lnfectious keratitis in Vietnam: etiology, organisms, and management at Vietnam National Eye Hospital

INTRODUCTION

The mean duration of inpatient treatment at VNEH following the diagnosis of infectious keratitis was 22.9±13.5d (range 7-98d), with the shortest duration for bacterial keratitis (21.4±12.8d) and the longest forkeratitis (26.0±15.2d). Half of the IK cases were successfully treated with medical therapy alone (995/1974 eyes, 50.4%). The rate of medical treatment failure was highest in microsporidial keratitis (38.2%), followed by fungal keratitis(28.1%), and viral keratitis (11.9%). Corneal debridement was performed in 23% of affected eyes, most commonly in those affected withkeratitis (39.4%). AC washout,indicated if a thick exudate was present posterior to the cornea or for diagnostic purposes, was most commonly performed for eyes with fungal keratitis (28.1%) and least commonly for eyes withkeratitis (4.5%; Table 4).Amniotic membrane transplantation (AMT) was typically performed in the setting of a persistent epithelial defect,most commonly in cases of viral ulceration (19.9%) and least commonly in cases of fungal ulceration (1.5%). A total of 337 eyes underwent corneal transplantation: penetrating keratoplasty (PK) in 307 (15.6%) eyes and lamellar keratoplasty (LK) in 30 (1.5%) eyes. Microsporidial keratitis was associated with the highest percentage of infections requiring PK (29/81 cases, 35.8%) and HSV keratitis was associated with the highest percentage of infections requiring LK (12/226 cases, 5.3%). Evisceration was most commonly performed for fungal keratitis, which was also associated with the highest percentage of infections requiring evisceration(112/1115 eyes, 10.0%).On the day of discharge, 1689 (87.5%) eyes had VA of CF at less than 3 m. Only 52 (2.6%) eyes had VA 20/80 or better, and 141 (7.1%) eyes were no light perception following evisceration.

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The demographic profile and clinical features of IK vary significantly based on geographic region. The Asia Cornea Society Infectious Keratitis Study (ASCIKS) surveyed IK in senven Asian countries (India, China, Japan, South Korea,Thailand, the Philippines, and Singapore) and reported demographics, risk factors, organisms, and outcomes of IK in each of these countries. Though the ASCIKS has provided important insights into IK in Asia, it includes a minority of Asian countries, and thus data from other countries in Asia, especially those that are historically underrepresented in such multinational studies, is needed. Currently, there is no published data regarding IK in Vietnam. Therefore, the purpose of this study is to report the risk factors for, organisms associated with, treatments for and outcomes of nearly 2000 cases of IK managed at the Vietnam National Eye Hospital(VNEH) during a 5-year period.

It is difficult to determine a precise estimate of the global burden of IK, other than to suggest that it disproportionately affects poor, rural populations. Epidemiological studies have reported the incidence of IK to range from 3.6to 52.1per 100 000 people in North American and European countries versus 6.3to 799per 100 000 people in Asian countries.However, the true incidence of IK in Asia may be higher,particularly in economically less developed countries where data is currently lacking.

SUBJECTS AND METHODS

This is a retrospective study approved by the VNEH Research and Ethics Committee. Medical records of all patients who were treated at VNEH from January 1,2013 to December 31, 2017 and diagnosed with any type of IK, including bacterial, fungal, viral, microsporidial, andkeratitis, were reviewed.

All specimens for smear and culture were obtained by scraping the edge of a corneal infiltrate using a small sterilized curette or Kimura spatula at the slit lamp. Ⅰf there was no infiltrate, a corneal biopsy or anterior chamber (AC) tap was performed to obtain a specimen. If a keratoplasty was performed following the diagnosis of IK, the excised corneal tissue was used as a specimen for smear and culture. Specimens were prepared using Gram’s staining and 10% potassium hydroxide.Subsequent scrapings were inoculated directly onto various culture media for isolation of bacteria (blood and chocolate agar) and fungi (sabouraud dextrose agar). All bacterial media were incubated in 5% CO, whereas fungal media were stored in a 25C-30C incubator. Herpes simplex virus (HSV)keratitis was diagnosed based on the medical history (,prior history of HSV infection) and exam (decreased corneal sensation, dendritic epithelial lesions, geographic ulceration,). Cytology and polymerase chain reaction (PCR) were performed in selected cases.

