Posterior capsule opacification (PCO), which causes significant visual symptoms including light scatter and reduced visual quality, is the most frequent complication of cataract surgery.1 This secondary cataract is typically treated with neodymium:yttrium-aluminum-garnet (Nd:YAG) laser capsulotomy, a non-invasive and gold standard treatment procedure.2 Despite its simplicity, reliability, and effectiveness, potential complications, such as increased intraocular pressure (IOP), cystoid macular edema, retinal hemorrhages or detachment, and intraocular lens (IOL) dislocation, along with the unnecessary burden on healthcare systems, highlight the importance of PCO prevention as a crucial goal.2,3

The pathophysiology of PCO is multifactorial. Factors such as the cataract surgery technique, the material and design of the IOL, the patient’s age, coexisting ocular and systemic diseases contribute to the incidence of PCO.4 Following cataract surgery, remaining lens epithelial cells (LECs) proliferate, migrate and differentiate to develop PCO, and inflammation plays a crucial role in initiation of wound-healing response and transdifferentiation of LECs into a myofibroblast phenotype.5,6 These differentiated myofibroblastic cells secrete extracellular matrix proteins, that are not typically present in the lens. Among these proteins are matrix metalloproteinases, which play a role in cell migration, and inflammatory cytokines such as transforming growth factor-beta (TGF-β) and fibroblast growth factor 2 (FGF-2). Both TGF-β and FGF-2 are implicated in the development of PCO and the epithelial-to-myofibroblast transition. Additionally, oxidative stress activates TGF-β1 through the production of reactive oxygen species, further contributing to this process.6,7 Given the role of inflammation in the development of PCO, various anti-inflammatory drugs, including triamcinolone acetonide, diclofenac, and dexamethasone, have been investigated in both clinical and experimental studies for their possible benefits in preventing PCO.8,9

Potential inflammatory biomarkers calculated from complete blood cell count (CBC) including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR), have been proposed as prognostic indicators in various systemic diseases.10 These markers have also been widely studied in several ocular diseases such as different types of glaucoma, retinal vascular diseases, age-related macular degeneration, ocular surface diseases, and keratoconus.11,12 The degradation of the blood-aqueous humor barrier during cataract surgery causes cytokine-mediated immune response; therefore the influence of systemic inflammation in the pathogenesis of PCO should not be neglected.13 Ozates et al reported a high incidence (50.9%) of PCO as a complication of cataract surgery in patients with systemic disease–associated uveitis. They emphasized that eyes with early and frequent recurrences were more susceptible to developing PCO.14 To the best of our knowledge, previous studies have not demonstrated an association between inflammatory biomarkers derived from CBC and PCO. This study aims to assess the relationship between these inflammatory indicators and the development of clinically significant PCO requiring treatment with Nd:YAG laser capsulotomy.

This retrospective study was conducted at a tertiary university hospital and institutional ethical committee approval (IRB No:49838221–050.01.04–54) was obtained before the study commenced. Researchers participating in the study adhered to the principles of the Declaration of Helsinki, and all participants provided written informed consent.

The medical charts of patients with age-related cataracts who developed clinically significant PCO after cataract extraction surgery and underwent Nd:YAG laser capsulotomy between January 2021 and December 2022 were retrospectively reviewed (Nd:YAG laser group). The control group was selected from age- and sex-matched patients with age-related cataracts who also had cataract extraction surgery and did not develop PCO during the same time period.

The exclusion criteria for our study were as follows: 1) a history of any other ocular disease or ocular surgery; 2) intraoperative complications; and 3) cataract etiologies other than age-related cataracts. Additionally, since CBC-derived inflammatory biomarkers are influenced by various systemic conditions,15 patients with a history of diseases such as diabetes mellitus, hypertension, hyperlipidemia, malignancy, active or chronic inflammatory diseases, or allergic diseases were also excluded.

The demographic characteristics of the patients in our clinic’s registry, medical history, ocular comorbidities, preoperative ocular measurements, preoperative and postoperative CBC, enzyme-linked immunosorbent assay (ELISA), coagulation test results, surgical events, complications and postoperative results were accessed through a secure web-based RedCAP system by trained researchers.

