To the Editor
Asthma prevalence has been on the rise in the past decades, although its drivers are incompletely understood.1,2 While exposure to allergens and gram-negative endotoxin is associated with asthma and wheeze,3 the link between other microbial exposures, which stimulate the human immune system in myriad ways, and the risk of asthma remains unclear. One microbe, the gram-positive bacterium Staphylococcus aureus, exacerbates atopic eczema and contributes to development of chronic rhinosinusitis with nasal polyposis via a TH2-biased immune response to bacterial superantigen proteins such as staphylococcal enterotoxins (SE),4 suggesting that S aureus could also affect TH2-driven airway disease.
Interestingly, although 1 study found no significant associations between S aureus nasal colonization in neonates and subsequent asthma outcomes,5 2 other studies found evidence for a diagnosis of asthma being a risk factor for S aureus colonization, including 1 study using data from the National Health and Nutrition Examination Survey (NHANES) 2001–2002.6,7 Building on these findings, we evaluated S aureus nasal colonization as a risk factor for a range of asthma-associated outcomes, including diagnosis, symptoms, and exacerbations, among the US population using data from NHANES 2001–2004. We also examined the effect of age on relationships between S aureus colonization and asthma- and wheeze-related outcomes.
NHANES, a nationally representative survey, includes data on demographic characteristics, health status, and nutrition of noninstitutionalized US residents ages 1 to 85 years old. Details on the conduct of NHANES surveys are available online at http://www.cdc.gov/nchs/nhanes.htm. This analysis includes respiratory outcomes related to self-reported symptoms of wheeze and asthma in the past year. Population-standardized prevalence rates were calculated, and unadjusted and adjusted associations between S aureus nasal colonization and asthma and wheeze outcomes were examined using logistic regression modeling to estimate odds ratios (OR) using Stata 13.1 (Stata, College Station, Tex). Details on these methods are available in this article’s Online Repository at www.jacionline.org.
In NHANES 2001–2004, an estimated 28.4% (95% CI: 27.3%, 29.6%) of the population was nasally colonized with S aureus. Table I provides prevalence rates of asthma and wheeze outcomes in the NHANES 2001–2004 cohort among the 16,234 participants 6 to 85 years old, as described in this article’s Online Repository at www.jacionline.org. In the analysis of associations between S aureus and outcomes related to wheeze and asthma, age appeared to modify the effects of exposure, with positive associations observed among younger individuals (~6–30-year-olds) and negative associations observed among older individuals (~31–85-year-olds) (Fig E1). S aureus colonization in the younger group was associated with increased population prevalence rates for respiratory outcomes (Fig E2).
TABLE I.
Participant characteristics and prevalence rates for S aureus colonization among 6- to 85-year-old NHANES participants, 2001–2004
| Sample | S aureus colonized | Not S aureus colonized | X2 | ||
|---|---|---|---|---|---|
| Demographic characteristics | |||||
