ORIGINAL PAPER
Nagoya J. Med. Sci. 85. 289–298, 2023
doi:10.18999/nagjms.85.2.289

The role of inflammatory biomarkers in predicting
primary acquired nasolacrimal duct obstruction andpostoperative recurrence
Rüveyde Garip and Ahmet Kürşad Sakallıoğlu
Department of Ophthalmology, Trakya University School of Medicine, Edirne, Turkey

ABSTRACTThis study aims to determine the relationship between systemic inflammatory biomarkers and primaryacquired nasolacrimal duct obstruction and to evaluate whether they can be used as indicators in determining
the risk of recurrence after dacryocystorhinostomy. This retrospective, comparative case series was conductedwith 57 primary acquired nasolacrimal duct obstruction patients and 58 age- and gender-matched controls.
All subjects underwent a complete ophthalmologic examination and complete blood count measurements.
The mean neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and systemic immune-inflammationindex were significantly higher in patients with primary acquired nasolacrimal duct obstruction (p =0.005, p = 0.01, and p = 0.003, respectively). In recurrent patients, the neutrophil-to-lymphocyte ratio
was significantly higher than in those who did not develop a recurrence (p = 0.029). The area under the
curve was determined as 0.775 (p = 0.029) for the neutrophil-to-lymphocyte ratio in predicting recurrence.
The neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and systemic immune-inflammation index
levels were significantly higher in patients with primary acquired nasolacrimal duct obstruction comparedto healthy controls. The neutrophil-to-lymphocyte ratio might be used as a simple and inexpensive indicatorfor predicting recurrence in patients with primary acquired nasolacrimal duct obstruction.
Keywords: inflammation, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, primary acquired
nasolacrimal duct obstruction, systemic immune-inflammation index
Abbreviations:
PANDO: primary acquired nasolacrimal duct obstruction
DCR: dacryocystorhinostomy
NLR: neutrophil-to-lymphocyte ratio
PLR: platelet-to-lymphocyte ratio
SII: systemic immune-inflammation index
CBC: complete blood countThis is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
License. To view the details of this license, please visit (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Received: May 16, 2022; accepted: June 23, 2022
Corresponding Author: Rüveyde Garip, MD
Department of Ophthalmology, Trakya University School of Medicine, Balkan yerleşkesi, Edirne 22030,
TurkeyTel: +90 5063288987, Fax: +90 (284) 235 76 41, E-mail: ruveydegarip@trakya.edu.tr
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Rüveyde Garip and Ahmet Kürşad Sakallıoğlu

INTRODUCTION
Primary acquired nasolacrimal duct obstruction (PANDO) is a common ophthalmologic problemof the lacrimal passages that causes epiphora.1 PANDO is characterized by idiopathic inflammationand fibrosis, resulting in partial stenosis or complete occlusion of the nasolacrimal duct.2,3 Many
factors have been suggested that trigger the inflammation in PANDO, such as infection in the
conjunctiva, sinusitis, and nasal pathway diseases.1,3 Although the main etiological factors causing
PANDO remain unknown, it is recognized that chronic inflammation has a prominent role in its
pathogenesis.2-4 Dacryocystorhinostomy (DCR), which is based on the creation of an alternative
pathway for drainage of tears between the lacrimal sac and nasal cavity, is considered the gold
standard treatment for PANDO.5
Recently, white blood cells, neutrophil, monocyte, platelet, neutrophil-to-lymphocyte ratio(NLR), and platelet-to-lymphocyte ratio (PLR) have been proposed as indicators of subclinicalsystemic inflammation.6 These simple and inexpensive methods for assessing inflammation havebeen used as predictors of several ocular diseases, including dry eye,7 retinal vein occlusion,8
neovascular glaucoma,6 diabetic retinopathy,9 and age-related macular degeneration.10
The systemic immune-inflammation index (SII) is a novel inflammatory biomarker that has
been proposed as a prognostic indicator in various diseases, such as cancer,11 stroke,12 cardiovascular diseases,13,14 and systemic inflammatory disorders.15 Tang et al16 suggested that NLR
and SII might serve as inflammatory predictors in primary open-angle glaucoma patients. Ozcan
et al17 reported that the SII is superior to other inflammatory biomarkers in dry eye patients.
Atum and Alagöz18 reported higher NLR and lower mean platelet volume levels in PANDO
patients compared to healthy controls and suggested that NLR and mean platelet volume counts
were associated with PANDO.
Based on this knowledge, it has been hypothesized that there might be a relationship between
subclinical systemic inflammation and the development of PANDO. Therefore, this study aims
to determine the relationship of inflammatory biomarkers, including NLR, PLR, and SII, with
PANDO and to evaluate whether they can be used as indicators in determining the risk ofrecurrence after DCR.

