Letters / Ann Allergy Asthma Immunol 112 (2014) 175e183
Interestingly, little is known about the timing and triggers of ACEI angioedema. It may occur within days to years of the initiation of therapy and is sometimes known to occur in the setting of a surgical intervention or other stressors.2 Epidemiologically, ACEIinduced angioedema most commonly occurs in African American women between the ages of 32 and 92 years.7 In one series, ACEI angioedema accounted for 64% of all patients with angioedema presenting for acute care.2 The angioedema associated with ACEIs is widely believed to result from an excess of bradykinin, which some studies have suggested may interact with histamine.8,9 Despite this potential link to an allergic type response, no published data support an association of ACEI angioedema with seasonal variation and common allergy triggers. We sought to determine whether there is a seasonal variation in the incidence of ACEI and ARB angioedema and if a correlation exists with temperature, dew point, or pollen counts, hypothesizing from clinical observation that this may be so. We performed a retrospective medical record review using a single institution’s electronic health records to identify all cases of angioedema (International Classification of Diseases, Ninth Revision, code 995.1) from all emergency department patient visits from 2009 to 2011. Cases that had an ACEI or ARB recorded as an active patient medication were included for analysis. Patients with discharge diagnoses of angioedema who were not taking ACEIs or ARBs were excluded, and there were also no patients at our institution younger than 18 years. Daily mean temperature and dew point were obtained for the region from the National Oceanic and Atmospheric Administration website. Local pollen counts were obtained from the US Army Centralized Allergen Extract Lab, the local American Academy of Allergy, Asthma, and Immunologyecertified counting station. Data were analyzed using Poisson regression to evaluate for variation in seasonal incidence and multivariate logistic regression to evaluate for temperature and dew point correlation (Stata statistical software, version 12.1; StataCorp, College Station, Texas). A separate analysis was performed for pollen count correlations because counts are only recorded a mean of 3.8 days per week, yielding 605 observations in the 1,095-day study period. The study site is a 901-bed urban teaching hospital in Washington, DC, with an emergency department with approximately 90,000 patient encounters per year. The study was approved by the MedStar Washington Hospital Center Institutional Review Board. A total of 217 cases were included for analysis. Multivariate logistic regression of temperature and dew point revealed a nonstatistically significant model with (P ¼ .63) and individual odds ratios of 0.99 (P ¼ .64) and 1.00 (P ¼ .47), respectively. Poisson regression analysis for seasonal variation also produced a nonsignificant model with P values for spring, summer, and fall (winter was used for reference) of .07, .47, and .12, respectively.
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A separate multivariate logistic regression of temperature, dew point, and pollen counts restricted to the 605 days with pollen count observations also produced a nonstatistically significant model with a P ¼ .67. The above analyses were also repeated excluding cases where an ARB but not an ACEI was documented on the patient’s medication list (n ¼ 210), and the models were again not statistically significant, yielding P values for temperature, dew point, and pollen count of .21, .42, and .64, respectively. During a 3-year period at a single institution in the midAtlantic region, no seasonal variation was identified in cases of ACEI- and ARB-induced angioedema. Furthermore, no association was identified with mean daily temperature, dew point, or pollen counts for the region. Limitations to this study include a lack of information on patient’s baseline atopic status, the retrospective nature of the study, and the fact that the study was limited to a single institution. Acknowledgments Thanks to Susan E Kosisky, chief microbiologist at the US Army Centralized Allergen Extract Lab, for providing pollen count data for analysis. Matthew Wilson, MD William Frohna, MD Graham Trent, BS Diane Sauter, MD Washington Hospital Center Washington, DC [email protected] References [1] Cicardi M, Zingale LC, Bergamaschini L, Agostoni A. Angioedema associated with angiotensin-converting enzyme inhibitor use: outcome after switching to a different treatment. Arch Intern Med. 2004;164:910e913. [2] Malde B, Regalado J, Greenberger PA. Investigation of angioedema associated with the use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers. Ann Allergy Asthma Immunol. 2007;98:57e63. [3] Peltekis G, Palaskas D, Samanidou M, et al. Severe migratory angioedema due to ACE inhibitors use. Hippokratia. 2009;13:122e124. [4] Dandona P, Dhindsa S, Ghanim H, et al. Angiotensin II and inflammation: the effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade. J Hum Hypertens. 2007;21:20e27. [5] Bas M, Adams V, Suvorava T, et al. Nonallergic angioedema: role of bradykinin. Allergy. 2007;62:842e856. [6] Agostoni A, Cicardi M, Cugno LC, et al. Angioedema due to angiotensinconverting enzyme inhibitors. Immunopharmacology. 1999;44:21e25. [7] Seidman MD, Lewandowski CA, Sarpa JR, et al. Angioedema related to angiotensinconverting enzyme inhibitors. Otolaryngol Head Neck Surg. 1990;102:727e731. [8] Austin CE, Dear JW, Neighbour H, et al. The contribution of histamine to the action of bradykinin in the human nasal airway. Immunopharmacology. 1996; 34:181e189. [9] Ishizaka T, Iwata M, Ishizaka K. Release of histamine and arachidonate from mouse mast cells induced by glycosylation-enhancing factor and bradykinin. J Immumol. 1985;134:1880e1887.