Phacoemulsification surgery was performed under topical anesthesia by the same single surgeon using ultrasound technology (CENTURION® Vision System), and the same type of hydrophobic acrylic IOL (Acriva, 6 mm optical and 13 mm haptical size with a sharp edge and no haptic angulation) was implanted into the capsular bag. All patients received the same postoperative treatment: 0.5% moxifloxacin drops, 0.1% nepafenac drops, and 1% prednisolone acetate drops were applied every two hours for a week, then gradually reduced and stopped over three weeks. Only one eye per patient, with the indication for cataract surgery, was included in the study.

At each follow-up, measurements of best-corrected visual acuity (BCVA), anterior and posterior segment slit lamp examinations (SL-1800, Nidek Co., Ltd., Aichi, Japan), IOP measurements (NT-2000, Nidek Co., Ltd., Aichi, Japan) and examination of posterior capsule were performed. Clinically significant PCO was considered present when Elschnig pearls or fibrosis were detected in the central zone of the posterior capsule. The requirement of Nd:YAG laser capsulotomy (YC-1800, Nidek Co., Ltd., Aichi, Japan) was determined when the BCVA decreased by at least 20%, and the patient complained of blurred vision.

Blood samples were collected from all participants after 6–8 hours of fasting. Preoperative CBC testing is routinely conducted prior to cataract surgery, while postoperative CBC results were obtained from routine tests conducted during visits to primary care. Hematology analyzers were used to conduct a complete blood count, and the results were collected. Subsequently, the NLR, PLR, and MLR were calculated by dividing the neutrophil, platelet, and monocyte count by the lymphocyte count, respectively.

The minimum required sample size was determined using G*Power software, based on an effect size of 0.5 and a power of 0.9, resulting in a calculation that 70 patients per group were necessary to achieve statistical significance. Statistical analyses were conducted using SPSS version 23.0 for Windows (SPSS, Inc., Chicago, IL). The Shapiro–Wilk test was used to assess the normality of the data distribution. Descriptive statistics were reported as mean ± standard deviation (SD) for normally distributed variables. Categorical variables were analyzed using the chi-square test. An independent-samples t-test was performed to compare parameters between the groups, with a Welch t-test applied if the assumption of homogeneity of variances was violated. For non-normally distributed variables, a Mann–Whitney U-test was used to assess differences between the Nd:YAG laser capsulotomy group and the control group. Additionally, an analysis of covariance (ANCOVA) was conducted to evaluate the significance of changes in CBC parameters between preoperative and postoperative measurements, controlling for baseline scores. All analyses were performed with a 95% confidence interval, and a p-value of less than 0.05 was considered statistically significant.

A total of 124 patients who developed clinically significant PCO after cataract extraction surgery and underwent Nd:YAG laser capsulotomy between January 2021 and December 2022 were identified in our electronic medical record system. Fifty-four patients were subsequently excluded based on both the exclusion criteria and missing blood test data. Finally, a total of 70 patients were included in the Nd:YAG laser capsulotomy group. The control group consisted of 70 pseudophakic patients who did not develop any signs of PCO during the same period.

The mean age of patients and controls was 71.83±8.46 and 72.05±9.15 years, respectively. The mean interval for the Nd:YAG laser capsulotomy group (the period from the day of cataract surgery to the day of laser capsulotomy) and the control group (the period from the day of cataract surgery to the last visit within the study time frame) were 25.59±12.66 and 21.78±10.13 months, respectively. All demographic data of the subjects are listed in Table 1, and no significant differences were observed in terms of age, sex, or mean interval.

Table 1 Demographic Distribution of the Patients in Both Groups

An independent-samples t-test was run to determine if there were differences in parameters between the groups (Table 2). Data are mean ± SD, unless otherwise stated. There were no outliers in the data, as assessed by inspection of a boxplot. The data for each group level were normally distributed, as confirmed by the Shapiro–Wilk test (p˃0.05). However, the assumption of homogeneity of variances was not met for four variables, as assessed by Levene’s test for equality of variances. Consequently, a Welch t-test was used to evaluate differences in preoperative white blood cell counts and postoperative monocyte, neutrophil, and mean corpuscular volume scores due to the violation of homogeneity of variances (Table 2). No statistically significant differences were found between the groups for any of the parameters (Table 2).

