Skip to main content
NCBI home page
PLOS One logoLink to PLOS One
. 2021 Mar 23;16(3):e0249073. doi: 10.1371/journal.pone.0249073

Correlation between choroidal structure and smoking in eyes with central serous chorioretinopathy

Kazuyoshi Okawa 1, Tatsuya Inoue 1,*, Ryo Asaoka 2,3,4, Keiko Azuma 2, Ryo Obata 2, Rei Arasaki 1, Shouko Ikeda 1, Arisa Ito 1, Maiko Maruyama-Inoue 1, Yasuo Yanagi 1, Kazuaki Kadonosono 1
Editor: Demetrios G Vavvas5
PMCID: PMC7987178  PMID: 33755707

Abstract

Purpose

A smoking habit can cause various health problems encompassing retinal diseases including central serous chorioretinopathy (CSC). The aim of the current study was to investigate the effect of smoking on the choroidal structure in patients with CSC.

Methods

The choroidal vascular index (CVI) was calculated using the binarized OCT images. Baseline parameters (age, refractive error [SE], subfoveal choroidal thickness [SFCT] and CVI) were compared between smokers and non-smokers using Wilcoxon rank sum test. Moreover, the associations between SFCT and the baseline parameters were analyzed using a multivariate linear regression followed by the AICc model selection.

Results

Among 75 CSC patients, 45 patients were smokers and 30 patients were non-smokers. No significant differences in age and SE were seen between the smoking group and the non-smoking group. A significant difference in the SFCT was seen between two groups (382.0 ± 68.2 μm in the smoking group vs. 339.3 ± 52.3 μm in the non-smoking group, p = 0.0038), while no significant difference was observed in the CVI (p = 0.32). The optimal model for SFCT included the variables of age, SE and past history of smoking among the baseline parameters. Additionally, increased pack years was associated with increased SFCT.

Conclusion

Cigarette smoking was associated with an increased SFCT in patients with CSC. Thicker choroid in smoking CSC patients may be an important modulator of the disease.

Introduction

Central serous chorioretinopathy (CSC) is characterized by serous retinal detachment accompanied by the dysfunction of the retinal pigment epithelium (RPE). Recent studies have clarified the change in the choroid. First, CSC is generally characterized by choroidal vascular hyperpermeability (CVH) on indocyanine green angiography [1–3]. Additionally, enhanced depth imaging (EDI-OCT) [4], which allows for the visualization of the choroidal structure, clarified the ratio of the luminal area to the total choroidal area, known as the choroidal vascular index (CVI) to be increased in CSC. As such, functional and anatomical abnormalities of the choroid (so-called “pachychoroid”) are considered to be associated with CSC [5,6]. Specifically, increased osmotic pressure, presumably due to an increased area of the choroidal vessels, is thought to be associated with choroidal hyperpermeability, causing RPE detachment, leading to the accumulation of fluid in the subretinal space. Interestingly, eyes with acute CSC had a higher CVI than eyes without CSC or eyes with resolved CSC [7], suggesting that CVI is dynamically associated with CSC, which may change during the course of disease depending on the activity.

A smoking habit is a modifiable risk factor that is associated with retinal diseases including CSC [8–11]. Interestingly, recent detailed examinations of choroidal structural changes in healthy smokers has suggested that the CVI was significantly smaller in smokers than in non-smokers whereas the foveal retinal thickness (FRT) and the subfoveal choroidal thickness (SFCT) were unchanged [12]. Although the pathological significance of such differences in healthy subjects remains unclear, it raises a possibility that there may be some differences in the choroidal pathologies of CSC patients between smokers and non-smokers. Interestingly, smoking was reportedly associated with poor visual outcome in CSC patients [13]. Since the choroidal flow, as well as choroidal thickness, seems to have abnormal regulation in CSC patients, a smoking habit in CSC patients may be related with not only CVI, but also choroidal thickness. The hypothesis prompted us to investigate the effect of a smoking habit on the choroidal structure, including the choroidal thickness and CVI, in patients with CSC.

Methods

The present study was a cross-sectional study conducted at a single center. The medical records of patients with CSC were retrospectively reviewed. This study was approved by the Ethics Committee of the Yokohama City University Medical Center. The study protocol adhered to the tenets of the Declaration of Helsinki and written informed consent was obtained from all eligible patients.

All the patients underwent a comprehensive ophthalmic examination including visual acuity, refractive error measurement, and OCT measurement, and the diagnosis of CSC was made based on OCT, fluorescein angiography, and indocyanine green angiography (ICGA) findings. In the current study, 4 patients did not undergo ICGA due to the allergy. For the remaining 71 eyes, we investigated the incidence of CVH. Spectral domain OCT (Spectralis, Heidelberg Engineering) was used to measure the FRT, and the SFCT was estimated using an EDI technique. EDI-OCT examinations were performed between 9:00 and 11:00 a.m. because choroidal thickness is known to exhibit diurnal fluctuations [14]. The exclusion criteria were as follows: (1) the absence of a detailed medical history; (2) a history of previous ocular surgery (other than uncomplicated cataract surgery) or other retinal disorders; (3) the presence of high myopia (−6.0 diopter or greater), and (4) the presence of choroidal neovascularization or polypoidal choroidal vasculopathy, and (5) a history of steroid use.

