http://informahealthcare.com/jas ISSN: 0277-0903 (print), 1532-4303 (electronic) J Asthma, Early Online: 1–6 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/02770903.2014.974816
ORIGINAL ARTICLE
Oral hygiene and dental status as factors related to asthma in high school and college students Mario H. Vargas, MD, MSc1,2, Francisco Macedo-Sa´nchez, MD3,4, Cuauhte´moc Solı´s-Torres, CPA, MSc3, Horacio Rubio-Monteverde, MD3, and Marı´a E.Y. Furuya, MD, PhD1
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1
Unidad de Investigacio´n Me´dica en Enfermedades Respiratorias, Hospital de Pediatrı´a, Centro Me´dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Me´xico DF, Mexico, 2Departamento de Investigacio´n en Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias, Me´xico DF, Mexico, 3Direccio´n General de Servicios Me´dicos, Universidad Nacional Auto´noma de Me´xico, Me´xico DF, Mexico, and 4 Servicio de Consulta Externa, Instituto Nacional de Enfermedades Respiratorias, Me´xico DF, Mexico Abstract
Keywords
Objective: Considering that oral microbiota might modulate immune responses, we explored if customary oral care procedures might influence immune-driven diseases such as asthma. Methods: This was a retrospective, cross-sectional analysis of responses to a self-completion medical questionnaire applied to subjects entering into college and high school programs during 2006–2011. Results: Responses from 329 780 students aged 14–24 years (97.6% of the original population) were analyzed. The prevalence of lifetime asthma was 4.01%. Subjects with asthma were slightly older, taller and heavier than subjects without asthma, and these differences were equally present in males and females. Subjects currently having two or more decayed teeth had asthma less frequently than those with one or none decayed tooth, with an odds ratio (OR) ¼ 0.86 and 95% confidence interval (95% CI) 0.83–0.89. In contrast, asthma was reported more frequently among students having two or more missing or filled teeth [OR ¼ 1.1 (95% CI 1.04–1.17) and OR ¼ 1.05 (95% CI 1.01–1.09), respectively]. From 2008 onwards, subjects also responded questions about oral hygiene incorporated into the core questionnaire. In these subjects, the use of toothpaste as well as the frequency and duration of toothbrushing were unrelated to asthma; regular use of mouthwash was associated with asthma in women [OR ¼ 1.16 (95% CI 1.07–1.25)], but not in men [OR ¼ 1.04 (95% CI 0.96–1.13)]. Results of multiple logistic regressions were in line with these findings. Conclusions: Our results suggested that oral hygiene and dental status could be novel factors influencing asthma development, and thus further studies to confirm and clarify this association are warranted.
Caries, dental care, DMF index, oral microbiota, oral rinse, toothpaste
Introduction Scientific knowledge about mechanisms involved in the pathogenesis of asthma has greatly improved over the last decades, but the primary causes of this complex disease remain questionable. The so-called hygiene hypothesis postulates that reduced exposure to microorganisms or their products favor the development of allergic-type, TH2-driven responses of the immune system [1]. Although basic research and epidemiological studies provide support for this hypothesis, the specific microorganism(s) whose absence promotes the allergic process remain uncertain. Contrary to the hygiene hypothesis, the colonization of airways by some specific infecting agents such as syncytial respiratory virus, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Correspondence: Dr. Mario H. Vargas, Unidad de Investigacio´n Me´dica en Enfermedades Respiratorias, Hospital de Pediatrı´a, Centro Me´dico Nacional Siglo XXI, IMSS. Av. Cuauhte´moc 330, CP 06720, Me´xico DF, Mexico. Tel: +55-56276900. E-mail: mhvargasb@ yahoo.com.mx
History Received 31 July 2014 Revised 18 September 2014 Accepted 5 October 2014 Published online 5 November 2014
Streptococcus pneumoniae, Hemophilus influenzae, and/or Moraxella catarrhalis, has been postulated as favoring the development of asthma [2–4]. More recently, a wider panorama of the potential role of microorganisms in the development of asthma is emerging. In this regard, the characterization of microbial diversity in the airways through metagenomic techniques has unveiled notable differences between asthmatic and non-asthmatic airways. The majority of studies exploring the airways microbiota coincided in that patients with asthma possess significantly greater bacterial diversity, with overrepresentation of bacteria belonging to the Proteobacteria phylum [5–8]. Interestingly, in 2011, Charlson et al. reported that the composition of airway microbiota in healthy subjects was indistinguishable from microbiota present in the oropharynx, although in progressively lower amounts as more distal was the airway sampled [9]. The authors speculated that the oropharynx was the source of the tracheobronchial microbiota, most likely by microaspiration. The oral cavity contains a vast array of different microorganisms that make up its
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M. H. Vargas et al.