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For each patient, the following data were obtained from medical records: demographics, duration of symptoms, details of past and concurrent ocular and systemic diseases, history of ocular trauma, contact lens wear, and prior ocular medications.Clinical exam findings evaluated included visual acuity (VA),infiltrate characteristics (appearance, location, dimensions,depth), presence of a hypopyon, and associated anterior segment findings. Intraocular pressure and lens and fundus exam results were included when available.Etiologies of IK were determined based on microbiology results and treatment outcomes. If smears and/or cultures from an eye demonstrated a bacterium and another microorganism(, fungus, virus,or microsporidia), the other organism was considered to be the pathogenic organism for classification purposes. In cases of negative or lack of microbiologic results, patients were treated empirically, and the causative agent of the patient’s ⅠK was identified based on response to therapy or clinical impression.Bacterial keratitis was treated with a topical antibiotic, typically a fluoroquinolone. In severe cases of bacterial infection,patients were initially treated with combined fortified cefazolin(33 mg/mL) and gentamycin (14 mg/mL) eye drops after corneal scraping. The treatment regimen was subject to modification according to the patient’s clinical response and microbiological results. Natamycin 5% or amphotericin B 0.15% was used for patients with suspected or culture-proven fungal keratitis and acyclovir 3% ointment was prescribed for patients with suspected or confirmed HSV keratitis. In the case ofor microsporidial keratitis, both a fluoroquinolone antibiotic eye drop and an antifungal eye drop were prescribed. For keratitis complicated by impending corneal perforation, actual perforation, and/or scleral or intraocular extension, systemic antibiotics were commonly prescribed. Therapeutic keratoplasty was performed if the IK was unresponsive to at least 2mo of medical treatment, in the setting of an impending perforation (descemetocele) and following development of a corneal perforation. Evisceration was performed following corneal perforation if donor corneal tissue was unavailable, following spread of infection to the vitreous cavity or sclera, and following extrusion of the intraocular contents.

Statistical analyses were performed using SPSS v, 20.0 software (IBM Corp., Armonk, NY, USA), with<0.05 considered to be statistically significant.

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RESULTS

The most frequently isolated fungal pathogen in this study was, followed by. Of note, yeast‐associated keratitis was not identified in our study.The ACSIKS also reportedto be the most common cause of IK in China (30.9%) and in India(25.7%), which have comparable climates and exposure risks to Vietnam. Filamentous fungi such asandthrive in tropical regions like Vietnam, whereas yeast such asare more common in temperate areas and are more likely to affect patients with preexisting ocular surface disease and/or predisposing systemic diseases.

The 1070 of the 1974 eyes (54.2%) had one or more predisposing risk factor(s) for IK (Table 1). The most frequently identified risk factor was ocular trauma (676 cases,34.2%), which included trauma secondary to agricultural(360 cases, 53.3%), industrial (128 cases, 18.9%) and housework-related (188 cases, 27.8%) injuries.

Stromal infiltration that progressed to involve more than two‐thirds of the corneal thickness was observed in 74.9% of cases and was significantly more common in eyes with fungal keratitis than keratitis associated with non-fungal pathogens(82.2%63.7%,<0.001). Hypopyon was observed in 740(40.6%) eyes, most commonly in eyes affected with fungal(47.1%) and bacterial (39.1%) keratitis and least commonly in eyes affected withkeratitis (6.1%).

Corneal scraping and smear were performed in 1706 (86.4%) eyes. Bacteria (=1107, 64.9%)and fungi (=1092, 64.0%) were the most commonly identified pathogens on smear. Ⅰn 640 (37.5%) eyes, two different classes of microbes were isolated from a single smear, most commonly a bacterium and a fungus [614 (36.0%) eyes; Table 2].Cultures were performed for 1212 of the 1974 eyes diagnosed with ⅠK, with positive results in 481 (39.7%). A significantly higher percentage of fungal cultures were positive compared to bacterial cultures [50.8% (426/838)14.7% (55/374);<0.05], withbeing the most commonly cultured organism (Table 3).

In 42 cases of IK,microbiologic results were negative and thus patients were treated empirically. Based on clinical features and response to therapy, 23 of these cases were diagnosed as fungal and 19 were diagnosed as bacterial.

Based on the results of the corneal smears, cultures, PCR testing, and clinical diagnosis, fungal keratitis was the most common type of IK,accounting for 57% of cases, followed by bacterial keratitis(25%), HSV keratitis (11%), microsporidial keratitis (4%) andkeratitis (3%,<0.05; Figure 1).