Urinary triclosan levels and recent asthma exacerbations Triclosan is a broad-spectrum antimicrobial chemical with endocrine and immune effects.1,2 The primary source of exposure is considered personal care products (eg, toothpaste and hand soap), but multiple potential sources and routes of exposure exist.2 Because the airway microbiome may be important in the development or maintenance of asthma,3,4 we hypothesized that levels Disclosures: Authors have nothing to disclose. Funding: This work was supported by a grant from the American Academy of Allergy, Asthma and Immunology and Food Allergy Research and Education (Dr Savage).
of the antimicrobial chemical triclosan may be associated with asthma prevalence and control. We previously demonstrated in a cross-sectional study a significantly increased risk of aeroallergen and food sensitization with increasing urinary triclosan levels in US children. Triclosan levels were positively associated with the risk of atopic asthma, although the association did not reach statistical significance.5 A cross-sectional Norwegian study also found that triclosan was associated with aeroallergen sensitization and rhinitis but not with asthma.6 In a mouse model of asthma, triclosan increased bronchial hyperresponsiveness, total IgE, pulmonary eosinophilia, and interleukin 13.1 Given these
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Letters / Ann Allergy Asthma Immunol 112 (2014) 175e183
inconsistent findings in humans and the effects of triclosan on respiratory disease in a mouse model, we combined National Health and Nutrition Examination survey (NHANES) data for a 6-year period to increase our power to detect an association between triclosan and asthma prevalence and control. Data were obtained from the 2005-2006, 2007-2008, and 20092010 National Health and Nutrition Examination Survey.7 Sociodemographic data, medical condition and smoking questionnaire responses, anthropometry, pulmonary function test results, and urinary triclosan levels were used. Asthma prevalence was determined from the question, “Has a doctor or health professional ever told you that you have asthma?” Participants who answered affirmatively were asked, “Do you still have asthma?” Participants who responded yes to this question were asked, “During the past 12 months have you had an episode of asthma or an asthma attack?” which we used as a measure of asthma control. In a randomly selected one-third subsample of participants 6 years and older, urinary triclosan was measured by solid-phase extraction coupled online to high-performance liquid chromatography and tandem mass spectrometry (see eMethods and eResults for additional details). All participants underwent spirometry in 2007-2010, unless medically contraindicated. Those 12 years and older answered questions regarding smoking history. Statistical analyses were performed with Stata statistical software, version 12.0 (StataCorp, College Station, Texas). In all analyses, the primary sampling units, strata, and weights were used to account for the survey design and nonresponse and generate estimates that are representative of the US noninstitutionalized civilian population. Missing data were considered to be missing at random. Triclosan had a nonnormal distribution, and triclosan levels were divided into tertiles as performed previously.5 The c2 test was used to determine whether there were differences in characteristics between participants who varied according to asthma prevalence and control. Linear regression was used to determine whether urinary triclosan levels varied by asthma prevalence and control. Multivariable logistic regression was used to determine the association between urinary triclosan level and asthma prevalence and asthma control. Predicted probabilities for reporting an asthma attack in the last year were derived from a logistic regression model by using logtransformed values of urinary triclosan as a continuous variable. A total of 31,034 individuals participated in the 3 surveys included in this analysis. A total of 7,303 had complete data for the analysis of urinary triclosan and asthma prevalence, and 639 had complete data for the analysis of urinary triclosan and asthma control. Demographic characteristics of the study participants are given in eTable 1. Log-transformed urinary triclosan levels were higher in individuals with asthma reporting an asthma attack within the last year compared with individuals with asthma not reporting an asthma attack in the last year (1.25 vs 1.05 ng/mL; P < .03). After adjusting for age, sex, race, and height, individuals with asthma had significantly lower lung function parameters compared with those who did not (see eMethods and eResults). In a multivariate model that adjusted for urinary creatinine level, age, race, sex, and poverty-index ratio, urinary triclosan was not associated with asthma prevalence (adjusted odds ratio [OR] for asthma in the third tertile of triclosan compared with the first tertile, 1.14; 95% confidence interval [CI], 0.89e1.46). Among individuals who reported a diagnosis of current asthma, triclosan was positively associated with reporting an asthma attack in the last year (adjusted OR for asthma attack in the third tertile of urinary triclosan, 1.79; 95% CI, 1.01e3.15; and adjusted OR for asthma attack in the second tertile of urinary triclosan, 1.89, 95% CI, 1.15e3.13; P for trend ¼ .05; Fig 1). In a sensitivity analysis of a subset of 372 adults who had additional data, similar point estimates for the association between urinary triclosan and recent asthma attack were identified after adjusting for smoking status and body mass
Figure 1. Predicted probability of reporting an asthma attack within the last year (with 95% confidence intervals) by urinary triclosan level. Horizontal bar inset indicates triclosan levels within each tertile of urinary triclosan.
