To evaluate the association between sensitization to indoor allergens and glaucoma in participants of the National Health and Nutrition Examination Survey (NHANES).
Retrospective cross-sectional study.
This study examined the association between serum immunoglobulin E (IgE) levels for a panel of common indoor allergens and glaucoma for 2005–2006 NHANES participants. The exposures of interest were serum IgE levels to a panel of common indoor allergens. The outcome of interest was a clinical diagnosis of glaucoma based on the Rotterdam criteria. Logistic regression modeling was performed to assess the association between each type of IgE and glaucoma, while controlling for age, ethnicity, and steroid use. All estimates were weighted based on the multistage NHANES sampling design.
Among a weighted total of 83 308 318 participants, the overall prevalence of glaucoma was 3.2% (95% confidence interval [CI]: 2.8%, 3.6%). The majority of patients were non-Hispanic white (n = 10 547 654; 77.1%). The American dust mite antigen had the highest proportion of participants with positive IgE values (n = 12 093 038; 14.5%). In the full model including all allergen-specific IgE subtypes as predictors, there were statistically significant associations between IgE subtypes and glaucoma for the cockroach (odds ratio [OR] = 2.78; 95% CI = 1.34, 5.76), cat (OR = 3.42; 95% CI = 1.10, 10.67), and dog (OR = 0.24; 95% CI = 0.06, 0.96) antigens.
In NHANES, participants with glaucoma had significantly higher odds of sensitization to the cockroach and cat allergens compared to those without glaucoma. These findings indicate the need for further research to elucidate the role of chronic indoor allergen exposure in the development of glaucomatous optic neuropathy.
Glaucoma is the second-leading cause of blindness worldwide. Its etiology is multifactorial, and autoimmune dysregulation has been proposed as a contributing factor. Wax and associates reported that several patients with normal-tension glaucoma who tested positive for anti-Ro/Sjogren syndrome antigen A (SSA) antibodies had elevated titers for additional autoimmune antibodies, including antinuclear antibody, rheumatoid factor, anti-ribonuclear protein, anti-Smith protein, and immunoglobulin G (IgG). Another study by Wax and associates revealed that several glaucoma patients had elevated levels of monoclonal paraproteins and nonspecific antibodies to deoxyribonucleic acid and ribonucleic acid.
Allergies are a specific type of immunologic abnormality where the body is abnormally sensitized to environmental allergens, leading to pathologic autoimmune responses such as rhinitis, asthma, and anaphylaxis. Previous researchers have proposed that indoor and outdoor allergens lead to differing responses because of the duration and frequency of allergen exposure. Platts-Mills and associates suggested that outdoor allergens are only transiently inhaled because outdoor air is constantly moving, while indoor allergens are constantly inhaled because indoor air is still. Therefore, outdoor allergens have been observed to be associated with temporary conditions such as conjunctivitis and rhinitis, while indoor allergens are associated with chronic inflammatory diseases such as asthma.
Given that glaucoma is a chronic condition and that previous literature has suggested an inflammatory component in glaucoma pathophysiology, our hypothesis was that exposure to indoor allergens could be a potential autoimmune mechanism contributing to the development of glaucoma. To this end, the purpose of this study was to examine the association between serum immunoglobulin E (IgE) levels for indoor allergens and glaucoma in participants of the 2005–2006 National Health and Nutrition Examination Survey (NHANES).
Study Design and Description of Database
This was a retrospective cross-sectional study using data from the 2005–2006 NHANES database. The NHANES program began in the early 1960s and was designed to assess the health and nutritional status of adults and children in the United States (US). The survey includes interviews, physical examinations, and blood draws. In 2005–2006, the NHANES performed additional examination and laboratory testing that included Humphrey matrix frequency doubling perimetry testing (N30-5 FDT), optic disc photographs, and serum IgE levels for a panel of common environmental allergens. The survey examines a nationally representative sample of about 10 000 persons per iteration and produces weighted estimates meant to be representative of the US population. Data accumulation was performed by the National Center for Health Statistics (NCHS) with approval from the NCHS Ethics Review Board (Protocol #2005-06). Data from NHANES are publicly available and anonymous, so this study received Institutional Review Board exemption from the University of California, Los Angeles.
