葡萄膜炎相关细胞因子与趋化因子基因多态性的研究进展
【摘要】 葡萄膜炎是一组累及虹膜、睫状体、脉络膜或三者同时受累的炎症性病变。尽管目前对葡萄膜炎的诊断和治疗有了很大的进展，仍有35%～45%患者视力最终丧失。其病因和发病机制仍不太清楚，可能与环境及免疫遗传因素有关。很多研究显示人类组织相容性抗原基因多态性在葡萄膜炎的发病中起重要作用；近年来，非人类组织相容性抗原基因包括细胞因子和趋化因子基因亦被报道在葡萄膜炎的发病机制中起重要作用。本文对葡萄膜炎相关的细胞因子和趋化因子基因多态性的研究进展进行综述。
【关键词】 葡萄膜炎 基因多态性 细胞因子 趋化因子 Original article
Corneal ulceration and subsequent scarring is a leading cause of ocular morbidity and unilateral blindness in developing countries. Resnikoff et al estimated that corneal opacity was the cause of blindness in 45% of cases worldwide[1]. An estimate from the Malaysian National Eye Survey (1996) showed that the prevalence of corneal opacities causing visual impairment was 0.04% and blindness caused by corneal disease was 3.42%[2].
The knowledge of risk factors, clinical features, causative organisms and their antibiotic sensitivity is essential in successful treatment[3]. Prompt institution of the appropriate antibiotic therapy remains the cornerstone of treatment. This demands clinical suspicion of a microbial cause for keratitis, knowledge of the likely agents in a particular community, reliable microbiological investigations and the availability of effective antibiotics.
This study analyzes the cases admitted for management of corneal ulcers at UMMC over a 34 month period.
MATERIALS AND METHODS
This is a cross sectional analytical study of patients diagnosed with corneal ulcers. We recorded age, gender, ethnicity, presence of known risk factors, clinical features, microbiology results, outcome of the lesion and best corrected visual acuity after two months of follow up. This study was carried out from July 2003 to April 2006.
All patients admitted to UMMC with a diagnosis of corneal ulcer were included in this study. Corneal ulcer was diagnosed when there was disruption in the continuity of the corneal epithelium, with evidence of underlying stromal infiltration or inflammation. Patients without epithelial defects or corneal infiltrates were excluded.
Visual acuity was assessed using a standard metric Snellen chart on admission, followed by a complete slitlamp examination of the anterior segment and fundus. Site and size of the ulceration, as well as presence of hypopyon were recorded. After instillation of 5g/L propacaine hydrochloride, corneal scrapings were taken with the bevel of a sterile needle. The specimens were innoculated onto blood, chocolate and sabouraud agar plates. The material was also smeared on glass slides for Gram staining in all cases and also potassium hydroxide (KOH) preparation whenever fungal infection was suspected. They were then sent to the microbiology lab for microscopic examination and culture and sensitivity testing. Additional cultures were performed on contact lenses, their containers and their solutions when available.
All patients were aggressively treated with a broadspectrum empirical antibiotic therapy based on clinical suspicion of the causative organism. Choice of antibiotic was generally based on the appearance of the ulcer and any predisposing factors. Therapy was modified daily depending on the clinical response and culture and sensitivity results of corneal scraping.
This study included the subsequent outcome of the ulcers, whether complicated or otherwise. An ulcer was considered healed when there was reepithelialisation and notable resolution of the infiltrate. Patients with healed ulcers were further followedup in the eye clinic for the next two months. After this period, the residual scar and BCVA were noted.
Statistical Analysis Statistical analysis was done using Statistical Products and Services Solution (SPSS) 12.0. In this study, analyses were done using Chisquare and Pearson correlation tests. A level of significance of P<0.05 was used.
RESULTS
Demographic Characteristics A total of 87 eyes of 84 patients were included. One patient was admitted for bilateral corneal ulcers and another patient had three separate admissions for recurrence of herpetic keratitis. There were 46 female and 38 male patients. The ethnic distribution was 44(52%) Malays, 20 (24%) Chinese, 10 (12%) Indians and 10 (12%) foreign nationals including 6 Indonesians, 1 Burmese, 1 Vietnamese, 1 Bangladeshi and 1 Jordanian. In the three main local ethnic groups, more females were affected but in the group of foreigners all those affected were males.