Binarization of the OCT images was performed to calculate the total choroidal area (TCA), stromal area (SA), luminal area (LA), and CVI, as previously reported [15]. Briefly, the choroidal area of the horizontal EDI-OCT images across the fovea was binarized using the Niblack method with ImageJ software (Fig 1). The images were converted to 8 bits, and the Niblack auto-local threshold was applied to binarize the images to separate the choroidal luminal and stromal areas. Then, CVI was calculated as luminal pixels/total choroidal pixels in total choroidal area with a width of 6,000μm.

Fig 1. Binarization of an OCT image in a patient with CSC.

Fig 1

Open in a new tab

(A) Representative image of the horizontal EDI-OCT scan in CSC eye with serous retinal detachment. (B) Binarized OCT image using Niblack method. Yellow line indicates the border of the choroid. Subsequently, the CVI was calculated as luminal (black) pixels/total choroidal pixels in each eye. CSC, central serous chorioretinopathy; CVI, choroidal vascular index.

Statistical analyses

To investigate the relationship between smoking and CSC types (classic or chronic), the chi-squared test was conducted. Baseline parameters (age, refractive error, logMAR visual acuity, FRT, SFCT and CVI) were compared between smokers and non-smokers using the exact Wilcoxon rank sum test. In addition, the associations between SFCT and CVI and the baseline parameters (age, refractive error, and history of smoking) were analyzed using a multivariate linear regression. Subsequently, model selection was performed to identify the optimal linear regression model using the second-order bias-corrected Akaike’s information criterion (AICc) index from all 24 patterns consisting of four variables (age, refractive error, history of smoking/hypertension). The AIC is a well-known statistical measurement used in model selection, and the AICc is a corrected version of the AIC that provides an accurate estimation even when the sample size is small [16,17]. The variables selected using this model were regarded as being statistically significant. All statistical analyses were performed using the statistical programming language R (ver. 3.4.3, The R Foundation for Statistical Computing, Vienna, Austria).

Results

Table 1 shows the baseline characteristics of the patients in the present study. Among 75 eyes in 75 CSC patients (58 males and 17 females) with serous retinal detachment (SRD), 19 patients were classic CSC and 56 were chronic CSC. 45 patients were smokers and 30 patients were non-smokers. In the smoking group, 10 eyes were classic CSC and 35 eyes were chronic CSC. On the other hand, 9 eyes were classic and 21 eyes were chronic CSC in non-smoking group. There was no significant relationship between smoking and CSC type (p = 0.63, chi-squared test). Thirty-one patients were current smokers, and the remaining 14 patients were non-current smokers. The mean patient age was 47.1 ± 6.0 years (mean ± standard deviation). No significant difference in age was seen between the smoking group (47.2 ± 6.3 years) and the non-smoking group (46.8 ± 5.5 years, p = 0.74, Wilcoxon rank sum test). The Brinkman index (BI, number of cigarettes smoked per day multiplied by the number of years of smoking) was 221.9 ± 238.6 in the smokers group. The mean spherical equivalent of the refractive error also showed no significant difference between the smoking and non-smoking groups (-1.31 ± 1.80 diopter vs. -2.06 ± 1.84 diopter, p = 0.10). A significant difference in the SFCT was seen between the smoker and non-smoker groups (382.0 ± 68.2 μm vs. 339.3 ± 52.3 μm, p = 0.0038, Wilcoxon rank sum test, Fig 2A), while no significant difference was observed in the CVI (64.6 ± 2.1% vs. 65.3 ± 2.3%, p = 0.32, Fig 2B). Forty-one of 45 smoking patients (91.1%) had CVH and 23 of 26 non-smoking patients (88.5%) had CVH. The prevalence of CVH was numerically higher in smoking group than that in non-smoking group, however, the difference was not statistically significant (p = 0.95, chi-squared test).

Table 1. Baseline characteristics of patients.

Parameter Smoking group Non-smoking group P value
Number of patients, eyes 45, 45 30, 30 -
Age (years) 47.2 ± 6.3 46.8 ± 5.5 0.74
BI 221.9 ± 238.6 - -
Refraction (diopter) -1.31 ± 1.80 -2.06 ± 1.84 0.10
LogMAR VA 0.057 ± 0.24 -0.000089 ± 0.21 0.11
SFCT (μm) 382.0 ± 68.2 339.3 ± 52.3 0.0038
CVI (%) 64.6 ± 2.1 65.3 ± 2.3 0.32
FRT (μm) 367.8 ± 106.5 360.3 ± 130.1 0.69
Open in a new tab

BI: Brinkman index, logMAR VA: Logarithm of the minimum angle of resolution of visual acuity, SFCT: Subfoveal choroidal thickness, FRT: Foveal retinal thickness, CVI: Choroidal vascular index.

Fig 2. Comparison of SFCT and CVI between smokers and non-smokers in patients with CSC.

Fig 2

Open in a new tab

A significant difference in SFCT was seen between smokers and non-smokers (A, p = 0.0038, Wilcoxon rank sum test), but no significant difference in CVI was seen (B, p = 0.32, Wilcoxon rank sum test). SFCT, subfoveal choroidal thickness; CVI, choroidal vascular index; CSC, central serous chorioretinopathy.