The majority of cases involved unilateral ulcers (98.9%), whereas 22 (1.1%) cases involved bilateral ulcers. In the setting of bilateral ulceration, viral keratitis was the most common etiology, identified in 11 (50%) patients. On presentation, the majority of affected eyes had VA less than count fingers (CF) at 3 m (1838 eyes; 93.1%), with only 34(1.7%) eyes having VA better than 20/80. The area of corneal involvement was 4 to 6 mm in diameter in 820 (42.1%) eyes and greater than 6 mm in diameter in 929 (47.1%) eyes.The 4.7% (93/1974) of eyes progressed to descemetocele formation while 19.8% (391/1974) of eyes progressed to corneal perforation, which developed most frequently in eyes with fungal keratitis (22.4%) and least frequently in eyes withkeratitis (4.5%).

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One eye might be treated with more than one kind of eye drop. A total of 1126 eyes had been treated with topical and/or systemic antimicrobial therapy prior to referral to VNEH, most commonly antibiotic (30.9%) and antifungal (20.6%) drugs, while 46.8% of eyes were treated with an unknown medication before evaluation at VNEH (Table 1).

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Infectious keratitis (IK) is a vision-threatening corneal condition that is a major public health concern in tropical and developing countries, particularly within South, Southeast,and East Asia. Even with optimal treatment regimens, some cases of severe keratitis can result in permanent blindness or loss of the eye. IK is clinically characterized by the presence of corneal ulceration with or without stromal infiltration, and frequently leads to corneal scarring, the fourth leading cause of blindness worldwide. Complications of IK, including corneal perforation, persistent infection, and corneal scarring,are leading indications for corneal transplantation in many developing countries in Asia.

DISCUSSION

We report the first large retrospective study evaluating the etiology, organisms, and management of IK in Vietnam.Many of the results that we report are consistent with those in published series of IK from other Asian countries. In regard to patient demographics, the higher incidence of IK in men in Vietnam is consistent with prior reports on higher occurrences of eye injuries among men compared to women. Similarly,the findings that more than half of the individuals with ⅠK in Vietnam were between 18 and 60 years old, the age range of the working population, and that the majority of affected individuals were farmers and lived in rural regions, are consistent with demographics reported in other studies of IK in Asia. Additionally, our finding that ocular trauma, primarily associated with agricultural exposures, was the most common risk factor for IK in Vietnam is consistent with what was has been reported in South India (92.2%), China (66.8%), and Australia (43.9%).

Based on smear results in our study, bacteria and fungi were the most common microbes isolated in polymicrobial infections. There are several explanations for this finding: the resident bacterial flora may be simultaneously isolated during specimen collection; given the ubiquity of fungi and bacteria in the agricultural environment, both microbes may be introduced into the corneal stroma through ocular trauma; prolonged use of topical corticosteroids in certain patients may suppress the local immune response, potentially facilitating opportunistic infections; and two organisms may establish synergistic interactions, such that the primary organism establishes a“niche” for the secondary organism to become pathogenic.The relatively low percentage of bacterial cultures that were positive (14.7%), despite a clear clinical presentation of bacterial keratitis, is consistent with percentages previously reported in the United States (23.7%)and Thailand (25.6%).The low percentage of positive bacterial cultures may be due to a variety of reasons, including culturing after the initiation of topical antibiotics and difficulty obtaining a sufficient corneal specimen in the setting of a corneal perforation or impending perforation. Our finding ofas the most common bacterium isolated, followed byis consistent with prior series, not only from Asia but also from around the globe.Our finding that fungal keratitis is the most common type of IK in Vietnam, with a 2.3:1 ratio of fungal to bacterial keratitis, is comparable to reports from several other tropical Asian countries, including China and India. Mycotic ocular infections largely predominate in regions with large agricultural and manual labor workforces, as in Vietnam,especially among individuals exposed to ocular trauma from plant material. In our study, the higher incidence of fungal keratitis may also be due in part to increased referral of these cases to VNEH, a tertiary eye-care center with access to antifungal therapy, as antifungal agents are largely unavailable at provincial and district hospitals. Natamycin, which is not always commercially available in Vietnam, may debatably have limited effectiveness in treating deeper keratitis due to poor corneal penetration. Given the fact that more than 80% of cases of fungal keratitis involved more than twothirds of the corneal thickness on presentation to VNEH, the primary treatment for fungal keratitis at our hospital is topical amphotericin B 0.15% compounded in house.