MATERIALS AND METHODSThis retrospective, comparative case series was conducted with 115 participants in the Ophthalmology Department of the Trakya University School of Medicine. This study was carriedout in accordance with the principles of the Declaration of Helsinki and was approved by theinstitutional Human Research and Ethics Committee (Approval code: TÜTF-GOBAEK 2022/55).
Written informed consent was obtained from all participants before enrollment.
The study group consisted of 57 patients who underwent DCR surgery because of theestablished diagnosis of PANDO. Fifty-eight healthy individuals who were admitted to theophthalmology outpatient clinic for a routine ophthalmological examination were included in thecontrol group. In both the study and control groups, participants who had a medical history ofdisorders influencing inflammatory biomarkers, such as diabetes mellitus, cardiovascular diseases,
arterial hypertension, chronic obstructive lung disease, hyperthyroidism, hypothyroidism, anemia,
malignancies, renal dysfunction, liver dysfunction, hematologic or autoimmune disorders, andchronic systemic inflammatory diseases, or those who had a history of prior ocular surgery,ocular inflammation, age-related macular degeneration, retinal occlusive disease, or glaucoma were
excluded. Patients who were taking anti-inflammatory therapies were also excluded.
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Demographic data, such as age and sex, were noted from the medical records of all patients.
White blood cell, lymphocyte, neutrophil, platelet, and mean platelet volume values were recorded
from the complete blood count (CBC). The CBC parameters of each participant were measured
by the fluorescent flow cytometry method using the Sysmex XE-2100 (Sysmex Corporation, Kobe,
Japan) automated hematology system. The counts of white blood cells, neutrophils, lymphocytes,
monocytes, platelets, and mean platelet volume were measured as part of the automated CBC.
The NLR and PLR were calculated as the ratios of neutrophil-to-lymphocyte and platelet-tolymphocyte, respectively. SII was calculated as platelet count x (neutrophil/lymphocyte).
All surgeries were performed by the same surgeon (RG). The patients in the study group weredivided into two subgroups according to the presence or absence of postoperative recurrence.
Postoperative recurrence or DCR failure is defined as recurrent epiphora and the observation of
insufficient anatomical patency with lacrimal irrigation.
Statistical analysis was performed using IBM SPSS Statistics 20 (SPSS Inc, Chicago, IL, USA)for Windows. Parametric data were presented as mean ± standard deviation, and categorical data
were presented as percentages. The Kolmogorov–Smirnov test was used to assess data normality,
and an independent t-test was performed to compare variables between the study group andhealthy subjects when data normality was assumed. A Mann–Whitney U test was performed
if the normal distribution was rejected. Chi-square was used for the comparison of categoricalvariables between the two groups. Receiver operator characteristic curve analyses were performed
to determine the optimal cut-off points of SII, NLR, and PLR for the discrimination of PANDO
patients from healthy individuals and recurrent cases from nonrecurrent patients. The areas under
the curves were calculated for each parameter as measures of the accuracy of the tests. Statisticalsignificance was considered as p < 0.05.

RESULTS
One hundred and fifteen individuals were included in the study. The study group consistedof 57 patients, and the control group consisted of 58 healthy individuals. The mean age was
60.8 ± 12.9 years (range 30–88) in the study group and 60.7 ± 9.0 years (range 43–87) in thecontrol group. There were 9 males (15.8%) and 48 females (84.2%) in the study group and 9
males (15.5%) and 49 females (84.5%) in the control group. There were no significant differences
between the two groups in terms of age and gender (p = 0.948 and p = 0.968, respectively).
DCR failure was observed in six patients (10.5%).
The laboratory characteristics and p-values of the patients and the control group are shown in
Table 1. Although no statistically significant differences were observed between the two groups
in terms of white blood cell, neutrophil, lymphocyte, platelet, and mean platelet volume values(p > 0.05, independent sample t-test), NLR, PLR, and SII values were found to be statisticallysignificantly higher in the study group compared to the control group (independent sample t-test,
p = 0.005, p = 0.01, and p = 0.003, respectively).
A receiver operator characteristic curve analysis was used to determine the predictive valuesof NLR, PLR, and SII (Fig. 1). The calculated areas under the curves and optimal cut-off values
for each parameter are shown in Table 2. According to the receiver operator characteristic curve
analysis, the areas under the curves of NLR, PLR, and SII were 0.638 (p = 0.011), 0.616(p = 0.032), and 0.626 (p = 0.02), respectively. The optimal cut-off value of NLR to predict
PANDO was > 1.66, with a sensitivity of 61% and a specificity of 55% (95% confidence
interval: 0.538–0.739). The optimal cut-off value of PLR to predict PANDO was > 106.46,
with a sensitivity of 61% and a specificity of 55% (95% confidence interval: 0.512–0.720). The
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Table 1 The meanWBC, neutrophil, lymphocyte, platelet, NLR, PLR, MPV, and SII values of the study andcontrol groups

