Associations between signs and symptoms of dry eye disease: a systematic review

Figures & data

Figure 1 Preferred reporting items for systematic reviews and meta-analyses flow diagram.

Note: ^aOf which 33 articles reported unique studies.

Table 1 Studies reporting associations between symptoms and clinical signs/tests in DED

Study	Country	Study design	Population, N	Age, mean (SD),a sex, % female	Method for symptom assessment	Clinical sign/test	Correlationcoefficientb	Significance	Statisticaltest used
Symptom measurement using OSDI, NEI VFQ-25, or VAS
Schiffman et al^Citation22	USA	Clinic-based validation study	Normal (N=30); DED (N=109)	Normal: 54.5 (13.4), 83; DED: 57.5 (13.9), 79	OSDI	TBUT Schirmer tear test Total staining (LG) Total staining (F)	−0.14 −0.21 0.13 0.19	NS S (P=0.01) NS S (P=0.02)	Spearman
Amparo et al^Citation24	USA	Retrospective, clinic-based, cohort study	DED (N=186)	54 (15), 66	OSDI	Corneal staining (F) Tear osmolarity	0.31 −0.091	S (P<0.001) NS	Pearson or Spearman
Vitale et al^Citation35	USA	Clinic-based study	Primary SS (N=42)	54.9 (12.7), 95	OSDI NEI VFQ-25	TBUT Schirmer tear test Total staining (F + LG) TBUT Schirmer tear test Total staining (F + LG)	0.06 0.04 0.19 0.24 −0.04 0.20	All NS	Spearman
Sullivan et al^Citation37	USA and EU	Retrospective, clinic-based cohort study	Normal (N=82); DED (N=262)	Normal and DED: 46.1 (16.4), 73	OSDI	TBUT Schirmer tear test Corneal staining (F) Conjunctival staining (LG)	0.09c 0.06c 0.15c 0.14c	NR	Pearson
Adatia et al^Citation42	Canada	Clinic-based study	SS (N=18)	54.3 (10.6),d 89	OSDI SSD	Corneal staining (LG) Corneal staining (LG)	−0.2278 −0.2736	All NS	Pearson
Tuisku et al^Citation54	Finland	Clinic-based study	Normal (N=10); SS (N=20)	Normal: 49.8 (5.0), 90; SS: 54.5 (7.0), 90; SS: 54.5 (7.0), 95	OSDI VAS	Corneal staining (F) Schirmer tear test TBUT Corneal staining (F) Schirmer tear test TBUT	0.56 −0.47 −0.32 0.54 −0.51 −0.33	S (P<0.01) S (P<0.01) NS S (P<0.01) S (P<0.01) NS	Spearman
Pult et al^Citation28	Germany	Clinic-based study	Normal non-contact lens wearers (N=47)	Median age, 35 (range 19–70), 64	OSDI	NIBUT Corneal staining (F + LG) Conjunctival staining (F + LG)	−0.591 0.012 0.060	S (P<0.001) NS NS	Pearson or Spearman
Kastelan et al^Citation55	Croatia	Clinic-based study	Contact lens wearers (N=16)	32 (6.3), 38	OSDI	Schirmer tear test	−0.50	NR	Pearson
Ozcura et al^Citation29	Turkey	Prospective clinic-based study	Normal and DED (N=68)	44.25 (11.13), 79	OSDI	Schirmer tear test TBUT	−0.182 −0.296	NS S (P=0.01)	Pearson
Yoon et al^Citation56	South Korea	Clinic-based study	DED (N=50)	51 (12.1), 82	OSDI	Corneal staining (F + LG)	0.297	NS	Spearman
Versura et al^Citation23	Italy	Clinic-based study	Normal (N=25); DED (N=105)	Normal: 44.5 (12.5), 72; DED: 54.8 (15), 76	OSDI	Tear osmolarity	0.223	S (P-value NR)	Pearson
de A F Gomes et al^Citation57	Brazil	Clinic-based study	Systemic sclerosis (N=45), of whom DED (N=22)	Normal: 48.7 (10.1), 91.3; DED: 53.5 (14.7), 86.4	OSDI	TBUT Schirmer tear test Conjunctival staining (RB)	−0.22 −0.11 0.07	NS	Spearman
Bunya et al^Citation16	USA	Cross-sectional study	SS (N=49)	53.7 (15.9), 92	OSDI	Schirmer tear test Tear osmolarity	0.20 −0.39	NS S (P<0.01)	Spearman
Machado et al^Citation58	Brazil	Prospective, randomized, comparative, crossover study	DED (N=30)	Group Ae: 42 (15.96), 87; group Be: 47.67 (10.23), 73	OSDI	Corneal staining (RB, group A)e Corneal staining (RB, group B)e Corneal staining (LG, group A)e Corneal staining (LG, group B)e	0.341 0.521 0.328 0.453	NS S (P<0.05) NS NS	Pearson
Frequency of symptom instruments
Schein et al^Citation7,Citation8	USA	Population-based prevalence study	N=2,420 elderly participants	73.5 (5.1), 58	Dry eye symptoms (six-item questionnaire)	Schirmer tear test RB	NR NR	NS NS	Chi-squared test for proportions
Macri et al^Citation59	USA and Italy	Case-controlled study	Normal (N=32); MGD (N=54); ATD (N=39)	Normal: 59.79 (14.60); MGD: 60.15 (13.95); ATD: 60.38 (14.23), % female NR for this study.	Frequency of symptoms, eleven-item questionnaire	Corneal staining (F) Schirmer tear test	0.504 −0.437	All S (P<0.0001)	Spearman Pearson
Macri and Pflugfelder^Citation60	USA	Case-controlled study	Normal (N=19); MGD (N=37); ATD (N=43)	Normal: 59.4 (15.4); MGD: 59.7 (17.5); ATD: 66.3 (16.2), % female NR for this study.	Frequency of symptoms, eleven-item questionnaire	Corneal staining (F) Schirmer tear test	0.47 −0.34	All S (P<0.001)	Spearman