permanent microbiota. Around 280 bacterial species have been cultured from the mouth, but this number rises to nearly 700 by additionally using culture-independent methods such as 16S rRNA gene-based molecular cloning [10]. Up to 96% of mouth-related taxa are contained in six major phyla: Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Spirochaetes and Fusobacteria [10]. Although the majority of bacteria usually found in the mouth maintain a commensal relationship with the host, under certain circumstances some of these may become pathogenic and cause diseases such as dental caries [11]. The bacteria most frequently associated with human caries are those belonging to a group of phenotypically similar microorganisms, the so-called mutans streptococci, from which Streptococcus mutans and Streptococcus sobrinus, are the major pathogens. These bacteria are transmitted to the child from primary caregivers (mainly the mother) [12,13]. At present, it is fully acknowledged that microbial communities living on body surfaces (skin and mucosal membranes) profoundly influence the development and shape of the immune system [14], and this modulatory role has been also ascribed to oral microbiota [15]. Thus, it is reasonable to speculate that subtle modifications of microbiota of the mouth due to procedures commonly employed in oral hygiene such as toothbrushing with toothpaste and the use of mouthwash [16–18], might modulate immune responses, hence promoting (or protecting from) the development of asthma. The Universidad Nacional Auto´noma de Me´xico is the largest educative institution in Mexico, and each year it accepts 65 000 students for entry into high school or college courses for the first time. Every student entering formal courses must fill out a self-completion automated medical questionnaire, which includes questions about lifetime asthma, current dental conditions and usual dental care. Thus, the objective of the present study was to analyze responses to this questionnaire with the aim to investigate at the individual level the potential relationships between asthma and dental status or oral hygiene.
Population and methods Study design In this retrospective and cross-sectional study, responses to the automated medical examination applied between 2006 and 2011 to students aged between 14 and 24 years were
J Asthma, Early Online: 1–6
analyzed. The questionnaire-based, automated medical examination is composed of three modules that include 210 multiple-choice items related to current or past illnesses and with major factors that confer risk or protection on the student’s health. In 2008, a fourth module comprising 13 items on oral hygiene was added to the core questionnaire. Specific questions and possible responses that were taken into account for the present report, as well as the proportion of missing data, are listed in Table 1. The protocol was approved by the institutional research boards of the Instituto Mexicano del Seguro Social (approval No. R-2012-785-010) and the Instituto Nacional de Enfermedades Respiratorias (approval no. E01-12). Data management Associations between asthma and other variables were analyzed through the chi-square test and the odds ratio (OR) with a 95% confidence interval (95% CI). Multiple logistic regressions were used to assess the potential influence of selected variables on the risk for asthma. Data analyses were performed using the IBM SPSS Statistics v19.0 software (IBM Corporation, Somers, NY). Statistical significance was set at p50.05 bimarginally.
Results Between 2006 and 2011, a total of 337 875 students filled out the automated medical examination questionnaire. All students aged between 14 and 24 years were initially selected for inclusion into the study, comprising 330 982 subjects. After excluding individuals not responding to the question about asthma, a final population of 329 780 subjects (97.6% of the original population) was included in the analysis. This population included a slightly higher proportion of females (53.0%) than males. The percentage of subjects who responded affirmatively to the question about asthma was 4.35% among males and 3.70% among females (p50.001), for a global prevalence of 4.01%. Although anthropometric differences between subjects with and without asthma were rather small, they reached statistical significance (p50.01 in all comparisons). Thus, subjects with asthma were slightly older (16.97 versus 16.85 years of age), taller (165.67 versus 164.64 cm in height) and heavier (weight, 63.14 versus 61.67 kg; body mass index [BMI], 22.92 versus
Table 1. Selected questions included in the medical questionnaire regarding asthma, dental status and oral hygiene. Question Of the following health problems, which have you had? Asthma With respect to your permanent teeth How many have you lost? How many have caries? How many are obtruded? How many times do you brush your teeth in a day?a How much time do you spend on your toothbrushing?a Which of these oral health helpers do you use?a Toothpaste Mouthwash a
Questions available from 2008 onwards.