Study group (N=57)

Control group (N=58)

p-valuemean ± SD

Min – Max

mean ± SD

Min – MaxWBC

2.3 ± 0.8

4.6 – 10.8

2.3 ± 0.5

4.6 – 9.1

0.591

Neutrophil

1.9 ± 0.6

0.7 – 3.7

1.7 ± 0.5

1.0 – 3,1

0.077

Lymphosit

2.3 ± 0.8

1.0 – 6.0

2.4 ± 0.4

1.6 – 3.5

0.389

Platelet

254.6 ± 58.2

122 – 379

242.1 ± 41.8

130 – 327

0.188

MPV

9.5 ± 1.2

7.2 – 12.4

9.3 ± 1.1

7.2 – 11.4

0.273

NLR

1.9 ± 0.6

0.6 – 3.7

1.7 ± 0.4

1.0 – 2.90.005*

PLR

121.7 ± 45.3

45 – 310

104.4 ± 21.5

62.8 – 143.9

0.01*

SII

487.7 ± 199.4

175.5 – 1147.0

396.9 ± 112.2

207.8 – 660.5

0.003*

N: number of participiants
WBC: white blood cell
MPV: mean platelet volume
NLR: neutrophil to lymphocyte ratio
PLR: platelet to lymphocyte ratio
SII: systemic immune inflammation index
SD: standard deviation
Min: minimum
Max: maximum*: statistical significanceFig. 1 Receiver operator characteristic curve analysis
Receiver operator characteristic curve (ROC) of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte
ratio (PLR), and systemic immune inflammation index (SII) for the prediction of primary acquired nasolacrimal
duct obstruction (PANDO).
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Table 2 The AUC, optimal cutoff, sensitivity, and specificity values of NLR, PLR, and SII levels obtained
from ROC analysis

Variable

AUC

95% CI

P value

Cutoff value

Sensitivity%

Specificity%

Study (N=57) vs control (N=58) groups
NLR

0.638

0.538–0.739

0.011

1.66

61

55

PLR

0.616

0.512–0.720

0.032

106.46

61

55

SII

0.626

0.524–0.727

0.02

394.95

60

52

0.029

2.06

83

70

Recurrent vs non-recurrent groups
NLR

0.775

0.573–0.976

AUC: area under the curve
NLR: neutrophil to lymphocyte ratio
PLR: platelet to lymphocyte ratio
SII: systemic immune inflammation index
ROC: receiver operator characteristic
CI: confidence interval
N: number of participiants

optimal cut-off value of SII to predict PANDO was > 394.95, with a sensitivity of 60% and a
specificity of 52% (95% confidence interval: 0.524–0.727).
Six patients developed recurrence after surgery. The mean surgery duration was 84.22 ± 3.93
minutes in the recurrent group and 81.28 ± 5.37 minutes in the nonrecurrent group. There wasno significant difference between the two groups in terms of surgery duration (p = 0.09). In six
patients who developed recurrence after surgery, the NLR was significantly higher than in those
who did not (Mann–Whitney U test, p = 0.029). Although the PLR and SII values were found tobe higher in cases with recurrence, the difference was not statistically significant (Mann–Whitney
U test, p = 0.263 and p = 0.16, respectively). Detailed information about the groups is shown in
Table 3. According to the receiver operator characteristic curve analysis (Fig. 2), the area under
the NLR curves was 0.775 (p = 0.029). The corresponding optimal cut-off value of NLR topredict postoperative recurrence was identified as 2.06, with a sensitivity of 83% and specificity
of 70% (95% confidence interval: 0.573–0.976).