index, as well as covariates mentioned above (see eMethods and eResults for details). In this large, nationally representative sample, we found that the likelihood of reporting an asthma attack increased with increasing urinary triclosan levels among individuals reporting current asthma. To our knowledge, this is the first epidemiologic report of an association between urinary triclosan levels and asthma control. This finding was consistent with the findings of Anderson et al,1 which demonstrated that triclosan can augment bronchial hyperresponsiveness in a mouse model of asthma. We had previously hypothesized that triclosan was associated with allergic disease because of its antimicrobial effects, potentially altering the human microbiome and subsequent immune development and function. Triclosan may modify the airway microbiome, rendering the airway epithelium more susceptible to pathogens or other environmental perturbations. This should be evaluated in future studies. Because of the cross-sectional design of our study, several limitations exist. Triclosan has a short half-life (0.4), suggesting frequent exposures despite a short half-life.9 Further, we expect this potential bias to be nondifferential with respect to the outcome and therefore would attenuate, not magnify, associations. In addition, patients with poorly controlled asthma may be more likely to use triclosan-containing hand soap or wash their hands more frequently than those with more controlled asthma, and we were unable to control for this with our observational study design. Confounding caused by topical use of triclosancontaining products is unlikely to solely underlie our findings, however, because only a small amount of triclosan is absorbed cutaneously (5%e6%) compared with orally (>80%; eg, from toothpaste).8,10 Overall, our findings are intriguing because there are consistent murine observations and they suggest a potential role for commonly used antimicrobial chemicals in asthma control. We did not identify an association between triclosan and asthma prevalence in the general population. This may have been limited by our ability to stratify results by atopic disease status because specific IgE data are not available in all NHANES survey years studied. In our previous study, which was limited to the 2005-2006 NHANES survey, which included specific IgE measurements, there was a positive but nonsignificant association between triclosan levels and atopic asthma defined by a history of physician-diagnosed asthma and detectible aeroallergen specific IgE.5
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In summary, in this large, nationally representative sample of more than 600 asthmatic patients, we found that triclosan exposure was associated with a more than 70% increased risk of reporting an asthma exacerbation in the last year. Exposure to triclosan may directly lead to asthma exacerbations, or elevated triclosan levels may be a marker for poor asthma control. Future prospective studies are needed to determine whether triclosan exposure has a role in the development and maintenance of allergy and allergic respiratory disease. Supplementary Data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.anai.2013.11.017. Jessica H. Savage, MD, MHS*,y Christina B. Johns, BA* Russ Hauser, MD, ScD, MPHz Augusto A. Litonjua, MD, MPHy,x,{ *Division of Rheumatology, Immunology, and Allergy Brigham and Women’s Hospital Boston, Massachusetts y Harvard Medical School Boston, Massachusetts z Harvard School of Public Health Boston, Massachusetts x Channing Division of Network Medicine Brigham and Women’s Hospital Boston, Massachusetts
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{
Division of Pulmonary and Critical Care Medicine Brigham and Women’s Hospital Boston, Massachusetts [email protected]
References [1] Anderson SE, Franko J, Kashon ML, et al. Exposure to triclosan augments the allergic response to ovalbumin in a mouse model of asthma. Toxicol Sci. 2013; 132:96e106. [2] Dann AB, Hontela A. Triclosan: environmental exposure, toxicity and mechanisms of action. J Appl Toxicol. 2011;31:285e311. [3] Goleva E, Jackson LP, Harris JK, et al. The effects of airway microbiome on corticosteroid responsiveness in asthma. Am J Respir Crit Care Med. 2013;188: 1193e1201. [4] Marri PR, Stern DA, Wright AL, Billheimer D, Martinez FD. Asthma-associated differences in microbial composition of induced sputum. J Allergy Clin Immunol. 2013;131:346e352. [5] Savage JH, Matsui EC, Wood RA, Keet CA. Urinary levels of triclosan and parabens are associated with aeroallergen and food sensitization. J Allergy Clin Immunol. 2012;130:453e460e7. [6] Bertelsen RJ, Longnecker MP, Lovik M, et al. Triclosan exposure and allergic sensitization in Norwegian children. Allergy. 2013;68:84e91. [7] Centers for Disease Control and Prevention. National Health and Nutrition Examination Survey data. www.cdc.gov/nchs/about/major/nhanes/nhanes20056/nhanes05_06.htm. Accessed June 3, 2013. [8] Sandborgh-Englund G, Adolfsson-Erici M, Odham G, Ekstrand J. Pharmacokinetics of triclosan following oral ingestion in humans. J Toxicol Environ Health A. 2006;69:1861e1873. [9] Teitelbaum SL, Britton JA, Calafat AM, et al. Temporal variability in urinary concentrations of phthalate metabolites, phytoestrogens and phenols among minority children in the United States. Environ Res. 2008;106:257e269. [10] Queckenberg C, Meins J, Wachall B, et al. Absorption, pharmacokinetics, and safety of triclosan after dermal administration. Antimicrob Agents Chemother. 2010;54:570e572.
Test-retest reliability of the International Study of Asthma and Allergies in Childhood questionnaire for a web-based survey Epidemiologic surveys are essential for providing fundamental insight into allergic diseases. However, in epidemiologic studies that use traditional approaches, such as paper questionnaires and interviews, the response rates have decreased in the past decades. This issue was even raised by the International Study of Asthma and Allergies in Childhood (ISAAC).1 The median response rates of active consents in the 6- to 7-year age group decreased from 84% in phase 1 to 78% in phase 3, which was conducted 7 years after phase 1.2 Another approach to data collection using the Internet is increasing in academic research.3 However, web-based surveys accounted for only 1% of epidemiologic articles in the 7 high-impact general medical and epidemiologic journals from 2008 to 2009.3 One of the reasons for this finding might be that there are few studies that investigate the reliability of the data collected via the Internet. Thus, this study aims to evaluate the reliability of the webbased ISAAC questionnaire. This study was conducted using the Macromill online research system (Macromill Inc, Tokyo, Japan), which maintains one of the largest research panels in Japan. Among the 2,598 monitors who resided in the Kyushu region and had children aged 6 to 12 years based on their background data, we randomly selected 958 parents to participate in the survey in September 2011 (time 1 survey). If a parent had 2 or more children aged 6 to 12 years, they were asked to complete the questionnaire for each child, and 1,254 children were recruited. For the test-retest study, we randomly selected 200 Disclosures: Authors have nothing to disclose. Funding: This study was supported by a grant from the Environmental Restoration and Conservation Agency, Japan.
