. The objective of this scoping review is to determine the nature and extent of the evidence for use of portable devices in the diagnosis of glaucoma. METHODS: We will consider studies conducted in all healthcare settings using portable devices for the detection of all type of adult glaucoma. We will also include any systematic reviews or scoping reviews, which relate to this topic. Searches will be conducted in MEDLINE, Embase, CENTRAL on the Cochrane Library and Global Health databases, from their inception to the present. Reference lists from publications identified in the searches will also be reviewed. Two authors will independently screen titles and abstracts, followed by full-text screening to assess studies for inclusion. Any disagreements will be discussed and resolved with a third author. Tables accompanied by narrative descriptions will be employed to discuss results and show how it relates to review questions. ETHICS AND DISSEMINATION: Ethical approval is not required in this review. Only published and publicly accessible data will be used. We will publish our findings in an open-access, peer-reviewed journal and develop an accessible summary of results and recommendations.

ReGAE 9: baseline factors for success following augmented trabeculectomy with mitomycin C in African-Caribbean patients.

BACKGROUND: To identify the baseline factors influencing success following trabeculectomy with mitomycin C in a case series of African-Caribbean patients. DESIGN: A prospective, observational and non-comparative cohort study. PARTICIPANTS: Forty-seven consecutive African-Caribbean patients (47 eyes) with glaucoma. METHODS: Association between trabeculectomy survival and study factors was examined using Fisher's exact test and the Wilcoxon rank sum test at 12, 24 and 36 months following trabeculectomy. Logistic regression was used to establish the combination of factors best predicting survival. MAIN OUTCOME MEASURES: Surgical success was based upon intraocular pressure reduction to ≤21 mmHg, ≤18 mmHg and ≤15 mmHg without glaucoma medication (criterion 1), or intraocular pressure reduction to ≤21 mmHg, ≤18 mmHg and ≤15 mmHg with or without glaucoma medication (criterion 2). RESULTS: Trabeculectomy survival at 36 months was significantly decreased with the use of preoperative acetazolamide, pseudophakic status and higher preoperative intraocular pressure (P < 0.05). In pseudophakic eyes, there was a lower rate of success for criterion 2 when aiming for an intraocular pressure ≤15 mmHg at 2 years post-trabeculectomy, the odds ratio being 12. CONCLUSIONS: Three major independent risk factors were identified that influenced trabeculectomy failure at 3 years in African-Caribbean ethnicity: the preoperative use of acetazolamide, pseudophakic status and higher preoperative intraocular pressure. The presence of these risk factors may guide the clinician to use a more aggressive antiproliferative and postoperative management regime to enhance survival rates in this high-risk population.

Innate immune responses and modified extracellular matrix regulation characterize bacterial infection and cellular/connective tissue changes in scarring trachoma.

Trachoma is the most common infectious cause of blindness and a major public health problem in many developing countries. It is caused by recurrent ocular infection with Chlamydia trachomatis in childhood, with conjunctival scarring seen later in life. The pathogenesis of trachomatous scarring, however, is poorly understood, and this study was carried out to investigate the immunofibrogenic correlates of trachomatous conjunctival scarring. A case-control study of 363 cases with conjunctival scarring and 363 control participants was conducted. Investigations included in vivo confocal microscopy (IVCM) assessment, quantitative real-time PCR gene expression, C. trachomatis detection, and nonchlamydial bacterial culture. Trachomatous scarring was found to be strongly associated with a proinflammatory, innate immune response with increased expression of psoriasin, interleukin-1ß, tumor necrosis factor alpha, defensin-ß4A, chemokine ligand 5, and serum amyloid A1. There was also differential expression of various modifiers of the extracellular matrix, including metalloproteinases 7, 9, 10, and 12, tissue inhibitor of matrix metalloproteinase 1, and secreted protein acidic cystein-rich-like 1. The expression of many of these genes was also significantly associated with the presence of nonchlamydial bacterial infection. These infections had a marked effect on conjunctival immune processes, including an increased inflammatory infiltrate and edema seen with IVCM. This study supports the possibility that the immunofibrogenic response in scarring trachoma is partly stimulated by nonchlamydial bacterial infection, which is characterized by the expression of innate factors.