Patients ages ranged from 9 to 87 years old (mean 34.8±19.2 years). The age group mode was 20 to 40 years. Gender difference was statistically significant (P<0.05) in contact lens wear (higher in females) and trauma (higher in males) but not in the ocular surface disease, previous surgery or glaucoma subgroups.
Risk Factors
Ocular risk factors The use of contact lenses was the most frequent ocular risk factor (47%). Ocular trauma or foreign body entry occurred in 25%, 24% had some form of ocular surface abnormality, 12% had a history of ocular surgery in the involved eye (either recent or in the past) and 9% had been diagnosed with glaucoma.
The majority of those with ocular trauma were bluecollar workers. Labourers (11 cases), factory workers (2 cases), grass cutters (2 cases), a gardener and a cook.
Of the ocular surface abnormalities, there were 6 eyes (7%) with bullous keratopathy; 5 of pseudophakic bullous keratopathy and 1 secondary to acute angle closure glaucoma. Chronic keratoconjunctivitis was seen in 5 cases (6%). There were 4 cases (5%) of herpetic keratitis, of which 3 were of the same patient who developed recurrence at different periods in time. Exposure keratopathy was seen in 3 eyes (3%); 1 patient had chronic progressive external ophthalmoplegia (CPEO) and had previous corrective surgery for ptosis, 1 patient was bedridden with spastic paralysis due to cerebrovascular accident (CVA) and the other one had thyroid eye disease (TED). 1 case was of dry eye due to StevenJohnson syndrome and 1 case of neurotrophic keratopathy was secondary to trigeminal nerve palsy in acoustic neuroma. Two patients each in the herpetic keratitis and chronic keratoconjunctivitis group were given topical steroids prior to presentation.
Table 1 Visual acuity during the course of this study
VAOn admissionOn discharge2 months after discharge>6/18203847<6/186/6017239<6/603/60412<3/601/60640<1/60PL36137NPL255Not available2317Total878787
Systemic risk factors Diabetes mellitus and hypertension were the most common systemic risk factors seen, with 7 (8%) and 8 cases (9%) respectively. There were 2 cases each of bronchial asthma, ischaemic heart disease, chronic osteomyelitis of the lower limbs and systemic lupus erythematosus (SLE). One of the cases who had chronic osteomyelitis was also an opium smoker. The other conditions with single occurrence were acoustic neuroma, autoimmune hepatitis, autoimmune haemolytic anaemia (AIHA), chronic obstructive airway disease, CVA, CPEO, pregnancy, psychiatric disorder, TED, StevenJohnson syndrome and glucose 6phosphate dehydrogenase deficiency (G6PD). The cases with SLE, autoimmune hepatitis and AIHA were on systemic steroids at the time of admission into this study.
Clinical Features
Visual acuity Visual acuity on admission (Table 1) was between <1/60 to perception of light in the majority (41%) of eyes. 2 eyes had no perception to light (NPL) for many years before presentation, 1 due to rubeotic glaucoma and the other due to a penetrating injury. We could not assess visual acuity in 2 patients, 1 with a psychiatric disorder and the other with spastic paralysis due to a CVA. On discharge, visual acuity was >6/60 in 61 eyes (70%). Eventually, the visual acuity at 2 months after discharge was >6/18 in 47 eyes (54%). However, there was also a considerable number of patients who defaulted followup at two months after discharge, 17 cases (20%). 2 eyes developed intractable endophthalmitis and one eye perforated, requiring eviscerations and enucleation respectively.
Thirtyfive eyes (78%) with a central ulcer had vision <3/60 on admission, of which 11 (24%) remained at that level 2 months after discharge. Only 7% of eyes with peripheral ulcers had vision <3/60 after the same duration of follow up. The BCVA was correlated to ulcer site (P<0.01) and size (P<0.01) but not to the age of the patient.