We then investigated factors associated with SFCT. As a result of AICc model selection, the optimal model for SFCT included the variables of age, refractive error expressed by the spherical equivalent (SE), and history of smoking among the variables of age, SE, and history of smoking or hypertension (Table 2). The optimal model formula was as follows:

Table 2. Relationship between smoking and SFCT.

Univariate analysis The optimal model
Variables Coefficient Stderr P value Coefficient Stderr P value
Age -3.39 1.22 0.0070 -3.40 1.12 0.0034
SE 10.64 3.97 0.0091 8.27 3.71 0.029
History of smoking 42.7 14.7 0.0049 37.7 13.9 0.0082
History of hypertension 8.43 22.36 0.71 N.S. N.S. N.S.
Open in a new tab

SFCT: Subfoveal choroidal thickness, Stderr: Standard error, SE: Spherical equivalent, N.S.: Not selected.

SFCT = 515.7–3.40 x Age (standard error [Stderr] = 1.12) + 8.27 x SE (Stderr = 3.71) + 37.7 x Smoking (Stderr = 13.9) (AICc = 827.6).

In the aforementioned analysis, a history of smoking, but not BI, was included in the variable due to colinearity between these two factors. When this analysis was performed using the BI instead of a history of smoking (Table 3), BI was selected as a predictive variable, and the formula for the optimal model for SFCT was as follows:

Table 3. Relationship between BI and SFCT.

Univariate analysis The optimal model
Variables Coefficient Stderr P value Coefficient Stderr P value
Age -3.39 1.22 0.0070 -4.47 1.19 0.00034
SE 10.64 3.97 0.0091 7.79 3.72 0.040
BI 0.063 0.031 0.046 0.088 0.030 0.0052
History of hypertension 8.43 22.36 0.71 N.S. N.S. N.S.
Open in a new tab

BI: Brinkman index, SFCT: Subfoveal choroidal thickness, Stderr: Standard error, SE: Spherical equivalent, N.S.: Not selected.

SFCT = 568.5–4.47 x Age (Stderr = 1.19) + 7.79 x SE (Stderr = 3.72) + 0.088 x BI (Stderr = 0.030) (AICc = 826.7).

On the other hand, the optimal model for CVI included SE and history of smoking among the baseline parameters. The formula for the optimal model was as follows:

CVI = 65.9 + 0.29 x SE (Stderr = 0.14)– 0.90 x Smoking (Stderr = 0.51) (AICc = 331.7)

However, unlike the results for SFCT, when the BI was used instead of a history of smoking, BI was not selected as an explanatory variable for CVI.

Moreover, we investigated the relationship between current smoking and the choroidal structure. No significant differences in SFCT and CVI were seen between current smokers and non-current smokers (p = 0.56 [Fig 3] and 0.98, respectively, Wilcoxon rank sum test). Furthermore, current smoking was not selected for the SFCT and the CVI using AICc model selection.

Fig 3. Comparison of SFCT between current and non-current smokers in patients with CSC.

Fig 3

Open in a new tab

No significant difference in SFCT was seen between current and non-current smokers (p = 0.56, Wilcoxon rank sum test). SFCT, subfoveal choroidal thickness; CSC, central serous chorioretinopathy.

Discussion

In the present study, the relationship between the choroidal structure and cigarette smoking was investigated in patients with CSC. As a result, a history of smoking was significantly correlated with an increased SFCT in CSC eyes with subretinal fluid (SRF). Importantly, the effect of smoking on the SFCT was dose (pack years)—dependent as shown in the prediction model, suggesting the association was not a mere chance finding. On the other hand, the presence of a history of smoking was associated with a decreased CVI.

The subfoveal choroid is significantly thicker in eyes with CSC [18,19], and the resolution of CSC is reportedly correlated with a reduction in the SFCT [20,21]. Moreover, a previous report suggested that the CVI was higher in acute CSC eyes, compared with contralateral non-CSC eyes [7]. Our present results demonstrated that the presence of a history of smoking was correlated with an increased SFCT and a decreased CVI, suggesting that the pathology of CSC may be somewhat different between smokers and non-smokers. Although there is no direct link between visual acuity and the choroidal thickness, corroborating evidence from prior observations [18–21] suggest that choroidal thickness may be associated with disease activity; further longitudinal study would be of interest to examine the effect of smoking on visual outcome in CSC patients. Previous studies have investigated the effect of smoking on the CVI, with varying results in normal subjects. Agrawal et al. reported that a univariate analysis demonstrated a significant correlation between cigarette smoking and the CVI, while a multivariate analysis showed no significant correlation [22]. On the contrary, Wei et al. suggested that smoking was associated with a smaller CVI in normal eyes [12]. Regarding CVI in CSC patients, a previous study reported that the CVI was increased in patients with acute CSC, compared with contralateral non-CSC eyes, suggesting the possibility that the CVI was influenced by the activity of CSC and vice versa [7]. In contrast, our present results for eyes with CSC suggested that the CVI was negatively associated with a smoking history. Recently, CSC has been considered as one of the pachychoroid spectrum diseases with focal or diffuse increase in choroidal thickness, dilated large choroidal vessels, and CVH. In pachychoroid spectrum diseases including CSC and polypoidal choroidal vasculopathy, CVH are associated with an increased SFCT and an increased CVI [23–25]. In the current study, the prevalence of CVH was compared between the smoking and non-smoking groups in eyes with CSC. As a result, the prevalence of CVH was higher in smoking group than in non-smoking group, however this difference was not significant. This may be because the frequency of CVH is high in eyes with CSC in general, which masked the difference between the smoking and non-smoking groups. It should be noted that the reason why a smoking habit causes the decreased CVI still remains unclear, and further studies are needed shedding light on this issue.