Table 2 The Comparison of Pre- and Postoperative Complete Blood Count Parameters Between the Groups (Independent t Test)

A Mann–Whitney U-test was run to assess differences in non-normally distributed variables between the Nd:YAG laser capsulotomy group and the control group. Distributions of the variables for both groups were similar, as assessed by visual inspection. The preoperative NLR scores for the Nd:YAG laser capsulotomy group (mean rank = 34.43) were statistically significantly higher than those of the control group (mean rank = 25.41) (p = 0.044). However, no significant differences were found for the other parameters (Table 3). An ANCOVA was run to examine the effect of changes in CBC parameters between the groups after controlling for preoperative scores. After adjusting for preoperative measurements, no statistically significant differences were observed between the groups for any of the parameters (Table 4).

Table 3 The Comparison of Pre-and Postoperative Complete Blood Count Parameters Between the Groups (Mann–Whitney U-Test)

Table 4 The Comparison of Differences in Pre- and Postoperative Values of Complete Blood Count Parameters (ANCOVA)

In the current study, we assessed the relationship between CBC-derived inflammatory biomarkers and the development of PCO. Our findings indicated that preoperative NLR was significantly higher in the Nd:YAG laser capsulotomy group compared to the control group. However, ANCOVA analysis did not reveal any significant changes over time between the groups. This suggests that elevated systemic inflammation before phacoemulsification surgery may predict PCO development. To the best of our knowledge, this is the first study to investigate the relationship between CBC-derived inflammation indicators and PCO.

PCO is a pathophysiological outcome of cataract surgery with multiple etiological factors.16 Following cataract surgery, the remaining LECs in the capsular bag are primarily implicated in PCO development.1 LECs can spread into the anterior chamber and capsular bag during cataract surgery, proliferate, migrate and transdifferentiate into myofibroblastic cells, resulting in PCO by forming fibrotic plaques in the posterior capsule.17 The development of PCO has been associated with various cytokines, matrix metalloproteinases, and growth factors, with a primary focus on TGF-β. Inflammation is believed to modulate and accelerate LECs behaviour, given that inflammatory mediators can accumulate more readily in the eye after the breakdown of the blood-aqueous humor barrier.18

In recent years, as inflammatory reactions have been recognized as playing crucial roles in various diseases, inflammatory indices based on white blood cell counts have been extensively examined as a potential biomarkers or prognostic factors. The NLR is easily derived by dividing the neutrophil count by the lymphocyte count from CBC measurements. NLR reflects the balance between innate (nonspecific) and acquired (specific) immune responses. Given that neutrophils are primary mediators of the innate immune response, responsible for phagocytosis, and the release of various cytokines, and lymphocytopenia is indicative of stress during inflammation, NLR serves as an excellent composite indicator of inflammation and stress.15 Ocular disorders associated with the anterior segment of the eye, such as dry eye, glaucoma, cataracts, pterygium and keratoconus entail a complex pathophysiology linked to oxidative stress and inflammation-mediated tissue damage.19 Given that an increased NLR indicates an imbalance between myeloid and lymphocyte lineages, researchers have extensively examined its relevance in these conditions, investigating its potential as a risk factor, predictor of prognosis, or indicator of therapeutic response. Previous studies have consistently shown higher NLR values in patients with dry eye and pterygium compared to healthy subjects.20–22 Karaca et al observed a significant increase in the NLR in patients with progressive keratoconus compared to stable and control groups.23 Researchers have presented evidence supporting NLR as a potential biomarker for both diagnosing and predicting the prognosis of various glaucoma types.24,25 Moreover, NLR has been associated with an elevated incidence and the prediction of complications during cataract surgery.26,27 In our study, we found that the preoperative NLR scores for the Nd:YAG laser capsulotomy group (mean rank = 34.43) were statistically significantly higher than those in the control group (mean rank = 25.41) (p = 0.044). However, when comparing the differences between pre- and postoperative NLR scores, we did not observe a statistically significant change between the groups.

MLR and PLR, calculated by dividing the monocyte and platelet counts by the lymphocyte count, respectively, have emerged as novel inflammatory prognostic markers in various diseases.28 Researcher have extensively explored the roles of the MLR and PLR across a wide range of ocular diseases, including diabetic retinopathy, Graves’ orbitopathy, and keratoconus. These studies investigate their potential as risk factors and indicators of disease severity.29–31 In this study, we observed that both pre- and postoperative PLR values tended to be higher in the PCO group, with a p-value greater than 0.05. However, no significant difference was found in terms of MLR between the groups in our study.