Gulati et al^Citation61	USA	Clinical validation study	Normal and DED (N=53)	56 (14), 83	Frequency of symptoms, two-item instrument	Corneal staining (F) TBUT Schirmer tear test Conjunctival staining (RB)	0.24 −0.38 −0.34 −0.0002	NS S (P<0.01) S (P=0.01) NS	Spearman
Nichols et al^Citation38	USA	Clinic-based study	DED (N=75)	Median 46.2 (range 21.4–81), 70	Dryness Grittiness Soreness Redness Fatigue	Total staining (F)/total staining (RB)/Schirmer tear test/TBUT	−0.09 to 0.18 −0.02 to 0.27− 0.13 to 0.12 −0.04 to 0.14 −0.10 to 0.15	All NS	Spearman
Guo et al^Citation19	People’s Republic of China	Population-based study	Normal and DED (N=1,816)	54.86 (11.72), 44	Six-item frequency of symptom questionnaire	TBUT ≤10 seconds Corneal staining (F) score ≥1 Schirmer tear test score ≤5 mm	0.41 0.361 0.164	All S (P<0.001)	Pearson
Lu et al^Citation20	People’s Republic of China	Population-based study	Normal and DED (N=1,840)	56.25 (12.26), 44	Six-item frequency of symptom questionnaire	TBUT ≤10 seconds Corneal staining (F) score ≥1 Schirmer tear test score ≤5 mm	0.302 0.339 0.195	All S (P<0.001)	Pearson
Severity of symptom or other symptom measures
Begley et al^Citation36	USA	Cross-sectional multicenter study	Normal (N=28); non-SS DED (N=73); SS (N=21)	Normal: 47 (NR), 68; non-SS DED: 52 (NR), 87; SS: 53 (NR), 100	Clinician grade	Schirmer tear test TBUT Corneal staining (F) Conjunctival staining (LG)	−0.394 −0.482 0.447 0.453	All S (P≤0.01)	Spearman
					Self-assessed severity	Schirmer tear test TBUT Corneal staining (F) Conjunctival staining (LG)	−0.323 −0.353 0.273 0.336	All S (P≤0.01)	Spearman
Afonso et al^Citation62	USA	Case-control study	Normal (N=40); DED (N=40)	Normal: 53 (22), NR; DED: 56 (17), NR	12-item symptom severity questionnaire	Schirmer tear test	−0.39	S (P<0.001)	Spearman
Nguyen et al^Citation27	USA	Prospective, nonrandomized, observational case series	DED (N=18)	56.6 (15), 72	Six-page Indiana University Dry Eye Questionnaire 2002	Schirmer tear test Conjunctival staining (RB) TBUT	−0.357 0.168 −0.229	All NS	Spearman
Yolton et al^Citation63	USA	Clinic-based study	Normal and DED (N=49)	41.3 (18.6), 57	Four-item severity of discomfort questionnaire	Total staining (RB) TBUT	0.24 −0.27	NS S (P<0.05)	Spearman Pearson
Nichols et al^Citation64	USA	Clinical validation study	DED (N=75)	Median 46.2 (range 21.4–81.0), 70	McMonnies questionnaire	Total staining (F) Total staining (RB) Schirmer tear test TBUT	0.09 0.09 −0.13 −0.19	All NS	Spearman
Cennamo et al^Citation65	Italy	Clinic-based study	Normal (N=15); DED (N=45)	Normal: 29 (NR), 47; DED: 34 (NR), 49	Dry eye sensation defined by itching, burning, irritation, and watering	Degree of alteration detected by Schirmer tear test Degree of alteration detected by TBUT	0.705 0.483	All S (P<0.01)	Spearman
Labbe et al^Citation21	People’s Republic of China	Population-based cross-sectional study	N=1,456; without DED (N=1,215); DED (N=241)	Without DED: 64.33 (9.38), 57.8; DED: 67.26 (9.60), 68.5	Three-item symptom questionnaire (eye dryness, grittiness, burning)	Schirmer tear test TBUT Corneal staining (F)	−0.04 −0.04 −0.001	NS NS NS	Pearson
Hay et al^Citation9	UK	Population-based cross-sectional study	Ocular and/or dry mouth symptoms (N=341)	Median 46 (male), median 49 (female), 55	Presence of ocular symptoms	Schirmer tear test	NR	Weak association (positive predictive value = 0.25)	Predictive value analysis
Cardona et al^Citation15	Spain	Prospective longitudinal study	Symptoms associated with tear deficiency (N=26)	37.73 (12.39), 62	Severity of scratchiness 18 other correlations for total staining (F), TBUT, total staining (LG) versus irritation, dryness, grittiness, soreness, vision changes, light sensitivity	Total staining (F) TBUT Total staining (LG)	0.47 −0.41 NR NR	S (P<0.05) S (P<0.05) NS NS	Spearman
Lin et al^Citation10	Taiwan	Population-based study	DED (N=459)	72.2 (5.1), 46	Eight-item interviewer-administered questionnaire	TBUT ≤10 seconds Schirmer tear test score ≤5 mm Corneal staining (F) score ≥1	NR NR NR	NS S (P<0.05) NS	Comparison of proportions by chi-squared test
Mizuno et al^Citation17	Japan	Multicenter study	DED (N=158)	62.5 (12.6), 91	General vision Eleven other NEI VFQ-25 subscales (Japanese version)	Total staining (F) Total staining (RB)/TBUT/Schirmer tear test Total staining (RB)/total staining (F)/TBUT/Schirmer tear test	−0.176 −0.019 to 0.111 −0.155 to 0.173	S (P<0.05) NS NS	Pearson
Singh Bhinder and Singh Bhinder^Citation11	India	Clinic-based study	DED (N=16)	48.56 (16.68), 44	Reflex epiphora	Total staining (LG) TBUT	NR NR	S (P<0.001) S (P=0.001)	Wilcoxon matched-pairs test