The present study had some limitations. First, this study was retrospective in nature, and the number of subjects was relatively small. Second, the choroidal structure in eyes with CSC is associated with the disease duration [26], however, this information was not available in the current study. Smoking cessation is usually recommended to CSC patients in clinical settings, however its effectiveness remains elusive. It would be interesting to examine the choroidal structural changes in eyes with CSC that are caused by smoking cessation.

In conclusion, cigarette smoking was associated with an increased subfoveal choroidal thickness in CSC patients. Smoking might be an important factor to modulate CSC by influencing the choroidal thickness.

Supporting information

S1 File

(CSV)

Click here for additional data file. (5KB, csv)

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

References

  • 1.Guyer DR, Yannuzzi LA, Slakter JS, Sorenson JA, Ho A, Orlock D. Digital indocyanine green videoangiography of central serous chorioretinopathy. Arch Ophthalmol. 1994;112(8):1057–1062. 10.1001/archopht.1994.01090200063023 [DOI] [PubMed] [Google Scholar]
  • 2.Piccolino FC, Borgia L. Central serous chorioretinopathy and indocyanine green angiography. Retina. 1994;14(3):231–242. 10.1097/00006982-199414030-00008 [DOI] [PubMed] [Google Scholar]
  • 3.Iida T, Kishi S, Hagimura N, Shimizu K. Persistent and bilateral choroidal vascular abnormalities in central serous chorioretinopathy. Retina. 1999;19(6):508–512. 10.1097/00006982-199911000-00005 [DOI] [PubMed] [Google Scholar]
  • 4.Spaide RF, Koizumi H, Pozzoni MC, Pozonni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol. 2008;146(4):496–500. 10.1016/j.ajo.2008.05.032 [DOI] [PubMed] [Google Scholar]
  • 5.Liegl R, Ulbig MW. Central serous chorioretinopathy. Ophthalmologica. 2014;232(2):65–76. 10.1159/000360014 [DOI] [PubMed] [Google Scholar]
  • 6.Ferrara D, Waheed NK, Duker JS. Investigating the choriocapillaris and choroidal vasculature with new optical coherence tomography technologies. Prog Retin Eye Res. 2016;52:130–155. 10.1016/j.preteyeres.2015.10.002 [DOI] [PubMed] [Google Scholar]
  • 7.Agrawal R, Chhablani J, Tan K-A, Shah S, Sarvaiya C, Banker A. CHOROIDAL VASCULARITY INDEX IN CENTRAL SEROUS CHORIORETINOPATHY. Retina. 2016;36(9):1646–1651. 10.1097/IAE.0000000000001040 [DOI] [PubMed] [Google Scholar]
  • 8.Burns DM. Cigarettes and cigarette smoking. Clin Chest Med. 1991;12(4):631–642. [PubMed] [Google Scholar]
  • 9.Ersoz MG, Arf S, Hocaoglu M, Sayman Muslubas I, Karacorlu M. Patient characteristics and risk factors for central serous chorioretinopathy: an analysis of 811 patients. Br J Ophthalmol. 2019;103(6):725–729. 10.1136/bjophthalmol-2018-312431 [DOI] [PubMed] [Google Scholar]
  • 10.Chakravarthy U, Wong TY, Fletcher A, et al. Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis. BMC Ophthalmol. 2010;10:31. 10.1186/1471-2415-10-31 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Seddon JM, George S, Rosner B. Cigarette smoking, fish consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: the US Twin Study of Age-Related Macular Degeneration. Arch Ophthalmol. 2006;124(7):995–1001. 10.1001/archopht.124.7.995 [DOI] [PubMed] [Google Scholar]
  • 12.Wei X, Kumar S, Ding J, Khandelwal N, Agarwal M, Agrawal R. Choroidal Structural Changes in Smokers Measured Using Choroidal Vascularity Index. Invest Ophthalmol Vis Sci. 2019;60(5):1316–1320. 10.1167/iovs.18-25764 [DOI] [PubMed] [Google Scholar]
  • 13.Türkcü FM, Yüksel H, Sahin A, et al. Effects of smoking on visual acuity of central serous chorioretinopathy patients. Cutan Ocul Toxicol. 2014;33:115–119. 10.3109/15569527.2013.810633 [DOI] [PubMed] [Google Scholar]
  • 14.Tan CS, Ouyang Y, Ruiz H, Sadda SR. Diurnal variation of choroidal thickness in normal, healthy subjects measured by spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2012;53(1):261–266. 10.1167/iovs.11-8782 [DOI] [PubMed] [Google Scholar]
  • 15.Azuma K, Tan X, Asano S, et al. The association of choroidal structure and its response to anti-VEGF treatment with the short-time outcome in pachychoroid neovasculopathy. PLoS One. 2019;14(2). 10.1371/journal.pone.0212055 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Nakagawa S, Schielzeth H. A general and simple method for obtaining R2 from generalized linear mixed-effects models. Methods in Ecology and Evolution. 2013;4(2):133–142. 10.1111/j.2041-210x.2012.00261.x. [DOI] [Google Scholar]
  • 17.Burnham KP, Anderson DR. Multimodel Inference: Understanding AIC and BIC in Model Selection. Sociological Methods & Research. 2004;33(2):261–304. 10.1177/0049124104268644 [DOI] [Google Scholar]
  • 18.Kim YT, Kang SW, Bai KH. Choroidal thickness in both eyes of patients with unilaterally active central serous chorioretinopathy. Eye (Lond). 2011;25(12):1635–1640. 10.1038/eye.2011.258 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Maruko I, Iida T, Sugano Y, Ojima A, Sekiryu T. Subfoveal choroidal thickness in fellow eyes of patients with central serous chorioretinopathy. Retina. 2011;31(8):1603–1608. 10.1097/IAE.0b013e31820f4b39 [DOI] [PubMed] [Google Scholar]
  • 20.Kim YK, Ryoo NK, Woo SJ, Park KH. Choroidal Thickness Changes After Photodynamic Therapy and Recurrence of Chronic Central Serous Chorioretinopathy. Am J Ophthalmol. 2015;160(1):72–84.e1. 10.1016/j.ajo.2015.04.011 [DOI] [PubMed] [Google Scholar]
  • 21.Kang NH, Kim YT. Change in subfoveal choroidal thickness in central serous chorioretinopathy following spontaneous resolution and low-fluence photodynamic therapy. Eye (Lond). 2013;27(3):387–391. 10.1038/eye.2012.273 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Agrawal R, Gupta P, Tan KA, Cheung CMG, Wong TY, Cheng CY. Choroidal vascularity index as a measure of vascular status of the choroid: Measurements in healthy eyes from a population-based study. Sci Rep. 2016;6:21090. 10.1038/srep21090 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Agrawal R, Chhablani J, Tan KA, et al. CHOROIDAL VASCULARITY INDEX IN CENTRAL SEROUS CHORIORETINOPATHY. Retina. 2016;36(9):1646–51. 10.1097/IAE.0000000000001040 [DOI] [PubMed] [Google Scholar]
  • 24.Jirarattanasopa P, Ooto S, Tsujikawa A, et al. Assessment of macular choroidal thickness by optical coherence tomography and angiographic changes in central serous chorioretinopathy. Ophthalmology. 2012;119(8):1666–78. 10.1016/j.ophtha.2012.02.021 [DOI] [PubMed] [Google Scholar]
  • 25.Liu B, Zhang X, Mi L, Peng Y, Wen F. Choroidal structure in subtypes of polypoidal choroidal vasculopathy determined by binarization of optical coherence tomographic images. Clin Exp Ophthalmol. 2019;47(5):631–637. 10.1111/ceo.13467 [DOI] [PubMed] [Google Scholar]
  • 26.Hanumunthadu D, van Dijk EHC, Dumpala S, et al. Evaluation of Choroidal Layer Thickness in Central Serous Chorioretinopathy. J Ophthalmic Vis Res. 2019;14(2):164–170. 10.4103/jovr.jovr_152_17 [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Demetrios G Vavvas