IK was diagnosed in 1974 eyes of 1952 patients, twenty-two of whom presented with bilateral IK. Of the 1952 patients diagnosed with ⅠK, significantly more were male (1056, 54.1%) than female (896 patients, 45.9%;<0.05). The mean age was 54.3±16.6y (range 2-98y), with the majority of patients (61.2%) between 18 and 60y. The majority of patients lived in rural regions (84.1%) and were farmers (66.3%). The mean time between onset of symptoms and presentation to the hospital was 19.3±14.4d. More than half of patients (52.7%) presented to the hospital within 14d after symptom onset, whereas 15.4% of patients presented to the hospital more than 30d after symptom onset (Table 1).

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While microsporidial keratitis accounted for only 4% of IK cases in this study, the number of cases has been increasing in Vietnam since it was initially reported in 2015and based on this study is currently the fourth most common cause of IK. It is necessary to raise awareness of this pathogen among ophthalmologists to facilitate earlier diagnosis and surgical intervention. Ⅰf a definitive diagnosis of microsporidial keratitis can be made early in the course of disease, timely management may prevent progression of keratitis and decrease the need for therapeutic keratoplasty. The lower incidence ofkeratitis (3.0%) identified in our study population is consistent with that reported in other studies, and is likely associated with the low percentage (1.4%) of keratitis cases associated with contact lens wear in this series.

Half of the IK cases were successfully treated with medical therapy, consistent with the 55.0% of IK cases successfully treated with medical therapy in the ACSIKS. The percentage of cases successfully treated medically was lowest for fungal keratitis, indicative of the more recalcitrant nature of fungal keratitis. The outcomes of fungal keratitis have been reported to be worse than those of bacterial keratitis, due in part to the limited efficacy of topical and systemic antifungal therapy.The 17.1% of eyes that required keratoplasty in this series is similar to the percentages reported by the ACSIKS in other Asian countries: 19.6% (China), 14.9% (Philippines) and 9.5% (India). In Vietnam, China, and India, IK is the main indication for PK. Unfortunately, these countries have limited access to corneal tissue despite high demand, with an estimated 2 million people in China and 7 million people in India currently waiting for a corneal transplantation. In these situations, surgeons may opt to use lower grade corneal tissue than those used for optical transplants, perhaps contributing to the high rates of graft failure and poor visual outcomes after corneal transplantation. The insufficient supply of donor corneal tissue is a contributing factor to the higher rate of evisceration in the majority of developing Asian countries such as Vietnam, the Philippines, and Thailand compared with more developed Asian countries and regions such as Japan,Singapore, and Taiwan, China.

In cases of IK that did not require surgical intervention,nearly 90% of patients had a VA in the affected eye of less than CF at 3 m on the day of discharge, and less than 5% had a VA ≥20/80. Unfortunately, follow‐up after discharge was limited for many of the patients, and thus long-term visual outcomes are unknown. The long-term visual outcomes in eyes requiring surgical intervention are likely even more guarded,even without inclusion of the eyes that required evisceration.Given poor short-term visual outcomes and higher rate of evisceration following IK in Vietnam than in more developed countries, there is a need to develop more effective measures to reduce corneal blindness through prevention. For example, eye protection may reduce the risk of ocular trauma, the primary cause of corneal infection in Vietnam and other developing Asian countries. Antibiotic or antiseptic prophylaxis following traumatic corneal abrasions in a village setting may also be effective in preventing both bacterial and fungal keratitis.

Limitations of this study include an inability to accurately assess the distribution of types of IK in the general population of Vietnam, given the disproportionately large number of fungal keratitis cases referred to VNEH, a tertiary referral hospital that receives severe cases of IK that may not be representative of all cases of IK in the population.Additionally, given the retrospective nature of the study,diagnostic and treatment protocols were not standardized, and the outcome of treatment following discharge from VNEH was not systematically collected. Further studies are needed to characterize long-term outcomes of IK in Vietnam.In conclusion, the present study found that in Vietnam, ocular trauma is the most common risk factor for IK, which is most commonly caused by fungi. The relatively high frequency of evisceration, the poor early visual outcomes and the shortage of donor corneal tissue for severe IK requiring keratoplasty indicate a need for greater emphasis on prevention and early treatment of ⅠK in Vietnam. As part of this effort, we believe that it is imperative to increase awareness of the importance of wearing eye protection during work and other activities that are associated with an increased risk of eye injury, especially among susceptible populations.

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