Hypopyon There were more corneal ulcers without hypopyon (59.8%) than with it (40.2%). 16 eyes (45%) in the contact lens group had hypopyon. Hypopyon was significantly correlated with central ulcers (P<0.05). There was no significant correlation between hypopyon ulcers with any of the ocular risk factors.
Ulcer site Of the ulcers, 51.7% were seen in the central cornea involving the pupillary area, 14.9% were in the paracentral region and 33.3% were in the peripheral cornea. The site of ulcer was not significantly correlated to any of the ocular risk factors.
Ulcer size Thirtyeight cases (43.6%) were 2 to 4mm in size, 28 (32.2%) larger than 4mm and 21 (24.1%) smaller than 2mm. There were statistically significant correlations between ocular surface disease and glaucoma with ulcer size.
Microbiology Results
Gram stain Of the 87 eyes, 69 (79%) had corneal scrapings done. 52 slides (75%) were reported as negative. The positive results are shown in Table 2. Gram negative bacilli were seen in 13 cases (19%).
Culture and sensitivity Positive growth of organism was seen in 51 cases (74%); 16 cases (23%) being polymicrobial and 35 cases (51%) involving single microbes. There was negative growth in 18 cultures (26%).
Nineteen types of organisms were isolated from the culture plates, as listed in Table 3. The most common organism detected was Pseudomonas aeruginosa, seen in 40 cultures (58%). Aspergillus sp. was the most frequently reported fungal pathogen. There were more gram negative organisms isolated (68%) than gram positive bacteria.
Treatment In this study, 36 eyes (41%) were started on intravenous antibiotics, 17 eyes (20%) had oral antibiotics alone and 34 eyes (39%) were not started on any systemic antibiotics. All but 1 (2%) of Pseudomonas aeruginosa cultures were sensitive to gentamicin. One case was resistant to chloramphenicol. There was one culture of gentamicinresistant Stenotrophomonas maltophilia and one of methicillinresistant Staphylococcus epidermidis.
Gentamicin (69%) was the commonest intravenous antibiotic given, followed by cefuroxime (67%) and ciprofloxacin (31%). Intravenous ceftazidime was used in 14% of cases. The most commonly used systemic antifungal was oral ketoconazole (4 cases).
All eyes were started on topical treatment of variable combination. The fluoroquinolones ciprofloxacin 3g/L and lomefloxacin 3g/L were used in 68 eyes (78%) as they have broad spectrum coverage, are well tolerated and are widely available commercially. Cefuroxime 50g/L was used in 21 eyes (24%). The fortified gentamicin 10g/L formulation was used in 65 eyes (75%), more than the weaker gentamicin 3g/L in 8 eyes (9%). Topical antifungals commonly used were amphotericin B 5g/L and itraconazole. Acyclovir ointment 30g/L was used in cases suspected of herpetic origin, in combination with antibiotic coverage.
Outcome
Corneal opacity There were 75 eyes (88%) which eventually developed corneal opacity after ulcer healing. Four cases had vascularisation, of which one developed uncontrolled secondary glaucoma and needed trabeculectomy.
Severe complications Endophthalmitis with impending perforation was seen in one case. Pseudomonas aeruginosa was isolated from it and treatment was with intravitreal amikacin and ceftazidime. It eventually healed with scarring. 2 other cases of endophthalmitis eventually required evisceration. Of these, 1 patient had a chronic psychiatric disorder and also had bilateral below knee amputations for gangrene. The other had rubeotic glaucoma in the same eye, as well as hypertension
Table 2 Distribution of gram stain results
Gram stain resultFrequency%Gram negative cocci23Gram negative bacilli1319Gram positive bacilli11.5Gram positive cocci11.5Negative5275Not done1821Total87100
Table 3 Frequency of organism cultured
MicroorganismsFrequencyGram positive bacteria Staphylococcus coagulase negative3 Streptococcus viridans2 Staphylococcus epidermidis1Gram negative bacteria Pseudomonas aeruginosa40 Enterobacter sp.4 Stenotrophomonas maltophilia4 Alcaligenes sp.3 Acinetobacter baumanii3 Serratia marcescan2 Klebsiella sp.1 Klebsiella pneumoniae1 Aeromonas sp.1 Acinetobacter sp.1 Citrobacter sp.1 Flavobacterium meningosepticum1 Mycobacterium sp.1Fungi Aspergillus sp.3 Curvularia lunata1 Paecilomyces lilaicinus1
and chronic osteomyelitis of the right foot. Staphylococcus coagulase negative sensitive to methicillin was isolated from the former while the latter had a negative culture.