| Row | Characteristic | n (%) | Population % [95% CI] | Population % [95% CI] | P value |
| I | Total | 16,234 | 28.4% [27.3%, 29.6%] | 71.6% [70.4%, 72.7%] | |
| II | Sex | <.001 | |||
| Female | 8,337 (51.4%) | 47.6% [45.1%, 50.1%] | 54.1% [52.9%, 55.3%] | ||
| Male | 7,897 (48.6%) | 52.4% [50.0%, 54.9%] | 45.9% [44.7%, 47.1%] | ||
| III | Ethnicity category | <.001 | |||
| NH white | 6,980 (43.0%) | 75.8% [71.7%, 79.3%] | 71.4% [66.5%, 75.8%] | ||
| NH black | 4,190 (25.8%) | 8.5% [6.4%, 11.1%] | 12.2% [9.7%, 15.2%] | ||
| Mex Am | 3,985 (24.6%) | 6.8% [5.2%, 8.7%] | 7.7% [5.6%, 10.4%] | ||
| Other/multi | 476 (2.9%) | 3.9% [3.0%, 5.0%] | 4.2% [3.2%, 5.5%] | ||
| Hispanic | 603 (3.7%) | 5.1% [3.2%, 8.2%] | 4.5% [2.9%, 7.1%] | ||
| IV | BMI category | .11 | |||
| Underweight | 325 (2.0%) | 1.7% [1.1%, 2.6%] | 1.9% [1.5%, 2.3%] | ||
| Normal | 6,665 (41.1%) | 29.5% [26.7%, 32.4%] | 31.4% [29.9%, 32.9%] | ||
| Overweight | 4,452 (27.4%) | 32.6% [30.2%, 35.0%] | 34.0% [32.3%, 35.8%] | ||
| Obese | 4,792 (29.5%) | 36.2% [33.4%, 39.1%] | 32.8% [31.1%, 34.6%] | ||
| V | Smoking in the home* | .01 | |||
| Yes | 3,371 (21.0%) | 18.4% [16.1%, 20.9%] | 22.5% [19.9%, 25.3%] | ||
| No | 12,689 (79.0%) | 81.6% [79.1%, 83.9%] | 77.5% [74.7%, 80.1%] | ||
| VI | Flu, pneumonia or ear infection‡ | .98 | |||
| Yes | 772 (5.1%) | 4.9% [3.8%, 6.3%] | 4.5% [3.9%, 5.3%] | ||
| No | 14,398 (94.9%) | 95.1% [93.7%, 96.2%] | 95.5% [94.7%, 96.1%] | ||
| Row | Characteristic | Mean (SD) | Mean [95% CI] | Mean [95% CI] | P value |
|---|---|---|---|---|---|
| VII | Age in years | 34.6 (23.3) | 46.0 [45.7, 46.3] | 46.3 [46.0, 46.6] | .12 |
| VIII | Number of health care visits in past year* | 1.97 (1.36) | 2.06 [1.98, 2.14] | 2.08 [2.04, 2.13] | .47 |
| IX | Family PIR (income)‡ | 2.39 (1.60) | 3.05 [2.92, 3.19] | 2.96 [2.86, 3.05] | .04 |
| X | Average household size | 3.73 (1.75) | 3.06 [2.96, 3.15] | 3.01 [2.93, 3.09] | .25 |
| Respiratory outcomes | |||||
|---|---|---|---|---|---|
| Row | Outcome | n (%) | Population % [95% CI] | Population % [95% CI] | P value |
| Wheeze outcomes: | |||||
| XI | Wheeze in the past year* | 2,091 (12.9%) | 14.9% [12.9%, 17.2%] | 15.2% [14.0%, 16.5%] | .57 |
| XII | Wheeze during exercise* | 1,011 (6.2%) | 6.3% [5.3%, 7.4%] | 7.0% [6.2%, 7.9%] | .92 |
| XIII | Nocturnal wheeze‡ | 922 (6.1%) | 6.6% [5.4%, 8.2%] | 6.5% [5.7%, 7.3%] | .21 |
| XIV | Emergency room visit for wheezing† | 785 (4.9%) | 5.8% [4.6%, 7.4%] | 5.0% [4.3%, 5.9%] | .05 |
| XV | Wheeze limits activities† | 779 (4.9%) | 5.6% [4.4%, 7.1%] | 5.5% [4.6%, 6.4%] | .48 |
| XVI | Medication for wheezing‡ | 562 (3.7%) | 3.2% [2.4%, 4.2%] | 4.2% [3.4%, 5.2%] | .23 |
| XVII | Miss work or school due to wheeze† | 408 (2.6%) | 1.7% [1.1%, 2.7%] | 1.9% [1.5%, 2.4%] | .15 |
| Asthma outcomes: | |||||
| XVIII | Asthma diagnosis ever* | 2,169 (13.4%) | 12.9% [11.4%, 14.6%] | 11.8% [10.7%, 12.9%] | .05 |
| XIX | Current asthma* | 1,315 (8.1%) | 7.7% [6.4%, 9.3%] | 7.3% [6.4%, 8.3%] | .19 |
| XX | Asthma attack in past year‡ | 672 (4.4%) | 4.6% [3.4%, 6.1%] | 3.5% [3.0%, 4.0%] | .02 |
| XXI | Emergency room visit for asthma§ | 206 (1.4%) | 1.2% [0.7%, 1.9%] | 0.8% [0.6%, 1.1%] | .13 |
The sample column displays absolute numbers and percentages.