Participants with optic disc photographs and FDT visual fields available in the 2005–2006 NHANES sample were included in the study. Participants with the following characteristics were excluded: (1) missing optic disc photographs or FDT visual fields; (2) age <40 years, because optic disc photographs and FDT visual fields were not collected for participants under age 40; and (3) documented alternative explanation for cup-to-disc ratio (CDR) findings (dysplastic disc or marked anisometropia) or for a visual field defect (retinal vascular disease, macular degeneration, or cerebrovascular disease). The presence of dysplastic disc, retinal vascular disease, and macular degeneration was assessed based on fundus photographs taken as part of the NHANES 2005–2006 study. The presence of anisometropia was assessed based on an objective refraction conducted as part of the NHANES 2005–2006 study. Cerebrovascular disease was based on self-report from the NHANES interview. Basic demographics that were analyzed included age and ethnicity, as both factors are known risk factors for glaucoma. Steroid use was also included as a covariate owing to its potential to be a confounder in the potential association between allergies and glaucoma. Steroid use was determined through the NHANES personal interview. Participants were asked during the household interview whether they had taken a prescription medication during the past month. Those who responded “yes” were asked to show containers of all their prescription medications to the interviewer. The interviewer entered the name of each prescription medication into a computer. For medications where no container was available, the interviewer asked the participant to verbally report the name of the medication. Steroid use was coded as a binary variable of steroid use vs no steroid use. Participants who reported use of any oral, ophthalmic, topical, inhaled, or injected steroids were counted as using steroids, and the remainder of participants were counted as not using steroids. Glaucoma medication use was not included as a covariate because it was presumed that only participants with glaucoma would be taking glaucoma medications, and that comparisons of glaucoma medication use in participants with vs without glaucoma would thus not be reliable.
The exposures of interest were total serum IgE levels and IgE levels specific to a panel of indoor allergens. Indoor allergens were chosen based on a nationally representative sample of household dust. Analysis of serum samples was conducted using the Pharmacia Diagnostics ImmunoCAP 1000 System. Total serum IgE was measured by the extent of its reaction to anti-IgE covalently coupled to the ImmunoCap reaction vessel, after washing, incubating with a developing agent, and comparison of the resulting eluate fluorescence with the response of calibrators. Allergen-specific IgE was measured by its reaction to specific allergens covalently bound to the reaction vessel. The IgE antibodies to specific indoor allergens that were tested included: Dermatophagoides farinae (American dust mite), Dermatophagoides pteronyssinus (European dust mite), cockroach, cat, dog, mouse, and rat. For participants where allergen-specific IgE measurements exceeded the total IgE value owing to cross-reactivity or conformationally equivalent epitopes of antigens for the allergens, total IgE measurements were coded as missing. For allergen-specific IgE levels, participants were considered negative if their serum IgE levels were <0.35 kilounits per liter (kU/L), while levels ≥0.35 kU/L were considered positive. For total IgE levels, values ≤119 kU/L were considered negative, while those >119 kU/L were considered positive. Cutoff values for allergen-specific and total IgE levels were based on the standard lower limit of detection for the laboratory assay used by NHANES. Quality control and quality assurance protocols met 1988 Clinical Laboratory Improvement Act mandates.
The primary outcome of interest was the prevalence of glaucoma as defined by the Rotterdam criteria, which defines open-angle glaucoma based on optic nerve appearance and visual field defects. Within NHANES, optic nerve appearance was assessed based on optic nerve photographs, and glaucomatous visual field defects were assessed by FDT visual fields. A clinical diagnosis of glaucoma was defined as having 2 or more abnormal points in at least 1 eye on the N30-5 FDT on 2 tests in the same eye, along with CDR in 1 eye or CDR asymmetry between eyes ≥97.5% of the normal NHANES population. The Rotterdam criteria were chosen to assess glaucoma because of the ability to produce an objective clinical definition of glaucoma with data available within NHANES based on these criteria, as reported by a recent study. Information on the incidence and subtype of glaucoma was not available in the 2005–2006 NHANES database.