children from the children who participated in the time 1 survey and asked their parents to complete the same questionnaire in October 2011 (retest survey). We used the web-based ISAAC questionnaire based on the Japanese version of the written questionnaire. It was a multiplepage design and automatically skipped questions that were irrelevant to the respondent. We estimated the prevalence of allergic symptoms based on the responses to the ISAAC core questions.1 Demographic differences among the study participants were compared using the c2 test or the Mann-Whitney test. P < .05 was considered statistically significant. Reliability was assessed using the proportion of agreement and the k coefficient. All analyses were performed using SPSS statistical software, version 19 (IBM, Armonk, New York). The study protocol was approved by the independent review board of the Tokyo Metropolitan Children’s Medical Center. A total of 184 study participants (93 boys and 91 girls; mean [SD] age, 8.8 [1.8] years) were analyzed for the assessment of test-retest reliability. The respondent characteristics between the time 1 survey and the retest survey were not significantly different. Life-long prevalence of allergic symptoms, especially skin symptoms, tended to be higher than the current prevalence (Table 1). The proportion of agreement for the questions on asthma and nose and/or eye symptoms was more than 90%, whereas that for the questions on eczema was less than 90%. The questions on current symptoms had k coefficients between 0.55 and 0.64. Of interest was that the k coefficients for the question on current eczema was lower than that for the question on eczema ever, which was opposite of those for respiratory symptoms. This study found that the web-based ISAAC questionnaire was reliable for the epidemiologic survey. Population-based studies using
Letters / Ann Allergy Asthma Immunol 112 (2014) 175e183
eMethods
181.e1
calculated as weight in kilograms divided by the square of height in meters.
Triclosan Assay The detection limit in 100 mL of urine was 2.3 ng/mL.1 For values less than the limit of detection, a value of the detection limit divided by the square root of 2 was used. Pulmonary Function Testing Spirometry was performed in the 2007-2008 and 2009-2010 National Health and Nutrition Examination Survey.1 Individuals 6 to 79 years old were eligible for the spirometry portion of the examination. Individuals were excluded if they reported current chest pain or a physical problem with forceful expiration; taking supplemental oxygen, recent surgery of the eye, chest, or the abdomen; or a recent myocardial infarction, stroke, tuberculosis exposure, or coughing up blood. Adults with a personal history of detached retina or a collapsed lung and children with painful ear infections were also excluded. Testing procedures followed guidelines of the American Thoracic Society (ATS).2 Spirometers were Ohio 822/827 dry-rolling seal volume spirometers, reconditioned for use in the current survey. The overall goal was for the participant to achieve 3 acceptable exhalation maneuvers by ATS criteria in which the 2 highest values for the forced vital capacity (FVC) and the forced expiratory volume in 1 second (FEV1) (each taken from an acceptable forced expiratory maneuver) revealed minimal variability (ie, the 2 largest FVC values taken from 2 acceptable curves should agree within 150 mL and similarly for the 2 largest values for the FEV1).
Statistical Analysis Linear regression was used to compare lung function parameters (FEV1, FVC, and FEV1/FVC ratio) between participants who did and did not report a history of asthma and between participants with asthma who did and did not report a history of an asthma attack in the last year. Covariates included in the model were race, age, height squared, and sex. In a sensitivity analysis, logistic regression was used to determine the association between urinary triclosan levels and recent asthma attacks, adjusting for age, race, sex, urinary creatinine, poverty index ratio, BMI, and smoking status. Fewer participants had complete data for this analysis in part because smoking status was only collected in those 12 years and older and in part because of missing smoking data even for those older than 12 years. Because of the small sample size, this analysis was performed without using survey weights, strata, and sampling units. eResults Pulmonary Function of the Study Participants
Participants 12 years and older provided a smoking history. Participants were categorized as never, former, and current smokers. Former smokers reported smoking more than 100 cigarettes in their lifetime but no current use, whereas current smokers reported current use. Never smokers denied smoking more than 100 cigarettes in their lifetime.
Compared with participants not reporting a history of asthma, those reporting a history of asthma had a significantly lower FEV1 (132 mL; 95% confidence interval [CI], 183 to 80 mL), FVC (74 mL; 95% CI, 136 to 11 mL), and FEV1/FVC ratio (0.024; 95% CI, 0.029 to 0.019) in models adjusted for age, height squared, sex, and race (n ¼ 4,503). Compared with participants reporting a history of asthma and no exacerbation within the last year, those with asthma reporting a recent exacerbation had similar FEV1 (mean difference, 99 mL; 95% CI, 47 to 246 mL), FVC (mean difference, 97 mL; 95% CI, 73 to 268 mL), and FEV1/FVC ratio (mean difference, 0.006; 95% CI, 0.11 to 0.23) in adjusted models (n ¼ 467).