DISCUSSION
The CBC is an inexpensive, reproducible, and reliable method that provides an evaluation of
the abnormalities in the hematopoietic and immune systems.16 It has been suggested that somebiomarkers obtained from a CBC, such as NLR, PLR, and SII, are indicative of subclinicalsystemic inflammation.6,11,13 Recently, these inflammatory biomarkers have been shown to havepredictive and prognostic importance in various eye diseases such as glaucoma,16 central retinal
artery occlusion,19 retinal vein occlusion,20 and keratoconus.21 Although the exact pathogenesis
of PANDO remains unclear, it is known that inflammation plays a prominent role.22 Considering
the inflammatory nature of PANDO, systemic inflammatory biomarkers may help predict both
the development of PANDO and the risk of recurrence after surgery.
In the present study, it was found that NLR, PLR, and SII levels in patients with PANDO
were higher than in healthy subjects. Atum and Alagöz18 reported higher NLR levels in PANDO

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Rüveyde Garip and Ahmet Kürşad Sakallıoğlu

Table 3 The mean WBC, neutrophil, lymphocyte, platelet, NLR, PLR, MPV, and SII values of patients withand without postoperative recurrence

Recurrent (N=6)

Non-recurrent (N=51)

p-valuemean ± SD

Min – Max

mean ± SD

Min – MaxWBC

7.4 ± 2.0

5.0 – 10.7

7.0 ± 1.3

4.6 – 10.8

0.815

Neutrophil

2.5 ± 0.7

1.6 – 3.2

1.8 ± 0.6

0.6 – 3.7

0.156

Lymphosit

1.9 ± 0.4

1.4 – 2.5

2.3 ± 0.8

1.0 – 6.0

0.152

Platelet

244.8 ± 43.2

181 – 295

255.7 ± 59.9

122 – 379

0.675

MPV

9.1 ± 1.0

8.0 – 10.5

9.5 ± 1.2

7.2 – 12.4

0.422

NLR

2.5 ± 0.7

1.6 – 3.2

1.8 ± 0.6

0.6 – 3.7

0.029*

PLR

136.3 ± 45.2

72.4 – 196.7

119.9 ± 45.5

45.0 – 310.0

0.277

SII

632.2 ± 249.6

346.9 – 904.7

470.7 ± 188.4

175.5 – 1147.0

0.168

N: number of participiants
WBC: white blood cell
MPV: mean platelet volume
NLR: neutrophil to lymphocyte ratio
PLR: platelet to lymphocyte ratio
SII: systemic immune inflammation index
SD: standard deviation
Min: minimum
Max: maximum*: statistical significanceFig. 2