22 Jan 2021

PONE-D-20-39783

Correlation between choroidal structure and smoking in eyes with central serous chorioretinopathy

PLOS ONE

Dear Dr. Inoue,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

this is an important study that both reviewers found worthwhile but made several comments to improve it 

We  look forward to the revised version

Please submit your revised manuscript by Mar 05 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Demetrios G. Vavvas

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.

3. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ

4. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Many thanks for the opportunity to review this interesting manuscript entitled “Correlation between choroidal structure and smoking in eyes with central serous chorioretinopathy”. This study investigated the effect of smoking on the choroidal structure in patients with CSC. The authors concluded that cigarette smoking was associated with an increased choroidal thickness in patients with CSC. Although this manuscript is interesting, I take this opportunity to comment on some issues.

1. Line 162: Although this study included 75 eyes with CSC, the authors did not describe the detail of the subjects. How many eyes with classic CSC or chronic CSC were included in smoking and non-smoking groups? How many patients had used steroid? Those characteristics reportedly affect the choroidal thickness and choroidal vascular index in eyes with CSC, major results in this study.

2. Line 165: “Thirty-one patients were current smokers, and the remaining 44 patients were non-current smokers.” Should be “Thirty-one patients were current smokers, and the remaining 14 patients were non-current smokers.”

3. Line 124: The exclusion criteria included the presence of high myopia (−6.0 diopter or greater). Were the eyes analyzed in this study all phakic? If pseudo-phakic eyes were included, how were the eyes with high myopia excluded? Did the authors measure the axial length?

4. Line 126: “the presence of choroidal neovascularization and polypoidal choroidal vasculopathy.” should be “the presence of choroidal neovascularization or polypoidal choroidal vasculopathy.”

5. Line 130: The authors should clarify the range of horizontal EDI-OCT image analyzed to calculate the choroidal vascular index.

6. Line 222: The authors stated “the presence of a history of smoking was associated with a decreased CVI”. However, the formula for the optimal model was CVI=65.9+0.29 x SE (Stderr=0.14, p=0.039) –0.90 x Smoking (Stderr=0.51, p=0.083). This formula means the history of smoking was not a significant factor for CVI.