Management of Filamentous Fungal Keratitis: A Pragmatic Approach.

Filamentous fungal infections of the cornea known as filamentous fungal keratitis (FK) are challenging to treat. Topical natamycin 5% is usually first-line treatment following the results of several landmark clinical trials. However, even when treated intensively, infections may progress to corneal perforation. Current topical antifungals are not always effective and are often unavailable. Alternatives topical therapies to natamycin include voriconazole, chlorhexidine, amphotericin B and econazole. Surgical therapy, typically in the form of therapeutic penetrating keratoplasty, may be required for severe cases or following corneal perforation. Alternative treatment strategies such as intrastromal or intracameral injections of antifungals may be used. However, there is often no clear treatment strategy and the evidence to guide therapy is often lacking. This review describes the different treatment options and their evidence and provides a pragmatic approach to the management of fungal keratitis, particularly for clinicians working in tropical, low-resource settings where fungal keratitis is most prevalent.

Longitudinal Location Influences Preference for Daylight Saving Time.

The chronobiology community advocates ending the biannual practice in many countries of adjusting their clocks to observe Daylight Saving Time (DST). Many governments are actively considering abandoning this practice. While sleep and circadian experts advocate the adoption of year-round standard time, most jurisdictions are instead considering permanent DST. In guiding advocacy, it is useful to understand the factors that lead governments and citizens to prefer the various options. In October 2021, the Canadian province of Alberta conducted a province-wide referendum on adopting year-round DST, in which more than 1 million valid votes were cast. As this referendum was tied to province-wide municipal elections, the results of the referendum were reported at the community level, allowing a geospatial analysis of preference for permanent DST. While the referendum proposal was narrowly defeated (49.8% in favor), a community-level analysis demonstrated a significant East-West gradient, with eastern communities more strongly in favor and western communities more strongly opposed to the year-round DST. Community size and latitudinal position also contributed to preference, with smaller and more northern communities showing more preference for year-round DST. These findings help identify how geospatial location can influence how citizens feel about the various time options and can further help guide public advocacy efforts by the sleep and circadian communities.

Microbial Keratitis in Nepal: Predicting the Microbial Aetiology from Clinical Features.

Fungal corneal infection (keratitis) is a common clinical problem in South Asia. However, it is often challenging to distinguish this from other aetiologies, such as bacteria or acanthamoeba. In this prospective study, we investigated clinical and epidemiological features that can predict the microbial aetiology of microbial keratitis in Nepal. We recruited patients presenting with keratitis to a tertiary eye hospital in lowland eastern Nepal between June 2019 and November 2020. A structured assessment, including demographics, history, and clinical signs, was carried out. The aetiology was investigated with in vivo confocal microscopy and corneal scrape for microscopy and culture. A predictor score was developed using odds ratios calculated to predict aetiology from features. A fungal cause was identified in 482/642 (75.1%) of cases, which increased to 532/642 (82.9%) when including mixed infections. Unusually, dematiaceous fungi accounted for half of the culture-positive cases (50.6%). Serrated infiltrate margins, patent nasolacrimal duct, raised corneal slough, and organic trauma were independently associated with fungal keratitis (p < 0.01). These four features were combined in a predictor score. The probability of fungal keratitis was 30.1% if one feature was present, increasing to 96.3% if all four were present. Whilst microbiological diagnosis is the "gold standard" to determine the aetiology of an infection, certain clinical signs can help direct the clinician to find a presumptive infectious cause, allowing appropriate treatment to be started without delay. Additionally, this study identified dematiaceous fungi, specifically Curvularia spp., as the main causative agent for fungal keratitis in this region. This novel finding warrants further research to understand potential implications and any trends over time.