The FDT examination was conducted in the dark by trained health technicians. A practice test was run prior to the actual test to determine whether the participant understood the procedure. The test always started with the right eye, followed by the left eye; and then the test was repeated for each eye. Nineteen visual field locations were tested and each location was tested until the participant responded. During each test, reliability checks were performed at random times, which included 3 false-positive tests and 3 blind spot tests. Participants were then classified as having normal, positive, insufficient, or unreliable FDT examinations; those with insufficient or unreliable examinations were excluded from the study population. The CDR was determined by using retinal images. The examination consisted of 2 45-degree nonmydriatic digital images of the retina taken by trained technicians. The first image was centered on the macula and the second on the optic nerve. Trained graders at the University of Wisconsin assessed vertical CDR in each eye using digital images that were evaluated as they initially appeared on the back of the digital camera. The images were reviewed by at least 2 of 9 trained graders. If the graders did not agree, a third grader reviewed the image. If there was a disagreement, an adjudicator made the final decision.
Sampling within NHANES occurs in 4 stages, starting with primary sampling units (PSUs) and followed by segments within PSUs (usually city blocks), households, and individuals. Based on this multistage probability sampling design, data are weighted and adjusted for nonresponse to produce weighted estimates meant to be representative of the US population. All data analyses in this study were based on weighted estimates using sample weights provided by NHANES.
Descriptive statistics were used to describe baseline characteristics for the study population. Age was analyzed as a continuous variable, and ethnicity and steroid use were analyzed as categorical variables. Total and allergen-specific IgE were analyzed as categorical variables, where participants with serum levels above the described cutoff values were considered positive and participants with serum levels below the cutoff values were considered negative. Glaucoma was assessed as a binary outcome based on the Rotterdam criteria.
Logistic regression modeling was used to examine the association between serum IgE levels and glaucoma. Separate unadjusted models were created for each allergen-specific IgE subtype as predictors of glaucoma. Partially adjusted models were then created including age, ethnicity, and steroid use as potential confounders for each IgE subtype and glaucoma. Because of the concern for cross-reactivity and epitope similarities, a final analysis was performed including all allergen-specific IgE subtypes, total IgE, and sensitization to any indoor allergen as predictors for glaucoma in the same model. All analyses were conducted with SAS version 9.3 (SAS, Cary, North Carolina, USA).
There were 83 308 318 subjects who met inclusion criteria in the weighted 2005–2006 NHANES sample and 1652 actual subjects who met inclusion criteria. The overall prevalence of glaucoma was 3.2% (n = 2 657 336; 95% confidence interval [CI] 2.8%, 3.6%) in the weighted sample and 5.1% (n = 84, 95% CI 4.0%, 6.1%) in the actual sample. In the weighted sample, the mean age was 57.5 years (standard error [SE] = 0.7 years) in the overall population and 62.2 years (SE = 1.3 years) in participants with glaucoma. In the actual sample, the mean age was 55.8 years (standard deviation [SD] = 11.7 years) in the overall population and 62.8 years (SD = 12.1 years) in participants with glaucoma. In the weighted sample, the majority of patients were non-Hispanic white in the overall population (n = 63 954 484; 76.7%), in participants with glaucoma (n = 1 404 960; 52.9%), and in participants without glaucoma (n = 62 549 524; 77.6%). In the actual sample, the majority of patients were non-Hispanic white in the overall population (n = 892; 53.2%) and in participants without glaucoma (n = 866; 54.3%), but the majority of participants with glaucoma were non-Hispanic black (n = 34; 40.5%). In the weighted sample, the American dust mite antigen had the highest proportion of participants with positive IgE values in the overall population (n = 12 093 038; 14.5%), in participants with glaucoma (n = 683 989; 25.7%), and in participants without glaucoma (n = 11 409 049; 14.1%). The same pattern was observed in the actual sample, with 15.8% of participants (n = 265) in the overall population with positive IgE values to the American dust mite antigen, 23.8% (n = 20) in participants with glaucoma, and 15.4% (n = 245) in participants without glaucoma. Additional descriptive statistics are outlined in Tables 1 and 2 .