Body Measurements
Sensitivity Analysis of Triclosan Levels and Recent Asthma Attacks
Height and weight were obtained on all study participants by trained health technicians. Body mass index (BMI) was
After adjusting for age, race, sex, poverty index ratio, urinary creatinine, smoking status, and BMI, among participants reporting
Smoking History
eTable 1 Sociodemographic characteristics of NHANES participants with urinary triclosan levels and information on asthma historya Characteristic
Sex Male Female Age, y 6e18 19 Ethnicity White African American Hispanic Other Poverty Index Ratio
Interestingly, little is known about the timing and triggers of ACEI angioedema. It may occur within days to years of the initiation of therapy and is sometimes known to occur in the setting of a surgical intervention or other stressors.2 Epidemiologically, ACEIinduced angioedema most commonly occurs in African American women between the ages of 32 and 92 years.7 In one series, ACEI angioedema accounted for 64% of all patients with angioedema presenting for acute care.2 The angioedema associated with ACEIs is widely believed to result from an excess of bradykinin, which some studies have suggested may interact with histamine.8,9 Despite this potential link to an allergic type response, no published data support an association of ACEI angioedema with seasonal variation and common allergy triggers. We sought to determine whether there is a seasonal variation in the incidence of ACEI and ARB angioedema and if a correlation exists with temperature, dew point, or pollen counts, hypothesizing from clinical observation that this may be so. We performed a retrospective medical record review using a single institution’s electronic health records to identify all cases of angioedema (International Classification of Diseases, Ninth Revision, code 995.1) from all emergency department patient visits from 2009 to 2011. Cases that had an ACEI or ARB recorded as an active patient medication were included for analysis. Patients with discharge diagnoses of angioedema who were not taking ACEIs or ARBs were excluded, and there were also no patients at our institution younger than 18 years. Daily mean temperature and dew point were obtained for the region from the National Oceanic and Atmospheric Administration website. Local pollen counts were obtained from the US Army Centralized Allergen Extract Lab, the local American Academy of Allergy, Asthma, and Immunologyecertified counting station. Data were analyzed using Poisson regression to evaluate for variation in seasonal incidence and multivariate logistic regression to evaluate for temperature and dew point correlation (Stata statistical software, version 12.1; StataCorp, College Station, Texas). A separate analysis was performed for pollen count correlations because counts are only recorded a mean of 3.8 days per week, yielding 605 observations in the 1,095-day study period. The study site is a 901-bed urban teaching hospital in Washington, DC, with an emergency department with approximately 90,000 patient encounters per year. The study was approved by the MedStar Washington Hospital Center Institutional Review Board. A total of 217 cases were included for analysis. Multivariate logistic regression of temperature and dew point revealed a nonstatistically significant model with (P ¼ .63) and individual odds ratios of 0.99 (P ¼ .64) and 1.00 (P ¼ .47), respectively. Poisson regression analysis for seasonal variation also produced a nonsignificant model with P values for spring, summer, and fall (winter was used for reference) of .07, .47, and .12, respectively.
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A separate multivariate logistic regression of temperature, dew point, and pollen counts restricted to the 605 days with pollen count observations also produced a nonstatistically significant model with a P ¼ .67. The above analyses were also repeated excluding cases where an ARB but not an ACEI was documented on the patient’s medication list (n ¼ 210), and the models were again not statistically significant, yielding P values for temperature, dew point, and pollen count of .21, .42, and .64, respectively. During a 3-year period at a single institution in the midAtlantic region, no seasonal variation was identified in cases of ACEI- and ARB-induced angioedema. Furthermore, no association was identified with mean daily temperature, dew point, or pollen counts for the region. Limitations to this study include a lack of information on patient’s baseline atopic status, the retrospective nature of the study, and the fact that the study was limited to a single institution. Acknowledgments Thanks to Susan E Kosisky, chief microbiologist at the US Army Centralized Allergen Extract Lab, for providing pollen count data for analysis. Matthew Wilson, MD William Frohna, MD Graham Trent, BS Diane Sauter, MD Washington Hospital Center Washington, DC [email protected] References [1] Cicardi M, Zingale LC, Bergamaschini L, Agostoni A. Angioedema associated with angiotensin-converting enzyme inhibitor use: outcome after switching to a different treatment. Arch Intern Med. 2004;164:910e913. [2] Malde B, Regalado J, Greenberger PA. Investigation of angioedema associated with the use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers. Ann Allergy Asthma Immunol. 2007;98:57e63. [3] Peltekis G, Palaskas D, Samanidou M, et al. Severe migratory angioedema due to ACE inhibitors use. Hippokratia. 2009;13:122e124. [4] Dandona P, Dhindsa S, Ghanim H, et al. Angiotensin II and inflammation: the effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade. J Hum Hypertens. 2007;21:20e27. [5] Bas M, Adams V, Suvorava T, et al. Nonallergic angioedema: role of bradykinin. Allergy. 2007;62:842e856. [6] Agostoni A, Cicardi M, Cugno LC, et al. Angioedema due to angiotensinconverting enzyme inhibitors. Immunopharmacology. 1999;44:21e25. [7] Seidman MD, Lewandowski CA, Sarpa JR, et al. Angioedema related to angiotensinconverting enzyme inhibitors. Otolaryngol Head Neck Surg. 1990;102:727e731. [8] Austin CE, Dear JW, Neighbour H, et al. The contribution of histamine to the action of bradykinin in the human nasal airway. Immunopharmacology. 1996; 34:181e189. [9] Ishizaka T, Iwata M, Ishizaka K. Release of histamine and arachidonate from mouse mast cells induced by glycosylation-enhancing factor and bradykinin. J Immumol. 1985;134:1880e1887.