7. Line 233: There are no evidences supporting the following statement: our findings may in part explain why the smoking was reportedly associated with poor visual outcome in CSC patients.

8. Line 244: The authors speculated that choroidal vascular hyperpermeability (CVH) might result in the lower CVI in patients with smoking history. In this study, all patients underwent indocyanine green angiography (ICGA). Therefore, the incidence of CVH in ICGA should be assessed. If the hypothesis is correct, the incidence of CVH should be significantly higher in smoking group compared to non-smoking group. In my opinion, if the fluid is accumulated in the choroid secondary to CVH, CVI might increase. Furthermore, previous studies investigating CSC eyes reported that the eyes with CVH showed significantly greater choroidal thickness compared to the eyes without CVH.

Reviewer #2: Dear Authors,

I have read your manuscript entitled “Correlation between choroidal structure and smoking in eyes with central serous chorioretinopathy”. The manuscript is written in a concise and clear manner and the conclusions are well supported by the presented data. Besides a couple of comments below, I have no major concerns and feel this manuscript fulfills the criteria for publication in PLOS ONE.

The only minor comment

Page 10 table 1 legend - please include the BI definition

Page 10 lines 165-166 - while previously stated 45 subjects were smokers and 30 - non-smoker, it is unclear what the following means: “31 patients were current smokers and 44 were non-current..”; the sum gives us 75 patients, does it mean there all smokers in the past, are these the same patients or different

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Mar 23;16(3):e0249073. doi: 10.1371/journal.pone.0249073.r002

Author response to Decision Letter 0

29 Jan 2021

Dear Prof. Vavvas

We appreciate you and the reviewers for the constructive and insightful comments. Please find our enclosed point-by-point responses (in red) to the reviewers’ comments. We hope that this revision will meet your expectations, and that our revised manuscript will better suit for publication on PLOS ONE.

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

this is an important study that both reviewers found worthwhile but made several comments to improve it. We look forward to the revised version

Thank you very for your insightful comments. Please see our responses below.

Reviewer #1: Many thanks for the opportunity to review this interesting manuscript entitled “Correlation between choroidal structure and smoking in eyes with central serous chorioretinopathy”. This study investigated the effect of smoking on the choroidal structure in patients with CSC. The authors concluded that cigarette smoking was associated with an increased choroidal thickness in patients with CSC. Although this manuscript is interesting, I take this opportunity to comment on some issues.

Thank you very for your constructive and insightful comments. Please see our responses to each comment.

1. Line 162: Although this study included 75 eyes with CSC, the authors did not describe the detail of the subjects. How many eyes with classic CSC or chronic CSC were included in smoking and non-smoking groups? How many patients had used steroid? Those characteristics reportedly affect the choroidal thickness and choroidal vascular index in eyes with CSC, major results in this study.

Thank you for very much your insightful comment. 19 classic CSC and 56 chronic CSC were enrolled in the current study. And patients who had used steroid were excluded from the current study. We have changed our manuscript as follows:

“Among 75 eyes in 75 CSC patients (58 males and 17 females) with serous retinal detachment (SRD), 19 patients were classic CSC and 56 were chronic CSC.”

“The exclusion criteria were as follows: (1) the absence of a detailed medical history; (2) a history of previous ocular surgery (other than uncomplicated cataract surgery) or other retinal disorders; (3) the presence of high myopia (−6.0 diopter or greater), and (4) the presence of choroidal neovascularization or polypoidal choroidal vasculopathy, and (5) a history of steroid use.”

2. Line 165: “Thirty-one patients were current smokers, and the remaining 44 patients were non-current smokers.” Should be “Thirty-one patients were current smokers, and the remaining 14 patients were non-current smokers.”

Thank you for your suggestion. We have revised our manuscript.

3. Line 124: The exclusion criteria included the presence of high myopia (−6.0 diopter or greater). Were the eyes analyzed in this study all phakic? If pseudo-phakic eyes were included, how were the eyes with high myopia excluded? Did the authors measure the axial length?

Thank you for the critical comment. The current study included 74 phakic eyes and only 1 pseudophakic eye. About the pseudophakic eyes, we measured axial length and denied the possibility that they were high myopic eyes.

4. Line 126: “the presence of choroidal neovascularization and polypoidal choroidal vasculopathy.” should be “the presence of choroidal neovascularization or polypoidal choroidal vasculopathy.”

We have changed the manuscript according to your comment. Thank you very much.

5. Line 130: The authors should clarify the range of horizontal EDI-OCT image analyzed to calculate the choroidal vascular index.

Thank you for the comment. The range of analyzed region was 6000μm wide. We have edited the manuscript in the Methods section according to the suggestion.

“Then, CVI was calculated as luminal pixels/total choroidal pixels in total choroidal area with a width of 6,000μm.”

6. Line 222: The authors stated “the presence of a history of smoking was associated with a decreased CVI”. However, the formula for the optimal model was CVI=65.9+0.29 x SE (Stderr=0.14, p=0.039) –0.90 x Smoking (Stderr=0.51, p=0.083). This formula means the history of smoking was not a significant factor for CVI.