Receiver operator characteristic curve analysis (ROC) of neutrophil-to-lymphocyte ratio (NLR) inrecurrent cases (green line: reference line)
Receiver operator characteristic curve (ROC) of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio(PLR), and systemic immune inflammation index (SII) for the prediction of recurrence after surgery.
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patients compared to the control group, similar to our results, but they found no significant
difference in PLR levels between the two groups. However, SII levels were not included, andthe inflammatory biomarkers in recurrent cases and the relationship of these biomarkers withrecurrence were not evaluated in their study.
Chronic inflammation signs have been shown in biopsy specimens of the lacrimal sac obtained
during DCR in patients with PANDO. Linberg and McCormick23 reported 16 cases of PANDO
seen with clinical chronic dacryocystitis, and they observed that in 14 of the 16 cases, a biopsyof the nasolacrimal duct revealed active chronic inflammation along the narrowed nasolacrimal
duct in early cases. They observed fibrosis and fibrous obstruction of the nasolacrimal duct
in intermediate and late cases. They suggested that the obliteration of the nasolacrimal duct
by inflammatory infiltrates and edema leads to PANDO and chronic dacryocystitis. Makselis
et al3 evaluated histopathologic specimens of patients with nasolacrimal duct obstruction andreported chronic nongranulomatous inflammation in 70.5% of the cases. They suggested thatchronic nongranulomatous inflammation is the most common histological finding in cases ofnasolacrimal duct obstruction. Based on this knowledge, considering the role of inflammationin the pathogenesis of PANDO, it can be suggested that systemic subclinical inflammation may
trigger inflammation in the nasolacrimal duct, play a role in disease pathogenesis, and affect thecourse of the disease and treatment success. In line with the results of the present study, higher
NLR, PLR, and SII levels, which are accepted as indicators of subclinical systemic inflammation,
may be indicative of the risk of PANDO development.
Amin et al24 found chronic nonspecific inflammation in the lacrimal sac biopsies of 33 patientswith nasolacrimal duct obstruction and emphasized that nonspecific inflammation-causing fibrosis
was the most common cause in these cases. They also evaluated the severity of inflammationin the lacrimal sac of all specimens by the clinical inflammation score, which is obtained byexamining the inflammatory cell infiltration density, fibrosis, and capillary proliferation. Patientswere divided into three groups—mild, moderate, and severe inflammation—according to clinicalinflammation scores. When the unsatisfactory surgical outcome was evaluated according to theclinical inflammation score, it was 0% in the mild group, 7.7% in the moderate group, and 40%
in the severe inflammatory group. In the same study, an increase in fibrosis density was observedin two patients who underwent revision DCR. Although the rate of unsatisfactory surgicaloutcomes was higher in the severe group, they could not find a significant relationship between
inflammatory infiltration, fibrosis, capillary proliferation, and surgical success. In another studyby Çiftçi et al,25 a significant increase in fibrosis density was observed in recurrent cases, andit was suggested that fibrosis-related changes were predominantly responsible for recurrence. A
wound-healing response occurs as a result of tissue damage caused by various reasons, such as
surgery, mechanical damage, infection, and autoimmune inflammation. As a result of this healing
response, damaged cells are replaced by restructuring the extracellular matrix. The wound-healing
response includes hemostasis, inflammation, activation, and proliferation of collagen-producing
cells, tissue remodeling, and resolution. If the resolution phase is not completed, this process
turns into abnormal extracellular matrix deposition, resulting in tissue fibrosis. Eventually, theabnormal wound-healing process progresses to chronic inflammation in which tissue destruction
and regeneration occur simultaneously, resulting in tissue fibrosis.26 Considering the relationshipbetween DCR recurrence and lacrimal sac fibrosis, which is suggested in the literature by biopsy
results, the abnormal chronic inflammation process that develops in the postoperative period
may be one of the causative factors for recurrence. Systemic inflammation biomarkers may be
proposed as indicators of inflammation that develops in the postoperative period. In the present
study, it was observed that the NLR was at higher levels in recurrent cases than in those without
recurrence. Patients with higher levels of inflammatory biomarkers may develop more fibrosis,
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with a stronger inflammatory response. Therefore, the NLR may be used to determine the riskof recurrence in PANDO patients before DCR surgery.
The failure rates for DCR have been reported to be between 6% and 14%. Various methods
have been proposed to reduce failure rates.27 In line with the results of the present study, incases with high NLR (cut-off value: 2.06) values in the preoperative period, ophthalmologists
and otolaryngologists might be aware of the risk of postoperative recurrence. In these cases,
precautions such as opening a sufficient osteotomy size,28 silicone intubation,29 intraoperative
mitomycin-c application,30 suturing the lacrimal sac to the nasal mucosa,31 and lacrimal irrigation
during the follow-up period32 can be applied to reduce recurrence.
The main limitations of this study are its retrospective nature and relatively small sample size.
More comprehensive studies, including larger numbers of recurrent cases, will better emphasize
the importance of systemic inflammatory biomarkers in detecting the recurrence of DCR. Anotherimportant limitation is the lack of biopsy examinations. Evaluation of the correlation between
inflammatory changes in biopsy specimens and systemic inflammatory biomarkers may help tobetter explain the relationship between them.
Overall, this is the first study to evaluate the relationship between DCR recurrence andinflammatory biomarkers. In conclusion, NLR, PLR, and SII levels were significantly higher in
PANDO patients than in healthy controls. NLR levels were significantly elevated in recurrent
cases. The NLR may be used as a simple, inexpensive, and reliable indicator for predicting
DCR failure in PANDO patients. More comprehensive studies, including biopsy specimens andserum inflammatory biomarkers, may highlight the relationship between systemic inflammation
and PANDO. Further investigations, including more patients, are needed to better understand thepossible role of serum NLR levels in the failure of DCR.

CONFLICT OF INTEREST
The authors declare that they have no conflicting interests.

FUNDINGNo financial support was received for this study.

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