This study has several limitations. We included a relatively small sample size of 70 patients in our study. Since CBC-based inflammatory markers can increase in a variety of diseases, we set broad exclusion criteria, which consequently limited the number of eligible patients. We did not evaluate other systemic inflammation markers such as C-reactive protein, beyond those derived from the CBC count. While it is possible that patients in the control group may develop PCO in subsequent years, the primary objective of this study was to investigate the potential relationship between PCO and blood-derived inflammatory parameters within the specified time period.

In conclusion, we observed that preoperative NLR scores were higher in patients who developed PCO. This finding suggests that elevated systemic inflammation may increase the risk of developing PCO following cataract surgery. Further research is needed to explore the role of systemic inflammation in the pathogenesis of PCO.

Institutional ethical committee approval (IRB No:49838221-050.01.04-54) was granted prior to the study, and researchers participating in the study were assured to follow the tenets of the Declaration of Helsinki.

The preliminary findings of this paper were uploaded to Authorea as a preprint and subsequently withdrawn from the system: https://sciety.org/articles/activity/10.22541/au.170664346.62086868/v1

The authors declare no conflicts of interest.

1. Awasthi N, Guo S, Wagner BJ. Posterior capsular opacification: a problem reduced but not yet eradicated. Archives of Ophthalmology. 2009;127(4):555–562. doi:10.1001/archophthalmol.2009.3

2. Karahan E, Er D, Kaynak S. An Overview of Nd:YAG Laser Capsulotomy. Med Hypothesis Discov Innov Ophthalmol. 2014;3(2):45–50.

3. Pandey S, Apple DJ, Werner L, et al. Posterior capsule opacification: a review of the aetiopathogenesis, experimental and clinical studies and factors for prevention. Indian J Ophthalmol. 2004;52(2):99–112.

4. Wu S, Tong N, Pan L, et al. Retrospective analyses of potential risk factors for posterior capsule opacification after cataract surgery. J Ophthalmol. 2018;2018(1):9089285. doi:10.1155/2018/9089285

5. Todorovic D, Vulovic TS, Petrovic N, Resan M, Sreckovic S The Influence of Inflammation in Posterior Capsule Opacification Development. Experimental and Applied Biomedical Research (EABR); 2022.

6. MEACOCK WR, SPALTON DJ, STANFORD MR. Role of cytokines in the pathogenesis of posterior capsule opacification. Br J Ophthalmol. 2000;84(3):332–336. doi:10.1136/bjo.84.3.332

7. Kubo E, Shibata T, Singh DP, et al. Roles of TGF β and FGF signals in the lens: tropomyosin regulation for posterior capsule opacity. Int J Mol Sci. 2018;19(10):3093. doi:10.3390/ijms19103093

8. Symonds JG, Lovicu FJ, Chamberlain CG. Differing effects of dexamethasone and diclofenac on posterior capsule opacification-like changes in a rat lens explant model. Exp. Eye Res. 2006;83(4):771–782. doi:10.1016/j.exer.2006.03.017

9. Allam G, Ellakkany R, Ellayeh A, et al. Outcome of pediatric cataract surgery with intraocular injection of triamcinolone acetonide: randomized controlled trial. Eur J Ophthalmol. 2018;28(6):633–638. doi:10.1177/1120672117754168

10. Fest J, Ruiter R, Ikram MA, et al. Reference values for white blood-cell-based inflammatory markers in the Rotterdam study: a population-based prospective cohort study. Sci Rep. 2018;8(1):10566. doi:10.1038/s41598-018-28646-w

11. Kurtul BE, Ozer PA. Neutrophil-to-lymphocyte ratio in ocular diseases: a systematic review. Int J Ophthalmol. 2019;12(12):1951–1958. doi:10.18240/ijo.2019.12.18

12. Shirvani M, Soufi F, Nouralishahi A, et al. The diagnostic value of neutrophil to lymphocyte ratio as an effective biomarker for eye disorders: a meta-analysis. Biomed Res Int. 2022;2022:5744008. doi:10.1155/2022/5744008

13. Konopińska J, Młynarczyk M, Dmuchowska DA, et al. Posterior capsule opacification: a review of experimental studies. J Clin Med. 2021;10(13):2847. doi:10.3390/jcm10132847

14. Ozates S, Berker N, Cakar Ozdal P, et al. Phacoemulsification in patients with uveitis: long-term outcomes. BMC Ophthalmol. 2020;20(1):109. doi:10.1186/s12886-020-01373-5