Thank you for your insightful suggestion. We apologize for the confusion. The optimal model was calculated by AICc model selection as mentioned in Methods section. Thus, we did not use p value in the estimation of the effect of variables, regardless of the 'by-product' of p values in the current analysis (Hasley, L. G. (2019). The reign of the p-value is over: what alternative analyses could we employ to fill the power vacuum? Biology Letters, 15. doi 10.1098/rsbl.2019.0174). To avoid confusion, we removed the p value descriptions.

“ CVI=65.9+0.29 x SE (Stderr=0.14) –0.90 x Smoking (Stderr=0.51) ”

7. Line 233: There are no evidences supporting the following statement: our findings may in part explain why the smoking was reportedly associated with poor visual outcome in CSC patients.

We appreciate the reviewer for raising this point. We agree the reviewer’s comment and have revised our manuscript as follows;

“further longitudinal study would be of interest to examine the effect of smoking on visual outcome in CSC patients.”

8. Line 244: The authors speculated that choroidal vascular hyperpermeability (CVH) might result in the lower CVI in patients with smoking history. In this study, all patients underwent indocyanine green angiography (ICGA). Therefore, the incidence of CVH in ICGA should be assessed. If the hypothesis is correct, the incidence of CVH should be significantly higher in smoking group compared to non-smoking group. In my opinion, if the fluid is accumulated in the choroid secondary to CVH, CVI might increase. Furthermore, previous studies investigating CSC eyes reported that the eyes with CVH showed significantly greater choroidal thickness compared to the eyes without CVH.

Thank you for the insightful and constructive suggestion. As you suggested, we investigated the incidence of CVH on ICGA. In the current study, 4 patients did not undergo ICGA due to the allergy. For the remaining 71 eyes, we investigated the incidence of CVH according to the reviewer’s recommendation. As a consequence, 41 of 45 smoking patients (91.1%) had CVH and 23 of 26 non-smoking patients (88.5%) had CVH. The prevalence of CVH was numerically higher in smoking group than that in non-smoking group, however, the difference was not significant presumably due to the fact that the frequency of CVH is basically high in eyes with CSC, even in those who never smoked, and therefore any additional effects would be difficult to assess due to the ceiling effect. We understand your hypothesis that if the fluid is accumulated in the choroid secondary to CVH, CVI might increase. However, due to the inherent difficulties in assessing the CVH in CSC on ICGA, to the best of our knowledge, there was no report to investigate the correlation between CVH and CVI in eyes with CSC. Additionally, it is possible that there is relative decrease in CVI due to the exudative change happening in the choroidal stroma in CSC. In support of this, in some inflammatory diseases, there is an increased choroidal thickness with concomitant decrease in CVI (Agarwal A et al. Choroidal structural changes in tubercular multifocal serpinginoid choroiditis. 2018 Ocul Immunol Inflamm. 25;134-145.). Further investigations are needed to clarify the relationship between CVH and CVI in CSC patients, however, the present study did not enroll normal control subjects so this is beyond the scope of our present study. Again, thank you very much for your insightful suggestion. We toned down our strong sentences according to your comments.

Reviewer #2: Dear Authors,

I have read your manuscript entitled “Correlation between choroidal structure and smoking in eyes with central serous chorioretinopathy”. The manuscript is written in a concise and clear manner and the conclusions are well supported by the presented data. Besides a couple of comments below, I have no major concerns and feel this manuscript fulfills the criteria for publication in PLOS ONE.

The only minor comment

Page 10 table 1 legend - please include the BI definition

Thank you for your comment. We have revised our manuscript according to the reviewer’s comment.

Page 10 lines 165-166 - while previously stated 45 subjects were smokers and 30 - non-smoker, it is unclear what the following means: “31 patients were current smokers and 44 were non-current.”; the sum gives us 75 patients, does it mean there all smokers in the past, are these the same patients or different

Thank you very much. These are the same patients and it means that 31 of 45 CSC patients were current smokers and remaining 14 patients were non-current past smokers. Therefore, we have revised the manuscript in Results section.

Attachment

Submitted filename: Response to Reviewer_Okawa.docx

Click here for additional data file. (19.9KB, docx)

Decision Letter 1

Demetrios G Vavvas

15 Feb 2021

PONE-D-20-39783R1

Correlation between choroidal structure and smoking in eyes with central serous chorioretinopathy

PLOS ONE

Dear Dr. Inoue,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The first reviewer has some more questions that require to be addressed before a final decision can be made. Can you please address these comments? Thank you 

Please submit your revised manuscript by Apr 01 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Demetrios G. Vavvas

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: 1. It has been reported that the choroidal thickness and choroidal vascular index are significantly different between classic and chronic CSC. However, the authors did not state the distribution of the CSC types in smoking and non-smoking groups. The distribution might affect the main results in this study.

2. There are no evidences supporting the following statement in the discussion: luminal area increase in the smoking group was accompanied by an increase in the stromal area as well because of the increased choroidal vascular permeability in CSC patients. Why was the luminal area increased in the smoking group? Moreover, in the response letter, the authors mentioned that increased choroidal thickness with concomitant decrease in CVI was reportedly observed in some inflammatory diseases, which might support their hypothesis. However, the pathophysiology in such inflammatory diseases is quite different from that in CSC.

Reviewer #2: Dear Editor,

Thank you for this opportunity to review the revised manuscript entitled “Correlation between choroidal structure and smoking in eyes with central serous chorioretinopathy”.