Perforation occurred in 4 eyes; one eye had a Gunderson conjunctival flap done while 2 others healed with cyanoacrylate tissue adhesive and bandage contact lens application. The final one was infected with the rare Paecilomyces lilaicinus which proved resistant to our treatment. The patient opted for alternative treatment at another centre but eventually developed perforation and had to have an enucleation done. He had SLE and AIHA, and was on systemic steroids.
Outcome and risk factors The rate for developing endophthalmitis was 8% while perforation leading to endophthalmitis occurred in 3.5%. The rate of evisceration and enucleation was 3.5%. Statistical analysis showed that the risk of perforation and endophthalmitis was significantly higher in eyes with previous ocular surgery (P<0.05) and ocular surface disease (P<0.01) but not in the contact lens wear, trauma or glaucoma groups. There was also no significant association with diabetes or hypertension.
DISCUSSION
Demographics and Risk Factors The slight female preponderance (1.2∶1) in this series differs from a few other studies where there were more males affected[4,5]. Considering the predominant predisposing factor in this study population was contact lens wear, the probable reason for the female preponderance was due to the popular use of contact lenses by this gender. Previously, most cases of microbial keratitis were associated with ocular trauma or ocular surface disease but the widespread use of contact lenses has changed the order of importance of these risk factors[6]. Contact lens wear is now the major cause of ulcerative keratitis in developed countries where there is a significant number of contact lens wearers. However, in the Malaysian state of Kelantan, where a significant part of the population is involved in the agriculture industry, trauma/ foreign body entry (52%) was the major risk factor associated with corneal infection. Only 4 patients (2%) were contact lens wearers[5].
Older average ages were seen in patients who had preexisting ocular surface disease (48.8 years), previous surgery (62.3 years) and glaucoma (71.6 years). This was also seen in the cases with diabetes mellitus (65.3 years) and hypertension (64.3 years).
Clinical Features Visual prognosis after bacterial keratitis has been reported to be affected by presence of associated risk factors, locality, anterior chamber reaction and depth of the ulcer[7]. In this study, best corrected vision 2 months after discharge was correlated with site and size of the ulcer. Ocular surface disease, previous surgery and glaucoma were also associated with poorer outcome. These factors appear to have an added destructive effect to the epithelial disruption and stromal derangement caused by the infection.
Microbiological Profile This study showed a good yield for culture and sensitivity inoculations, comparable to other published studies which reported incidences of 2767% for positive gram stains and 3676% for positive culture results[8]. Sensitivity testing has a place in following trends in antibiotic resistance that can guide the selection of the appropriate antibiotics for specific organisms.
Pseudomonas aeruginosa was the most frequently isolated bacteria (57%) in the cultures and it was also the main causative organism seen in the 3 main ocular risk factor groups. Contact lens wear (31 cases) contributed to the highest proportion of Pseudomonas ulcers. It has been suggested that this is due to a combination of minor trauma followed by corneal contamination with this soil and water based organism[9]. The dominance of pseudomonas keratitis has also been shown in other studies done in this region[5,9].
Aspergillus sp was the most frequently isolated fungi in this series. It is the most frequently reported fungal pathogen isolated in the tropics, together with Fusarium sp.[10]. Differences in the incidence of fungi are known to exist with respect to geographic locations, thus selecting antimycotics should take this into account. In temperate climates, Candida is most frequent, followed by Aspergillus.
It is interesting that only one case each of Pseudomonas aeruginosa and Stenotrophomonas maltophilia were resistant to gentamicin, which is the first line antibiotic for gram negative ocular infections used locally. Although treatment outcomes with fluoroquinolone monotherapy compare favourably with conventional combined therapy of fortified antibiotics[11], it appears that gentamicin may remain effective as the initial antibiotic of choice for gram negative cover in our local context.