Urinary triclosan levels and recent asthma exacerbations Triclosan is a broad-spectrum antimicrobial chemical with endocrine and immune effects.1,2 The primary source of exposure is considered personal care products (eg, toothpaste and hand soap), but multiple potential sources and routes of exposure exist.2 Because the airway microbiome may be important in the development or maintenance of asthma,3,4 we hypothesized that levels Disclosures: Authors have nothing to disclose. Funding: This work was supported by a grant from the American Academy of Allergy, Asthma and Immunology and Food Allergy Research and Education (Dr Savage).
of the antimicrobial chemical triclosan may be associated with asthma prevalence and control. We previously demonstrated in a cross-sectional study a significantly increased risk of aeroallergen and food sensitization with increasing urinary triclosan levels in US children. Triclosan levels were positively associated with the risk of atopic asthma, although the association did not reach statistical significance.5 A cross-sectional Norwegian study also found that triclosan was associated with aeroallergen sensitization and rhinitis but not with asthma.6 In a mouse model of asthma, triclosan increased bronchial hyperresponsiveness, total IgE, pulmonary eosinophilia, and interleukin 13.1 Given these
180
Letters / Ann Allergy Asthma Immunol 112 (2014) 175e183
inconsistent findings in humans and the effects of triclosan on respiratory disease in a mouse model, we combined National Health and Nutrition Examination survey (NHANES) data for a 6-year period to increase our power to detect an association between triclosan and asthma prevalence and control. Data were obtained from the 2005-2006, 2007-2008, and 20092010 National Health and Nutrition Examination Survey.7 Sociodemographic data, medical condition and smoking questionnaire responses, anthropometry, pulmonary function test results, and urinary triclosan levels were used. Asthma prevalence was determined from the question, “Has a doctor or health professional ever told you that you have asthma?” Participants who answered affirmatively were asked, “Do you still have asthma?” Participants who responded yes to this question were asked, “During the past 12 months have you had an episode of asthma or an asthma attack?” which we used as a measure of asthma control. In a randomly selected one-third subsample of participants 6 years and older, urinary triclosan was measured by solid-phase extraction coupled online to high-performance liquid chromatography and tandem mass spectrometry (see eMethods and eResults for additional details). All participants underwent spirometry in 2007-2010, unless medically contraindicated. Those 12 years and older answered questions regarding smoking history. Statistical analyses were performed with Stata statistical software, version 12.0 (StataCorp, College Station, Texas). In all analyses, the primary sampling units, strata, and weights were used to account for the survey design and nonresponse and generate estimates that are representative of the US noninstitutionalized civilian population. Missing data were considered to be missing at random. Triclosan had a nonnormal distribution, and triclosan levels were divided into tertiles as performed previously.5 The c2 test was used to determine whether there were differences in characteristics between participants who varied according to asthma prevalence and control. Linear regression was used to determine whether urinary triclosan levels varied by asthma prevalence and control. Multivariable logistic regression was used to determine the association between urinary triclosan level and asthma prevalence and asthma control. Predicted probabilities for reporting an asthma attack in the last year were derived from a logistic regression model by using logtransformed values of urinary triclosan as a continuous variable. A total of 31,034 individuals participated in the 3 surveys included in this analysis. A total of 7,303 had complete data for the analysis of urinary triclosan and asthma prevalence, and 639 had complete data for the analysis of urinary triclosan and asthma control. Demographic characteristics of the study participants are given in eTable 1. Log-transformed urinary triclosan levels were higher in individuals with asthma reporting an asthma attack within the last year compared with individuals with asthma not reporting an asthma attack in the last year (1.25 vs 1.05 ng/mL; P < .03). After adjusting for age, sex, race, and height, individuals with asthma had significantly lower lung function parameters compared with those who did not (see eMethods and eResults). In a multivariate model that adjusted for urinary creatinine level, age, race, sex, and poverty-index ratio, urinary triclosan was not associated with asthma prevalence (adjusted odds ratio [OR] for asthma in the third tertile of triclosan compared with the first tertile, 1.14; 95% confidence interval [CI], 0.89e1.46). Among individuals who reported a diagnosis of current asthma, triclosan was positively associated with reporting an asthma attack in the last year (adjusted OR for asthma attack in the third tertile of urinary triclosan, 1.79; 95% CI, 1.01e3.15; and adjusted OR for asthma attack in the second tertile of urinary triclosan, 1.89, 95% CI, 1.15e3.13; P for trend ¼ .05; Fig 1). In a sensitivity analysis of a subset of 372 adults who had additional data, similar point estimates for the association between urinary triclosan and recent asthma attack were identified after adjusting for smoking status and body mass
Figure 1. Predicted probability of reporting an asthma attack within the last year (with 95% confidence intervals) by urinary triclosan level. Horizontal bar inset indicates triclosan levels within each tertile of urinary triclosan.