All the comments are properly addressed. While responding to a very good point from reviewer 1 authors investigated the incidence of CVH as assessed by ICGA. Would suggest including it in the manuscript ( main or supplement).

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Mar 23;16(3):e0249073. doi: 10.1371/journal.pone.0249073.r004

Author response to Decision Letter 1

17 Feb 2021

Dear Prof. Demetrios G. Vavvas

We appreciate you and the reviewers for the constructive and insightful comments. Please find our enclosed point-by-point responses to the reviewers’ comments. We hope that this revision will meet your expectations, and that our revised manuscript will better suit for publication on PLOS ONE.

Reviewer #1: 1. It has been reported that the choroidal thickness and choroidal vascular index are significantly different between classic and chronic CSC. However, the authors did not state the distribution of the CSC types in smoking and non-smoking groups. The distribution might affect the main results in this study.

Thank you for the critical and constructive suggestion. In the smoking group, 10 eyes were classic CSC and 35 eyes were chronic CSC. In non-smoking group, 9 eyes were classic and 21 eyes were chronic CSC. To analyze the relationship between smoking status and CSC type (classic or chronic), the chi-squared test was conducted. As a result, there was no significant relationship between smoking and CSC type (p=0.63), which would imply that the distribution of the CSC type has only a negligible effect on the current results. We have revised our manuscript in the Results section.

2. There are no evidences supporting the following statement in the discussion: luminal area increase in the smoking group was accompanied by an increase in the stromal area as well because of the increased choroidal vascular permeability in CSC patients. Why was the luminal area increased in the smoking group? Moreover, in the response letter, the authors mentioned that increased choroidal thickness with concomitant decrease in CVI was reportedly observed in some inflammatory diseases, which might support their hypothesis. However, the pathophysiology in such inflammatory diseases is quite different from that in CSC.

Thank you for the insightful comment. We added this speculation, because we speculated that the luminal area increase in the smoking group was accompanied by an increase in the stromal area due to the increased choroidal vascular permeability, basing on a previous report by Wei et al. in which it was suggested that the increased stromal area in smoking group may be attributed to a chronic proinflammatory response (Ref 12). Nonetheless, we now totally agree with the reviewer’s comment. Furthermore, in the current study, we did not clarify this hypothesis. Moreover, we also agree with the reviewer’s comment that the pathophysiology of CSC is different from that of inflammatory disease. Thus, the too much speculative description in the Discussion is now deleted in the revised manuscript.

Reviewer #2: Dear Editor,

Thank you for this opportunity to review the revised manuscript entitled “Correlation between choroidal structure and smoking in eyes with central serous chorioretinopathy”.

All the comments are properly addressed. While responding to a very good point from reviewer 1 authors investigated the incidence of CVH as assessed by ICGA. Would suggest including it in the manuscript ( main or supplement).

Thank you for the insightful comment. We have added the following sentences, according to the reviewer’s recommendation.

Results

“Forty-one of 45 smoking patients (91.1%) had CVH and 23 of 26 non-smoking patients (88.5%) had CVH. The prevalence of CVH was numerically higher in smoking group than that in non-smoking group, however, the difference was not statistically significant.”

Discussion

“Recently, CSC has been considered as one of the pachychoroid spectrum diseases with focal or diffuse increase in choroidal thickness, dilated large choroidal vessels, and CVH. In pachychoroid spectrum diseases including CSC and polypoidal choroidal vasculopathy, CVH are associated with an increased SFCT and an increased CVI (23-25). In the current study, the prevalence of CVH was compared between the smoking and non-smoking groups in eyes with CSC. As a result, the prevalence of CVH was higher in smoking group than in non-smoking group, however this difference was not significant. This may be because the frequency of CVH is high in eyes with CSC in general, which masked the difference between the smoking and non-smoking groups. It should be noted that the reason why a smoking habit causes the decreased CVI still remains unclear, and further studies are needed shedding light on this issue.”

Attachment

Submitted filename: Response to Prof Vavvas2016.docx

Click here for additional data file. (146.9KB, docx)

Decision Letter 2

Demetrios G Vavvas

11 Mar 2021

Correlation between choroidal structure and smoking in eyes with central serous chorioretinopathy

PONE-D-20-39783R2

Dear Dr. Inoue,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Demetrios G. Vavvas

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have adequately addressed all the comments raised in this round of review. This reviewer feels the revised manuscript is now acceptable for publication.

Reviewer #2: Dear Authors,

i have read your revised manuscript entitled "Correlation between choroidal structure and smoking in eyes with central serous chorioretinopathy"and thank you for responding to all comments.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Acceptance letter

Demetrios G Vavvas

15 Mar 2021

PONE-D-20-39783R2

Correlation between choroidal structure and smoking in eyes with central serous chorioretinopathy

Dear Dr. Inoue:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Demetrios G. Vavvas

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 File

    (CSV)

    Click here for additional data file. (5KB, csv)
    Attachment

    Submitted filename: Response to Reviewer_Okawa.docx

    Click here for additional data file. (19.9KB, docx)
    Attachment

    Submitted filename: Response to Prof Vavvas2016.docx

    Click here for additional data file. (146.9KB, docx)

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting Information files.

    Articles from PLoS ONE are provided here courtesy of PLOS

    RESOURCES