15. Zahorec R. Neutrophil-to-lymphocyte ratio, past, present and future perspectives. Bratisl Lek Listy. 2021;122(7):474–488. doi:10.4149/BLL_2021_078

16. Wormstone IM, Wormstone YM, Smith AJO, et al. Posterior capsule opacification: what’s in the bag? Prog Retin Eye Res. 2021;82:100905. doi:10.1016/j.preteyeres.2020.100905

17. Raj SM, Raj SM, Kaid JSR, et al. Post-operative capsular opacification: a review. Int J Biomed Sci. 2007;3(4):237–250. doi:10.59566/IJBS.2007.3237

18. Kitaguchi-Iwakiri Y, Kamoi K, Takase H, et al. Long-term incidence of posterior capsular opacification in patients with non-infectious uveitis. Sci Rep. 2022;12(1):4296. doi:10.1038/s41598-022-08325-7

19. Dammak A, Pastrana C, Martin-Gil A, et al. Oxidative stress in the anterior ocular diseases: diagnostic and treatment. Biomedicines. 2023;11(2):292. doi:10.3390/biomedicines11020292

20. Celik T. Assessment of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in patients with dry eye disease. Ocul Immunol Inflamm. 2018;26(8):1219–1222. doi:10.1080/09273948.2017.1340486

21. Sekeryapan B, Uzun F, Buyuktarakci S, et al. Neutrophil-to-lymphocyte ratio increases in patients with dry eye. Cornea. 2016;35(7):983–986. doi:10.1097/ICO.0000000000000872

22. Gokmen O, Gokmen A. Evaluation of neutrophil-lymphocyte ratios, mean platelet volumes, and platelet-lymphocyte ratios in pterygium. Beyoglu Eye J. 2019;4(3):163–167. doi:10.14744/bej.2019.30164

23. Karaca EE, Özmen MC, Ekici F, et al. Neutrophil-to-lymphocyte ratio may predict progression in patients with keratoconus. Cornea. 2014;33(11):1168–1173. doi:10.1097/ICO.0000000000000260

24. Ozgonul C, Sertoglu E, Mumcuoglu T, et al. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as novel biomarkers of primary open-angle glaucoma. J Glaucoma. 2016;25(10):e815–e820. doi:10.1097/IJG.0000000000000392

25. Kurtul BE, Ozer PA, Kabatas EU. Elevated neutrophil-to-lymphocyte ratio in pseudoexfoliation syndrome. Eye. 2016;30(8):1045–1048. doi:10.1038/eye.2016.89

26. Gökce SE, Başkan C. Neutrophil lymphocyte ratio as a predictor of perioperative complications in patients with PEX syndrome during cataract surgery. Int Ophthalmol. 2022;42(4):1311–1316. doi:10.1007/s10792-021-02118-z

27. Kaliaperumal R, Venkatachalam R, Nagarajan P, Rangarajalu K, Sivanandham M, Sabapathy SK Study of neutrophil-to-lymphocyte ratio and its correlation with glycemic status in diabetic senile cataract patients. Ann Roman Soc Cell Biol. 2021;6633–6656.

28. Moosazadeh M, Maleki I, Alizadeh-Navaei R, et al. Normal values of neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio and platelet-to-lymphocyte ratio among Iranian population: results of Tabari cohort. Caspian J Intern Med. 2019;10(3):320–325. doi:10.22088/cjim.10.3.320

29. Yue S, Zhang J, Wu J, et al. Use of the monocyte-to-lymphocyte ratio to predict diabetic retinopathy. Int J Environ Res Public Health. 2015;12(8):10009–10019. doi:10.3390/ijerph120810009

30. Szydełko J, Litwińczuk M, Szydełko M, et al. Neutrophil-to-lymphocyte, monocyte-to-lymphocyte and platelet-to-lymphocyte ratios in relation to clinical parameters and smoking status in patients with graves’ orbitopathy—novel insight into old tests. J Clin Med. 2020;9(10):3111. doi:10.3390/jcm9103111

31. Elbeyli A, Kurtul BE. Systemic immune-inflammation index, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio levels are associated with keratoconus. Indian J Ophthalmol. 2021;69(7):1725–1729. doi:10.4103/ijo.IJO_3011_20