Although filtering surgery is a popular treatment for glaucoma, it poses the risk for postoperative, late-onset bleb-related infections, including blebitis and bleb-related endophthalmitis.1–6 These infections have been linked to several risk factors: avascular blebs,7 late-onset bleb leakage,8 inferior location of blebs,1,8,9 young age,8–11 and male sex.9 Recent large-scale multicenter studies have evaluated the relationship between these factors and bleb-related infections.10,11
The Japan Glaucoma Society initiated a 5-year-long, prospective multicenter study [Japan Glaucoma Society Survey of Bleb-related Infection (JGSSBI)] in 2005 to investigate the nature of late-onset bleb-related infections, particularly, the severity, prognosis, and bacteriological findings. The first 2 reports indicate that bleb leakage is highly frequent in eyes with repeated infections12 and that severe bleb-related infections involving the vitreous can significantly impair vision and elevate intraocular pressure within 12 months of onset.13
Seasonality is a risk factor for late-onset bleb-related infection.14,15 Ashkenazi et al14 reported winter season as a risk factor for such infections in Israel. Similarly, Hori et al15 reported that in Japan, the infections are most common in May, followed by April and July. However, no large-scale, multicenter trials have evaluated seasonality with other associated factors. As part of JGSSBI, we aimed to assess seasonal variations in the incidence of late-onset bleb-related infection after filtering surgery and evaluate the relationship between seasonality and other associated factors.
MATERIALS AND METHODS
JGSSBI has been described previously in detail.12,13 Eighty-two clinical centers participated in this prospective study, including 21 university hospitals, 23 public hospitals, and 38 private ophthalmology clinics. The observation period was set to 5 years, ending on March 31, 2010. A total of 157 initial bleb-related infections, encountered over 5 years, were identified (106 male and 50 female individuals including 1 bilateral case). The mean (±SD) patient age at the time of first infection was 59.3±17.7 years, and the mean interval between the last glaucoma surgery and first bleb-related infection was 6.9±5.8 years. Excluding the left eye in the case of bilateral infection, we analyzed 156 cases of late-onset bleb-related infection developing no earlier than 4 weeks postoperatively. In Japan, the seasons are winter from December to February; spring, from March to May; summer, from June to August; and autumn, from September to November. Other factors analyzed were age, sex, avascularity of the bleb, and bleb leakage before infection. Bleb appearance was assessed using a predetermined scoring system.
To analyze seasonal variations in the incidence of the infection, we used the Roger test, which evaluates the significance of cyclic trends according to the efficient score vector calculated for one seasonal peak.16 The Fisher exact test was used for categorical variables and Student t-test or 1-way analysis of variance for continuous variables. Logistic regression analysis was performed to investigate the relationship between seasons and other risk factors. Statistical significance was set at probability (P) values of <0.05. All statistical analyses were performed using the statistical package R (version 3.0.3).
First-time infections were noted in 53, 42, 33, and 28 patients during winter, spring, summer, and autumn, respectively. Monthly variation in the incidence of late-onset bleb-related infections was significant (P=0.018) (Fig. 1). Infections were most frequent in January and February and least frequent from August to November. Although we were unable to statistically analyze sex differences, infections among women were the highest from January to May and lowest from October to December.
Further, we analyzed the relationship between age and other factors by defining 2 age groups using the median age (63 y). Avascularity of the bleb could not be assessed in 28 patients (17 men; 11 women), and the status of bleb leakage was unknown in 22 patients (12 men and 10 women). Bleb avascularity was more common in men than in women, but not significantly different (P=0.088) (Table 1). Further, no significant differences were noted between age, sex, avascularity of the bleb, and bleb leakage before infection or between the 2 age groups in bleb avascularity (Table 1). Moreover, no significant association was observed between season and age, sex, bleb avascularity, or bleb leakage. However, season was significantly associated with sex (P=0.015) for patients aged below 63 years; the proportion of infections among women in this group was high in only spring (Table 2).
The percentage of affected women was considered as an explained variable in logistic regression analysis. Statistical analysis of all factors was impossible because the sample size was small. Therefore, we only regarded season, age, and season-age interaction as explanatory variables. Multiple logistic regression analysis revealed that the ratio of affected women to affected men was the highest in spring [odds ratio (OR), 8.43; 95% confidence interval (CI), 1.93-36.9; P=0.005]. The proportion of women was higher among patients aged 63 years or above than those aged below 63 years (OR, 4.51; 95% CI, 1.07-18.93; P=0.040), but the proportion of women aged 63 years or above was lower than that of women aged below 63 years only in spring (OR, 0.12; 95% CI, 0.02-0.82; P=0.030).