index, as well as covariates mentioned above (see eMethods and eResults for details). In this large, nationally representative sample, we found that the likelihood of reporting an asthma attack increased with increasing urinary triclosan levels among individuals reporting current asthma. To our knowledge, this is the first epidemiologic report of an association between urinary triclosan levels and asthma control. This finding was consistent with the findings of Anderson et al,1 which demonstrated that triclosan can augment bronchial hyperresponsiveness in a mouse model of asthma. We had previously hypothesized that triclosan was associated with allergic disease because of its antimicrobial effects, potentially altering the human microbiome and subsequent immune development and function. Triclosan may modify the airway microbiome, rendering the airway epithelium more susceptible to pathogens or other environmental perturbations. This should be evaluated in future studies. Because of the cross-sectional design of our study, several limitations exist. Triclosan has a short half-life (0.4), suggesting frequent exposures despite a short half-life.9 Further, we expect this potential bias to be nondifferential with respect to the outcome and therefore would attenuate, not magnify, associations. In addition, patients with poorly controlled asthma may be more likely to use triclosan-containing hand soap or wash their hands more frequently than those with more controlled asthma, and we were unable to control for this with our observational study design. Confounding caused by topical use of triclosancontaining products is unlikely to solely underlie our findings, however, because only a small amount of triclosan is absorbed cutaneously (5%e6%) compared with orally (>80%; eg, from toothpaste).8,10 Overall, our findings are intriguing because there are consistent murine observations and they suggest a potential role for commonly used antimicrobial chemicals in asthma control. We did not identify an association between triclosan and asthma prevalence in the general population. This may have been limited by our ability to stratify results by atopic disease status because specific IgE data are not available in all NHANES survey years studied. In our previous study, which was limited to the 2005-2006 NHANES survey, which included specific IgE measurements, there was a positive but nonsignificant association between triclosan levels and atopic asthma defined by a history of physician-diagnosed asthma and detectible aeroallergen specific IgE.5
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In summary, in this large, nationally representative sample of more than 600 asthmatic patients, we found that triclosan exposure was associated with a more than 70% increased risk of reporting an asthma exacerbation in the last year. Exposure to triclosan may directly lead to asthma exacerbations, or elevated triclosan levels may be a marker for poor asthma control. Future prospective studies are needed to determine whether triclosan exposure has a role in the development and maintenance of allergy and allergic respiratory disease. Supplementary Data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.anai.2013.11.017. Jessica H. Savage, MD, MHS*,y Christina B. Johns, BA* Russ Hauser, MD, ScD, MPHz Augusto A. Litonjua, MD, MPHy,x,{ *Division of Rheumatology, Immunology, and Allergy Brigham and Women’s Hospital Boston, Massachusetts y Harvard Medical School Boston, Massachusetts z Harvard School of Public Health Boston, Massachusetts x Channing Division of Network Medicine Brigham and Women’s Hospital Boston, Massachusetts
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Division of Pulmonary and Critical Care Medicine Brigham and Women’s Hospital Boston, Massachusetts [email protected]
References [1] Anderson SE, Franko J, Kashon ML, et al. Exposure to triclosan augments the allergic response to ovalbumin in a mouse model of asthma. Toxicol Sci. 2013; 132:96e106. [2] Dann AB, Hontela A. Triclosan: environmental exposure, toxicity and mechanisms of action. J Appl Toxicol. 2011;31:285e311. [3] Goleva E, Jackson LP, Harris JK, et al. The effects of airway microbiome on corticosteroid responsiveness in asthma. Am J Respir Crit Care Med. 2013;188: 1193e1201. [4] Marri PR, Stern DA, Wright AL, Billheimer D, Martinez FD. Asthma-associated differences in microbial composition of induced sputum. J Allergy Clin Immunol. 2013;131:346e352. [5] Savage JH, Matsui EC, Wood RA, Keet CA. Urinary levels of triclosan and parabens are associated with aeroallergen and food sensitization. J Allergy Clin Immunol. 2012;130:453e460e7. [6] Bertelsen RJ, Longnecker MP, Lovik M, et al. Triclosan exposure and allergic sensitization in Norwegian children. Allergy. 2013;68:84e91. [7] Centers for Disease Control and Prevention. National Health and Nutrition Examination Survey data. www.cdc.gov/nchs/about/major/nhanes/nhanes20056/nhanes05_06.htm. Accessed June 3, 2013. [8] Sandborgh-Englund G, Adolfsson-Erici M, Odham G, Ekstrand J. Pharmacokinetics of triclosan following oral ingestion in humans. J Toxicol Environ Health A. 2006;69:1861e1873. [9] Teitelbaum SL, Britton JA, Calafat AM, et al. Temporal variability in urinary concentrations of phthalate metabolites, phytoestrogens and phenols among minority children in the United States. Environ Res. 2008;106:257e269. [10] Queckenberg C, Meins J, Wachall B, et al. Absorption, pharmacokinetics, and safety of triclosan after dermal administration. Antimicrob Agents Chemother. 2010;54:570e572.
Test-retest reliability of the International Study of Asthma and Allergies in Childhood questionnaire for a web-based survey Epidemiologic surveys are essential for providing fundamental insight into allergic diseases. However, in epidemiologic studies that use traditional approaches, such as paper questionnaires and interviews, the response rates have decreased in the past decades. This issue was even raised by the International Study of Asthma and Allergies in Childhood (ISAAC).1 The median response rates of active consents in the 6- to 7-year age group decreased from 84% in phase 1 to 78% in phase 3, which was conducted 7 years after phase 1.2 Another approach to data collection using the Internet is increasing in academic research.3 However, web-based surveys accounted for only 1% of epidemiologic articles in the 7 high-impact general medical and epidemiologic journals from 2008 to 2009.3 One of the reasons for this finding might be that there are few studies that investigate the reliability of the data collected via the Internet. Thus, this study aims to evaluate the reliability of the webbased ISAAC questionnaire. This study was conducted using the Macromill online research system (Macromill Inc, Tokyo, Japan), which maintains one of the largest research panels in Japan. Among the 2,598 monitors who resided in the Kyushu region and had children aged 6 to 12 years based on their background data, we randomly selected 958 parents to participate in the survey in September 2011 (time 1 survey). If a parent had 2 or more children aged 6 to 12 years, they were asked to complete the questionnaire for each child, and 1,254 children were recruited. For the test-retest study, we randomly selected 200 Disclosures: Authors have nothing to disclose. Funding: This study was supported by a grant from the Environmental Restoration and Conservation Agency, Japan.