|Characteristic||Total Number (%); N = 83 308 317||Number (%) With Glaucoma; N = 2 657 336||Number (%) Without Glaucoma; N = 80 650 982|
|Age||Mean = 57.5 (SE = 0.7)||Mean = 62.2 (SE = 1.3)||Mean = 53.4 (SE = 0.6)|
|Non-Hispanic white||63 954 484 (76.7)||1 404 960 (52.9)||62 549 524 (77.6)|
|Non-Hispanic black||8 131 513 (9.8)||644 521 (24.3)||7 486 992 (9.3)|
|Mexican American||4 612 275 (5.5)||208 338 (7.8)||4 403 937 (5.5)|
|Other Hispanic||2 416 147 (2.9)||110 661 (4.3)||2 305 486 (2.9)|
|Other||4 193 898 (5.0)||288 856 (10.9)||3 905 042 (4.8)|
|History of steroid use|
|Yes||5 243 910 (6.3)||61 378 (2.3)||5 182 533 (6.4)|
|No||78 064 407 (93.7)||2 595 958 (97.7)||75 468 449 (93.6)|
|Characteristic||Total Number (%); N = 1678||Number (%) With Glaucoma; N = 84||Number (%) Without Glaucoma; N = 1594|
|Age||Mean = 55.8 (SD = 11.7)||Mean = 62.8 (SD = 12.1)||Mean = 55.4 (SD = 11.6)|
|Non-Hispanic white||892 (53.2)||26 (31.0)||866 (54.3)|
|Non-Hispanic black||384 (22.9)||34 (40.5)||350 (22.0)|
|Mexican American||293 (17.5)||16 (19.1)||277 (17.4)|
|Other Hispanic||44 (2.6)||3 (3.6)||41 (2.6)|
|Other||65 (3.9)||5 (6.0)||60 (3.8)|
|History of steroid use|
|Yes||91 (5.4)||3 (3.6)||88 (5.5)|
|No||1587 (94.6)||81 (96.4)||1506 (94.5)|
|IgE Type||Total Number (%) With Positive Levels; N = 83 308 318||Number (%) With Glaucoma With Positive Levels; N = 2 657 336||Number (%) Without Glaucoma With Positive Levels; N = 80 650 982|
|Total IgE||17 796 528 (21.4)||749 780 (28.2)||17 046 748 (21.1)|
|D farinae||12 093 038 (14.5)||683 989 (25.7)||11 409 049 (14.1)|
|D pteronyssinus||11 816 519 (14.2)||633 007 (23.8)||11 183 512 (13.9)|
|Cockroach||7 435 150 (8.9)||518 540 (19.5)||6 916 609 (8.6)|
|Cat||9 149 283 (11.0)||445 774 (16.8)||8 703 509 (10.8)|
|Dog||8 057 392 (9.7)||149 454 (5.6)||7 907 938 (9.8)|
|Mouse||434 765 (0.5)||0 (0.0)||434 765 (0.5)|
|Rat||1 019 167 (1.2)||0 (0.0)||1 019 167 (1.3)|
|IgE Type||Mean kU/L of IgE (SE) in All Participants; N = 83 308 318||Mean kU/L of IgE (SE) in Participants With Glaucoma; N = 2 657 336||Mean kU/L of IgE (SE) in Participants Without Glaucoma; N = 80 650 982|
|Total IgE||128.7 (9.4)||163.1 (50.5)||127.6 (9.4)|
|D farinae||1.5 (0.2)||0.7 (0.2)||1.5 (0.2)|
|D pteronyssinus||1.6 (0.2)||0.7 (0.2)||1.7 (0.2)|
|Cockroach||0.5 (0.0)||0.7 (0.2)||0.5 (0.1)|
|Cat||0.9 (0.2)||1.5 (1.1)||0.9 (0.2)|
|Dog||0.5 (0.1)||0.4 (0.2)||0.5 (0.1)|
|Mouse||0.3 (0.0)||0.3 (0.0)||0.3 (0.0)|
|Rat||0.3 (0.0)||0.3 (0.0)||0.3 (0.0)|
|IgE Type||Total Number (%) With Positive Levels; N = 1678||Number (%) With Glaucoma With Positive Levels; N = 84||Number (%) Without Glaucoma With Positive Levels; N = 1594|