Bacterial culture tests were performed in 139/156 cases (46, 40, 29, and 24 cases in winter, spring, summer, and autumn, respectively). Conjunctival scraping, anterior chamber tapping, and vitreous tapping were performed in 36, 14, and 7 cases of winter infections; 26, 11, and 8 cases of spring infections; 23, 8, and 9 cases of summer infections; and 16, 7, and 4 cases of autumn infections, respectively. Staphylococcus aureus, coagulase-negative Staphylococcus (CNS) spp., Streptococcus spp., and Corynebacterium spp. were the most common bacteria. S. aureus infections were more frequent in hot seasons (summer and autumn) than in cold seasons (winter and spring). Streptococcus spp. infections were more common in spring and summer. CNS spp., Streptococcus spp., Corynebacterium spp., and Enterococcus spp. were frequent in winter. Nevertheless, Streptococcus spp. was detected less frequently in winter than in summer and autumn, whereas CNS spp., Corynebacterium spp., and Enterococcus spp. were detected most commonly in winter. Further, CNS spp. were more common among women (7/27 vs. 7/46 cases; 25.9% vs. 15.2%), whereas Haemophilus influenzae was more common in men (4/46 vs. 0/27 cases; 8.7% vs. 0%) (Table 3).
We noted significant seasonal variation in late-onset bleb-related infections. Generally, infections were most common in January and February, but women were frequently affected from January through May. Overall, the proportion of women aged 63 years or above was greater than those aged below 63 years, but the proportion of women aged below 63 years was high only in spring. Further, bleb avascularity was more common among men than women. The causative bacterial agents also showed variations in seasonal and sex distribution. Thus, the following questions were raised: (1) Why were late-onset bleb-related infections frequent in winter? (2) Why did bacterial species show seasonal and sex variations? (3) Why did women, particularly those aged below 63 years, show a different trend?
Ashkenazi et al14 investigated 2 female (2 eyes) and 7 male (7 eyes) patients in Israel and reported winter as a risk factor for bleb-related infection, as noted in our study. They attributed this finding to the high intraocular pressure during winter, changes in hormonal activity, and/or cold-related changes in aqueous flow and conjunctival resistance. Wolner et al9 analyzed patients who developed the infection in a hospital in New York. Although they did not analyze the seasonality of bleb-related infection, they reported a significantly increased risk for bleb-related endophthalmitis among male patients and patients below 60 years old. They suspected that younger patients and male patients were perhaps more likely to be physically active, and to have occupational exposure to airborne pathogens, or other routes of exposure to infectious organisms.
Tokyo (latitude 35.7°N),17 Jerusalem (latitude 31.8°N),18 and New York City (latitude 40.7°N)19 have 4 seasons, vast differences in average monthly humidity, and considerable differences between their low winter and high summer temperatures.17–19 We speculated that the climate of Japan influences the incidence of bleb-related infection. Japan lies in the temperate zone. Although average temperatures in the northernmost (Hokkaido) and southernmost (Okinawa) points differ greatly, >90% of the population resides in the islands of Honshu, Shikoku, and Kyushu, which have similar average temperatures and tendencies of high temperature and humidity in summer and low temperatures and humidity in winter.20,21
The Collaborative Bleb-Related Infection Incidence and Treatment Study Group in Japan11 revealed young age as a risk factor and no significant difference between fornix-based conjunctival flaps and limbus-based conjunctival flaps in the incidence of bleb-related infection after trabeculectomy with mitomycin C, although a higher incidence in the case of limbus-based flaps has been reported elsewhere.7,22 Yamamoto et al11 speculated that the morphology of filtering blebs in Japanese patients may differ from that in other ethnic groups, and as speculated by Wolner et al,9 they suspected that age-related differences in physical activity and the consequent differences in the level of exposure to infective agents or trauma to the bleb may influence the onset of bleb-related infections.