Notes:

a Unless stated otherwise;

b increases in severity of symptoms/OSDI would be expected to be positively correlated with increases in ocular surface dye staining/tear osmolarity and negatively correlated with increases in TBUT/Schirmer tear test results.

c r²;

d mean age is given for females, the two male participants in the study were 57 years and 64 years old;

e dye instillation order, group A: RB followed by LG; group B: LG followed by RG.

Abbreviations: ATD, aqueous tear deficiency; DED, dry eye disease; EU, European Union; F, fluorescein; LG, lissamine green; MGD, meibomian gland disease; NEI VFQ-25, 25-item National Eye Institute Visual Function Questionnaire; NIBUT, noninvasive breakup time; NR, not reported; NS, not significant; OSDI, Ocular Surface Disease Index^©; S, significant; SD, standard deviation; SS, Sjögren’s syndrome; SSD, Symptom Severity of Discomfort scale; RB, rose bengal; TBUT, tear breakup time; VAS, visual analog scale.

Table 2 Summary of signs and symptom measures

	Description
Clinical signs/tests
Schirmer tear test	Assesses tear fluid availability. Severity grading: >10 mm, normal; 6–10 mm, mild-to-moderate; 0–5 mm, severe^Citation22
Ocular surface staining	Assesses damage of the ocular surface through staining of the cornea and/or conjunctiva with fluorescein dye, rose bengal, or lissamine green. Grading is on a scale ranging from absent to severe (increases with severity)
TBUT	Assesses tear film stability. After fluorescein instillation, the time interval between a complete blink and the first appearance of a dry spot in the precorneal tear film is measured; <10 seconds commonly associated with DED^Citation2
Tear osmolarity	Reflects the concentration of solutes in the tear film; an increase of tear osmolarity is a marker of DED^Citation1
Patient-reported symptom measures
OSDI	12-item questionnaire used to assess dry eye symptoms within the past week. 5-point Likert-type response format yielding scores ranging from 0 (least severe) to 100 (most severe)^Citation22
NEI VFQ-25	25-item vision-related quality of life measurement tool consisting of 12 subscales rated on a 0 (worst) to 100 (best) scale^Citation66
VAS	Psychometric response scale used for describing subjective characteristics or attitudes. Respondents mark the location on a 100 mm line that corresponds to the amount of pain, ocular comfort, or symptoms of dryness that they experience
Symptom severity and frequency assessments	Assessments of patient-reported severity (eg, absent, mild, moderate, severe) and frequency (eg, none, rarely, sometimes, often, all of the time) of common symptoms (eg, burning, stinging, grittiness, foreign body sensation, tearing, ocular fatigue, dryness)

Abbreviations: DED, dry eye disease; NEI VFQ-25, 25-item National Eye Institute Visual Function Questionnaire; OSDI, Ocular Surface Disease Index^©; TBUT, tear breakup time; VAS, visual analog scale.

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