S aureus rates are standardized to the population distribution.
Due to rounding, percents may not add up to 100%.
BMI category is based on percentile assignment for ages 1 to 20 and BMI for ages 21 to 85.
BMI, Body mass index; Mex Am, Mexican American; NH, non-Hispanic; PIR, poverty income ratio.
≤1% missing data.
1% to 4% missing data.
5% to 7% missing data.
8% to 10% missing data.
Table II displays models adjusted for a priori covariates and demonstrates that, for most outcomes, statistically significant interactions between S aureus colonization and age category were observed. For example, S aureus colonized individuals had a significant 1.52-fold (95% CI: 1.15, 2.00) increase in odds of nocturnal wheeze compared with noncolonized individuals among 6- to 30-year-olds, but S aureus–colonized individuals had a nonsignificant decrease in odds (OR 0.79, 95% CI: 0.53, 1.18) among 31- to 85-year-olds, with interactive effects present between S aureus colonization and age category (P = .01). Results were similar between unadjusted and adjusted models (Table E1).
TABLE II.
Adjusted associations between S aureus nasal colonization and asthma and wheeze
| Outcomes, OR [95% CI] | Whole population (age 6 to 85 y) | Age 6 to 30 y | Age 31 to 85 y | S aureus and age interaction |
|---|---|---|---|---|
| Sample size | n = 16,234 | n = 8,703 | n = 7,531 | |
| Wheeze outcomes: | ||||
| Wheeze in the past year† | 1.02 [0.87, 1.20] | 1.35 [1.06, 1.73]* | 0.85 [0.68, 1.06] | P = .006 |
| Wheeze during exercise† | 1.00 [0.82, 1.19] | 1.27 [0.95, 1.70] | 0.84 [0.67, 1.08] | P = .06 |
| Nocturnal wheeze§ | 1.05 [0.84, 1.34] | 1.52 [1.15, 2.00]** | 0.79 [0.53, 1.18] | P = .01 |
| Emergency room visit for wheezing‡ | 1.28 [1.00, 1.62]* | 1.50 [1.10, 2.03]* | 1.11 [0.70, 1.78] | P = .26 |
| Wheeze limits activities‡ | 1.11 [0.89, 1.38] | 1.41 [1.05, 1.90]* | 0.97 [0.72, 1.29] | P = .03 |
| Medication for wheezing§ | 0.93 [0.75, 1.14] | 1.52 [1.08, 2.14]* | 0.64 [0.48, 0.84]** | P < .001 |
| Miss work or school due to wheezeঠ| 1.03 [0.77, 1.39] | 1.42 [1.04, 1.94]* | 0.61 [0.32, 1.20] | P = .01 |
| Asthma outcomes: | ||||
| Asthma diagnosis ever† | 1.07 [0.92, 1.23] | 1.25 [0.99, 1.56] | 0.92 [0.76, 1.11] | P = .04 |
| Current asthma† | 1.08 [0.87, 1.35] | 1.27 [0.95, 1.70] | 0.93 [0.71, 1.22] | P = .06 |
| Asthma attack in past year§ | 1.37 [1.03, 1.83]* | 1.42 [0.92, 2.19] | 1.31 [0.94, 1.84] | P = .64 |
| Emergency room visit for asthma|| | 1.44 [0.89, 2.31] | 1.97 [1.05, 3.73]* | 0.85 [0.37, 1.94] | P = .09 |
OR are (odds for colonized)/(odds for noncolonized).