The highly virulent S. aureus is a common cause of bacterial eye infections (eg, bleb-related infection)4,23 and infections of the skin and soft tissue (eg, impetigo, boils, and abscesses). Similar to our study, others have shown seasonal variations in S. aureus infections of the skin, nasopharynx, and other soft tissues, with peak occurrences in warmer seasons than in winter.24 Studies have shown seasonal changes in colonization of Streptococcus spp. in the conjunctival sac25 and external ocular infections caused by Streptococcus spp.,26 which are greater in warmer seasons than in winter.
We noted that infections due to the highly virulent S. aureus and Streptococcus spp.27 were more frequent in hot seasons, whereas those due to the less virulent CNS spp., Corynebacterium spp., and Enterococcus spp.27 were more common in winter. In many reports, the percentage of Streptococcus spp. and S. aureus among conjunctival bacteria is reported to be <10%, respectively, which is not high.25,28,29 The seasonal variation in infection due to Streptococcus spp. and/or S. aureus observed in our study as other reports also show; in addition, we found that infections due to less virulent bacteria were more common in winter. The ocular surface of patients with less virulent bacteria may be vulnerable to infection during winter due to suppressed or abnormal ocular surface immunity30,31 in cold environments. Thus, immunological changes may play an important role in the seasonal variance of bleb-related infection.
Avascular and/or leaking blebs may be vulnerable to infection4,6; the risk may increase in winter especially. However, we did not note any significant association between season and bleb avascularity or bleb leakage. Further, infections were also noted in patients with vascular blebs, which are less likely to develop infections. The tear film, lacrimal glands, and Meibomian glands work with the conjunctival and corneal epithelium toward preserving the integrity and immune function of the ocular surface.30 Changes in the tear film and/or ocular surface immunity may correlate more strongly with the occurrence of bleb-related infection than bleb surface conditions in winter. Antiglaucoma medications32,33 and trabeculectomy can cause tear film disorder and ocular surface disease.33–37 Similarly, a cold environment can cause tear film disorder,38 whereas low-humidity conditions cause corneal and conjunctival epithelial disorder.39 Thus, the bleb surface condition may easily become medically compromised in cold temperatures and low humidity. Moreover, it was reported that improving the tear condition for late-onset bleb leaks in patients with ocular surface disease was an effective treatment.34 It is difficult to evaluate the epithelial failure without special methods such as taking photos of the bleb with a fundus camera in the fluorescein angiogram mode after staining with fluorescein dye.40 Hereafter, a suitable evaluation of the epithelial failure of the bleb wall must absolutely be done when the doctors attend to the outpatients who have blebs to prevent the bleb-related infections.
Why did women, particularly those aged below 63 years, show a different tendency? Hikichi et al41 found no seasonal pattern for dry eyes in Japan and a high prevalence of dry eyes among visual display terminal users and contact lens wearers. Modern technology has made our lives more comfortable, and if we use air conditioning both the office and home, it is easy to maintain a warm and humid environment in all seasons. The ocular surface environment depends more on levels of physical activity and lifestyle than on climate. Although many studies have evaluated the seasonality of the S. aureus infections, several reports have indicated difficulties in determining the seasonality of S. aureus infections among inpatients maintained in climate-controlled hospital environment.24 However, this is not the case for most people in daily life. As speculated by Wolner et al,9 we believe that men may have higher physical activity levels and greater risk of exposure to airborne pathogens through occupational or other activities compared with women. Thus, besides climate, physical activity level and lifestyle may contribute to the seasonal variation in the incidence and sex differences in the involved bacterial agents of bleb-related infections in Japan.
Hori et al15 analyzed late-onset bleb-related infection in Japan. However, they reported that patients were most often infected in May, followed by April and July. Although we could not discern the exact number of younger female patients in their study, the mean patient age was 51.8 years and the proportion of female patients was 40.3%. In the present study, the mean patient age was 59.3 years, 7.5 years older than in the study by Hori and colleagues, and the proportion of female patients was 32.1%, 8.2% lower than in that study. This means that the number of younger female patients may have been higher in the study by Hori and colleagues than in the present study. We found that a large number of younger female patients experience late-onset bleb-related infection in spring. A difference in the seasonality of bleb-related infection compared with the present study may thus be unsurprising.
Climatic conditions in different countries may vary considerably. Accordingly, there may be changes in the reported incidences of bleb-related infection after filtering surgery and the percentage of affected women.1,2,9,11,42 Therefore, large-scale studies need be performed worldwide to assess the effect of seasonality and sex on bleb-related infections and develop effective strategies for decreasing and preventing bleb-related infections.
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