Treatment and Outcome In this study, the most commonly used eyedrop was of the fluoroquinolone group (78%) followed by fortified gentamicin (75%) and then cefuroxime 5% (24%).
Severe complications were seen in 8% of cases, which is lower than in other reported studies in the literature; 16.9% by Reddy et al[5] and 24% by Ormerod et al[12]. The rate of healing into a scar was 88%, comparable to 80% in the study by Reddy et al[5]. The evisceration and enucleation rate of 3.5% was comparable to the 2% range reported in another series[12]. Most failures of therapy occurred in patients with advanced ulcers at the time of presentation, either due to existing predisposing conditions or because of late presentation.
Based on the findings of this study, where contact lens wear is a significant ocular risk factor in the development of corneal ulcers, appropriate education about lens care and hygiene among wearers should be emphasized. They should be advised to seek early and appropriate treatment if eye infection or trauma occurs and to avoid contact lens usage. Medical practitioners should have a higher level of suspicion of corneal infection in this group.
CONCLUSION
Contact lens wear is the most common predisposing factor for corneal ulcers, followed by trauma. They mostly occur in the younger population. Ocular surface diseases is an association in the older population and usually results in poorer visual prognosis. Gram negative microbes (68%) were more prevalent than gram positive organisms. Pseudomonas aeruginosa was the most frequently isolated bacteria in every ocular risk factor group.
【参考文献】
1 Resnikoff S, Pascolini D, Etyaale D, Kocur I, Pararajasegaram R, Pokharel GP, Mariotti SP. Global data on visual impairment in the year 2002. Bull World Health Organ 2004; 82(11):844855
2 Zainal M, Ismail SM, Ropilah AR, Elias H, Arumugam G, Alias D, Fathilah J, Lim TO, Ding LM, Goh PP. Prevalence of blindness and low vision in Malaysian population: results from the National Eye Survey 1996. Br J Ophthalmol 2002; 86(9):951956
3 World Health Organization. Guidelines for the Management of Corneal Ulcer at Primary, Secondary & Tertiary Care health facilities in the SouthEast Asia Region. World Health Organization Regional Office for
SouthEast Asia 2004
4 Morgan PB, Efron N, Brennan NA, Hill EA, Raynor MK, Tullo AB. Risk factors for the development of corneal infiltrative events associated with contact lens wear. Invest Ophthalmol Vis Sci 2005; 46(9):31363143
5 Reddy SC, Tan BC. Bacterial keratitis in Northeast Peninsula Malaysia: a review of 136 cases. Biomed Res 1999;10:113119
6 Roberts A, Kaye AE, Kaye RA, Tu K, Kaye SB. Informed consent and medical devices: the case of the contact lens. Br J Ophthalmol 2005;89(6):782783
7 Bourcier T, Thomas F, Borderie V, Chaumeil C, Laroche L. Bacterial keratitis: predisposing factors, clinical and microbiological review of 300 cases. Br J Ophthalmol 2003;87(7):834838
8 Levey SB, Katz HR, Abrams DA, Hirschbein MJ, Marsh MJ. The role of cultures in the management of ulcerative keratitis. Cornea 1997;16(4):383386
9 Sharma S, Gopalakrishnan S, Aasuri MK, Garg P, Rao GN. Trends in contact lensassociated microbial keratitis in Southern India. Ophthalmology 2003;110(1):138143
10 Srinivasan M. Fungal keratitis. Curr Opin Ophthalmol 2004;15(4):321327
11 Smitha S, Lalitha P, Prajna VN, Srinivasan M. Susceptibility trends of pseudomonas species from corneal ulcers. Indian J Med Microbiol 2005;23(3):168171
12 Ormerod LD, Hertzmark E, Gomez DS, Stabiner RG, Schanzlin DJ, Smith RE. Epidemiology of microbial keratitis in southern California, a multivariate analysis. Ophthalmology 1987;94(10):13221333
订阅登记：
请您在下面输入常用的Email地址、职业以便我们定期通过邮箱发送给您最新的相关医学信息，感谢您浏览首席医学网！