Adjusted models use survey weighting and account for gender, ethnicity, obesity, smoking in the home, episode of flu, number of health care visits, poverty income ratio, and household size.
Whole-population and within-age-stratum models use age as a continuous variable.
Models with the S aureus * age interaction term use age as a binary variable.
Boldface: P < .05:
P < .05;
P < .01.
≤1% missing data.
1% to 4% missing data.
5% to 7% missing data.
8% to 10% missing data.
Excluding 2,120 participants over 65 years old.
In this analysis of NHANES data, representative of the US population, S aureus nasal colonization was associated with increased risk of asthma prevalence, symptoms, and exacerbations in children and young adults. No associations were seen for most asthma-related outcomes among adults aged 31 to 85. Together, these findings implicate S aureus colonization in the pathogenesis of asthma prevalence and morbidity in children and young adults. While 2 prior epidemiologic studies evaluating risk factors for S aureus colonization identified asthma as 1 factor among many,6,7 no previous studies have evaluated whether S aureus colonization is a risk factor for asthma-related symptoms and exacerbations and whether these relationships are modified by age. Our hypothesized causal direction from S aureus colonization to asthma diagnosis and morbidity is biologically plausible. Numerous human and animal studies suggest that exposure to intrinsic or secreted components of S aureus (eg, peptidoglycan, SE) may exacerbate upper respiratory disease via local or systemic TH2-driven host immune responses,4,8 which could contribute to exacerbation or progression to lower airway disease.
This is the first study to note differences in associations between S aureus colonization and asthma outcomes among younger versus older participants, which we discuss further in this article’s Online Repository at www.jacionline.org. Because host responses, including atopic status, may mediate the relationships between S aureus colonization and asthma and wheeze, children and young adults, who typically are more atopic, could be more susceptible to the respiratory effects of S aureus than older adults. However, atopic status was not measured in NHANES 2001–2004, precluding our ability to explore this host factor as a potential mediator of the observed relationships. It is also possible that the associations between S aureus colonization and asthma outcomes were only observed in younger individuals because of misclassification of asthma in older adults. For example, adults are more likely to have comorbidities that can be mistaken for asthma, such as chronic obstructive pulmonary disease and congestive heart failure. However, removing individuals with heart disease, chronic bronchitis, and emphysema did not affect the findings (data not shown).
Like other NHANES analyses, this study is limited by its cross-sectional study design, precluding testing the causal direction for observed associations. Incomplete and biased measurement of staphylococcal enterotoxins in NHANES 2001–2004 limited our ability to analyze whether the relationship between S aureus and asthma outcomes differed according to the SE status of the colonizing isolate. Another potential limitation of this work is the assessment of only nasal colonization, because S aureus also may colonize skin, pharyngeal, and other sites.9 However, S aureus nasal colonization often shows a high correlation with skin carriage.9 Another limitation of this study is the potential for reverse causation, in which lower respiratory disease could be a risk factor for S aureus colonization, rather than vice versa. For example, lower respiratory disease or symptoms could cause more contact with health care facilities, and increased contact with health care facilities could promote S aureus colonization. However, our findings were robust to adjustment for the number of reported health care visits.
Prospective studies are needed to unpack not only the direction of causation, but also the host factors and underlying inflammatory mechanisms by which S aureus is associated with wheeze and asthma outcomes. Whether the epidemic of S aureus may drive the concurrent epidemic of asthma is unknown, but understanding the role of S aureus on respiratory outcomes could identify novel intervention efforts to reduce the burden of disease in younger populations.
Supplementary Material
Acknowledgments
We are grateful to Dr Corinne Keet for her assistance and thank faculty in the Center for Childhood Asthma in the Urban Environment for their technical expertise.