|Total IgE||429 (25.6)||25 (29.8)||404 (25.4)|
|D farinae||265 (15.8)||20 (23.8)||245 (15.4)|
|D pteronyssinus||255 (15.2)||18 (21.4)||237 (14.9)|
|Cockroach||173 (10.3)||16 (19.1)||157 (9.9)|
|Cat||172 (10.3)||12 (14.3)||160 (10.0)|
|Dog||151 (9.0)||5 (6.0)||146 (9.2)|
|Mouse||12 (0.7)||0 (0.0)||12 (0.8)|
|Rat||21 (1.3)||0 (0.0)||21 (1.3)|
|IgE Type||Mean kU/L of IgE (SD) in All Participants; N = 1678||Mean kU/L of IgE (SD) in Participants With Glaucoma; N = 84||Mean kU/L of IgE (SD) in Participants Without Glaucoma; N = 1594|
|Total IgE||158.9 (525.4)||153.9 (248.7)||159.2 (536.1)|
|D farinae||1.7 (11.9)||1.0 (4.3)||1.7 (12.1)|
|D pteronyssinus||1.7 (11.8)||0.9 (2.9)||1.8 (12.1)|
|Cockroach||0.6 (2.5)||0.7 (1.9)||0.6 (2.5)|
|Cat||0.9 (5.5)||1.0 (5.3)||0.9 (5.5)|
|Dog||0.5 (2.0)||0.4 (0.7)||0.5 (2.1)|
|Mouse||0.3 (1.0)||0.3 (0.0)||0.3 (1.0)|
|Rat||0.3 (0.9)||0.3 (0.0)||0.3 (0.9)|
In estimates based on the weighted sample, no statistically significant associations were noted between total IgE levels and glaucoma in the models both with and without all specific indoor allergen IgE covariates. In the individual models with each allergen-specific IgE subtype as a predictor excluding other IgE subtypes, there was a statistically significant association between IgE subtype and glaucoma for the cockroach (odds ratio [OR] = 3.01; 95% CI 1.37, 6.64), American dust mite (OR = 2.26; 95% CI 1.14, 4,47), and European dust mite (OR = 2.16; 95% CI 1.05, 4.42) antigens. In the model including all allergen-specific IgE subtypes as predictors, there were statistically significant associations between IgE subtypes and glaucoma for the cockroach (OR = 2.78; 95% CI 1.34, 5.76), cat (OR = 3.42; 95% CI 1.10, 10.67), and dog (OR = 0.24; 95% CI 0.06, 0.96) antigens. Similar trends were observed in estimates based on the actual sample; these estimates and additional results from logistic regression modeling can be found in Table 3 .
|Estimates Based on Weighted Frequencies|
|IgE Type||Unadjusted OR a||OR (95% CI) Adjusted for Age, Ethnicity, and Steroid Use a||OR (95% CI) Adjusted for Age, Ethnicity, Steroid Use, and Immune Cross-reactivity a|
|Total IgE||1.47 (0.72, 2.97)||1.24 (0.62, 2.50)||0.86 (0.44, 1.71)|
|D farinae||2.10 (1.13, 3.92)||2.26 (1.14, 4.47)||2.00 (0.71, 5.66)|
|D pteronyssinus||1.94 (0.99, 3.80)||2.16 (1.05, 4.42)||0.84 (0.28, 2.51)|
|Cockroach||2.59 (1.34, 5.00)||3.01 (1.37, 6.64)||2.78 (1.34, 5.76)|
|Cat||1.67 (0.75, 3.69)||2.23 (0.99, 5.03)||3.42 (1.10, 10.67)|
|Dog||0.55 (0.18, 1.66)||0.78 (0.25, 2.50)||0.24 (0.06, 0.96)|
|Mouse||— b||— b||— b|
|Rat||— b||— b||— b|