children from the children who participated in the time 1 survey and asked their parents to complete the same questionnaire in October 2011 (retest survey). We used the web-based ISAAC questionnaire based on the Japanese version of the written questionnaire. It was a multiplepage design and automatically skipped questions that were irrelevant to the respondent. We estimated the prevalence of allergic symptoms based on the responses to the ISAAC core questions.1 Demographic differences among the study participants were compared using the c2 test or the Mann-Whitney test. P < .05 was considered statistically significant. Reliability was assessed using the proportion of agreement and the k coefficient. All analyses were performed using SPSS statistical software, version 19 (IBM, Armonk, New York). The study protocol was approved by the independent review board of the Tokyo Metropolitan Children’s Medical Center. A total of 184 study participants (93 boys and 91 girls; mean [SD] age, 8.8 [1.8] years) were analyzed for the assessment of test-retest reliability. The respondent characteristics between the time 1 survey and the retest survey were not significantly different. Life-long prevalence of allergic symptoms, especially skin symptoms, tended to be higher than the current prevalence (Table 1). The proportion of agreement for the questions on asthma and nose and/or eye symptoms was more than 90%, whereas that for the questions on eczema was less than 90%. The questions on current symptoms had k coefficients between 0.55 and 0.64. Of interest was that the k coefficients for the question on current eczema was lower than that for the question on eczema ever, which was opposite of those for respiratory symptoms. This study found that the web-based ISAAC questionnaire was reliable for the epidemiologic survey. Population-based studies using
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eMethods
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calculated as weight in kilograms divided by the square of height in meters.
Triclosan Assay The detection limit in 100 mL of urine was 2.3 ng/mL.1 For values less than the limit of detection, a value of the detection limit divided by the square root of 2 was used. Pulmonary Function Testing Spirometry was performed in the 2007-2008 and 2009-2010 National Health and Nutrition Examination Survey.1 Individuals 6 to 79 years old were eligible for the spirometry portion of the examination. Individuals were excluded if they reported current chest pain or a physical problem with forceful expiration; taking supplemental oxygen, recent surgery of the eye, chest, or the abdomen; or a recent myocardial infarction, stroke, tuberculosis exposure, or coughing up blood. Adults with a personal history of detached retina or a collapsed lung and children with painful ear infections were also excluded. Testing procedures followed guidelines of the American Thoracic Society (ATS).2 Spirometers were Ohio 822/827 dry-rolling seal volume spirometers, reconditioned for use in the current survey. The overall goal was for the participant to achieve 3 acceptable exhalation maneuvers by ATS criteria in which the 2 highest values for the forced vital capacity (FVC) and the forced expiratory volume in 1 second (FEV1) (each taken from an acceptable forced expiratory maneuver) revealed minimal variability (ie, the 2 largest FVC values taken from 2 acceptable curves should agree within 150 mL and similarly for the 2 largest values for the FEV1).
Statistical Analysis Linear regression was used to compare lung function parameters (FEV1, FVC, and FEV1/FVC ratio) between participants who did and did not report a history of asthma and between participants with asthma who did and did not report a history of an asthma attack in the last year. Covariates included in the model were race, age, height squared, and sex. In a sensitivity analysis, logistic regression was used to determine the association between urinary triclosan levels and recent asthma attacks, adjusting for age, race, sex, urinary creatinine, poverty index ratio, BMI, and smoking status. Fewer participants had complete data for this analysis in part because smoking status was only collected in those 12 years and older and in part because of missing smoking data even for those older than 12 years. Because of the small sample size, this analysis was performed without using survey weights, strata, and sampling units. eResults Pulmonary Function of the Study Participants
Participants 12 years and older provided a smoking history. Participants were categorized as never, former, and current smokers. Former smokers reported smoking more than 100 cigarettes in their lifetime but no current use, whereas current smokers reported current use. Never smokers denied smoking more than 100 cigarettes in their lifetime.
Compared with participants not reporting a history of asthma, those reporting a history of asthma had a significantly lower FEV1 (132 mL; 95% confidence interval [CI], 183 to 80 mL), FVC (74 mL; 95% CI, 136 to 11 mL), and FEV1/FVC ratio (0.024; 95% CI, 0.029 to 0.019) in models adjusted for age, height squared, sex, and race (n ¼ 4,503). Compared with participants reporting a history of asthma and no exacerbation within the last year, those with asthma reporting a recent exacerbation had similar FEV1 (mean difference, 99 mL; 95% CI, 47 to 246 mL), FVC (mean difference, 97 mL; 95% CI, 73 to 268 mL), and FEV1/FVC ratio (mean difference, 0.006; 95% CI, 0.11 to 0.23) in adjusted models (n ¼ 467).
Body Measurements
Sensitivity Analysis of Triclosan Levels and Recent Asthma Attacks
Height and weight were obtained on all study participants by trained health technicians. Body mass index (BMI) was
After adjusting for age, race, sex, poverty index ratio, urinary creatinine, smoking status, and BMI, among participants reporting
Smoking History
eTable 1 Sociodemographic characteristics of NHANES participants with urinary triclosan levels and information on asthma historya Characteristic
Sex Male Female Age, y 6e18 19 Ethnicity White African American Hispanic Other Poverty Index Ratio