No specific sources of funding were used for this data analysis. The authors were supported by grants from the Johns Hopkins Fisher Center Discovery Program (004MAT2014 to E.M. and M.D.), the National Institute of Environmental Health Sciences (NIEHS; T32ES7141-29 to M.D.; R21ES024021 and P01ES018176 to M.M; P50ES015903, P01ES018176, P01ES018181, and R01ES019560 to E.M.), the Environmental Protection Agency (EPA; R832139 and STAR Grant RD83451501 to E.M.), and the National Institute of Allergy and Infectious Diseases (R01AI070630 and U01AI083238 to E.M.).
Footnotes
Disclosure of potential conflict of interest: M. F. Davis has received research support from the Johns Hopkins Fisher Center Discovery Program (004MAT2014), the NIEHS (T32ES7141-29), and Sogeval and has received travel support from the American College of Veterinary Dermatology. R. D. Peng has received research support from the National Institutes of Health (R01ES019560) and has received consultancy fees from Health Effects Institute. M. C. McCormack has received research support from the NIEHS (R21ES024021 NIEHS and EPA P01ES018176) and has received royalties from UpToDate. E. C. Matsui is a member of the EPA Science Advisory Board, has received consultancy fees from the EPA Expert Panel for Allergic Outcomes in Epidemiologic Research, is employed by Johns Hopkins University, and has received research support from the National Institutes of Health.
References
- 1.McHugh MK, Symanski E, Pompeii LA, Delclos GL. Prevalence of asthma among adult females and males in the United States: Results from the National Health and Nutrition Examination Survey (NHANES), 2001–2004. J Asthma. 2009;46:759–66. doi: 10.1080/02770900903067895. [DOI] [PubMed] [Google Scholar]
- 2.Zhang X, Morrison-Carpenter T, Holt JB, Callahan DB. Trends in adult current asthma prevalence and contributing risk factors in the United States by state: 2000–2009. BMC Public Health. 2013;13:1156. doi: 10.1186/1471-2458-13-1156. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Breysse PN, Diette GB, Matsui EC, Butz AM, Hansel NN, McCormack MC. Indoor air pollution and asthma in children. Proc Am Thorac Soc. 2010;7:102–6. doi: 10.1513/pats.200908-083RM. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Bachert C, Zhang N. Chronic rhinosinusitis and asthma: Novel understanding of the role of IgE ‘above atopy’. J Intern Med. 2012;272:133–43. doi: 10.1111/j.1365-2796.2012.02559.x. [DOI] [PubMed] [Google Scholar]
- 5.Bisgaard H, Hermansen MN, Buchvald F, Loland L, Halkjaer LB, Bonnelykke K, et al. Childhood asthma after bacterial colonization of the airway in neonates. N Engl J Med. 2007;357:1487–95. doi: 10.1056/NEJMoa052632. [DOI] [PubMed] [Google Scholar]
- 6.Graham PL, Lin SX, Larson EL. A U.S. population-based survey of Staphylococcus aureus colonization. Ann Intern Med. 2006;144:318–25. doi: 10.7326/0003-4819-144-5-200603070-00006. [DOI] [PubMed] [Google Scholar]
- 7.Halablab MA, Hijazi SM, Fawzi MA, Araj GF. Staphylococcus aureus nasal carriage rate and associated risk factors in individuals in the community. Epidemiol Infect. 2010;138:702–6. doi: 10.1017/S0950268809991233. [DOI] [PubMed] [Google Scholar]
- 8.Pastacaldi C, Lewis P, Howarth P. Staphylococci and staphylococcal superantigens in asthma and rhinitis: A systematic review and meta-analysis. Allergy. 2010;66:549–55. doi: 10.1111/j.1398-9995.2010.02502.x. [DOI] [PubMed] [Google Scholar]
- 9.Sollid J, Furberg A, Hanssen A, Johannessen M. Staphylococcus aureus: Determinants of human carriage. Infect Genet Evol. 2014;21:531–41. doi: 10.1016/j.meegid.2013.03.020. [DOI] [PubMed] [Google Scholar]
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