Possible responses
Missing data (%)
Yes/No
0.4
0/1/2/3/4/5/6/7/8/more 0/1/2/3/4/5/6/7/8/more 0/1/2/3/4/5/6/7/8/more 1/2/3 or more/none 30 s/1 min/1–3 min/3 min or more
1.8 2.3 2.0 3.7 3.8
Always/Sometimes/Never Always/Sometimes/Never
3.7 3.8
Dental status, oral hygiene and asthma
DOI: 10.3109/02770903.2014.974816
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22.67 kg/m2) than subjects without asthma (Table 2). These differences were equally present in both males and females. As can be observed in Table 3, in the whole population subjects having two or more decayed teeth had asthma less frequently than those with one or no decayed tooth [OR ¼ 0.86 (95% CI 0.83–0.89)]. In contrast, asthma was reported more frequently among subjects having two or more missing or filled teeth [OR ¼ 1.10 (95% CI 1.04–1.17) and OR ¼ 1.05 (95% CI 1.01–1.09), respectively]. From 2008 onwards, a subpopulation of 225 716 students responded to a questionnaire about oral hygiene. In these subjects, use of toothpaste as well as the frequency and duration of toothbrushing were not associated with asthma, but regular use of mouthwash was more often found among subjects with asthma. Analysis by gender corroborated that relationships between asthma and current caries, missing teeth or filled
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teeth occurred equally in both genders (Figure 1). However, regular use of mouthwash was associated with asthma in women [OR ¼ 1.16 (95% CI 1.07–1.25)], but not in men [OR ¼ 1.04 (95% CI 0.96–1.13)]. Results of the multiple logistic regression analysis (Table 4) were in line with the previously mentioned findings, i.e. in the whole population, the prevalence of asthma was lower according to the number of decayed teeth [adjusted OR ¼ 0.965 (95% CI 0.957–0.972)] or higher according to the number of missing teeth [adjusted OR ¼ 1.033 (95% CI 1.014–1.052)], and this was true when male and female students were evaluated separately. In addition, everyday use of mouthwash was also associated with a higher prevalence of asthma [adjusted OR ¼ 1.106 (95% CI 1.030–1.188)], but this tendency was solely observed among women [adjusted OR ¼ 1.180 (95% CI 1.065–1.309)].
Table 2. Anthropometric characteristics of the study population, and their relationship with asthma. All a
Males a
a
Females a
a
Characteristic
Asthma (n ¼ 13218)
No asthma (n ¼ 316562)
Asthma (n ¼ 6753)
No asthma (n ¼ 148380)
Asthma (n ¼ 6465)
No asthmaa (n ¼ 168182)
Age (years) Height (cm) Weight (kg) BMI (kg/m2)
16.97 ± 0.02** 165.67 ± 0.08** 63.14 ± 0.12** 22.92 ± 0.04**
16.85 ± 0.004 164.64 ± 0.02 61.67 ± 0.02 22.67 ± 0.007
17.06 ± 0.03** 171.45 ± 0.09** 67.56 ± 0.17** 22.93 ± 0.05**
16.96 ± 0.006 170.77 ± 0.02 66.48 ± 0.04 22.73 ± 0.01
16.89 ± 0.03** 159.63 ± 0.08** 58.54 ± 0.14** 22.92 ± 0.05**
16.75 ± 0.005 159.23 ± 0.02 57.45 ± 0.03 22.61 ± 0.01
BMI ¼ body mass index. Data correspond to mean ± standard error. **p50.01 versus the respective ‘‘No asthma’’ group.
a
Table 3. Association of asthma with dental status and oral hygiene in high school and college students.
Variable Decayed teeth 2 Missing teeth 2 Filled teeth 2 Use of toothpaste alwaysb Toothbrushings 2 per dayb Toothbrushings 1 minb Use of mouthwash alwaysb
Asthmaa (n ¼ 13218) 7008 1342 4516 8804 8220 4942 1571
No asthmaa (n ¼ 316562)
(54.2)** (10.3)** (34.8)** (99.3) (92.6) (55.7) (17.7)**
179 202 29 434 104 430 206 840 192 987 116 235 33 993
OR (95% CI)
(57.9) (9.5) (33.7) (99.4) (92.7) (55.9) (16.4)
0.86 1.10 1.05 0.84 0.98 0.99 1.10
(0.83–0.89) (1.04–1.17) (1.01–1.09) (0.65–1.08) (0.91–1.07) (0.95–1.04) (1.04–1.16)
OR (95% CI) ¼ odds ratio (confidence interval at 95%). Data are expressed as number (percent) of subjects. Data from 225 716 students (2008–2011 period). **p50.01 as compared with their respective ‘‘No asthma’’ group by chi-square test.
a
b
Figure 1. Variables related to oral hygiene and dental status and their relationship with the presence of asthma. Symbols correspond to the odds ratios (circles) and confidence intervals at 95% (horizontal lines) for male (A) and female (B) subjects.
Protective
(A)
Risk
(B)
Protective
Risk
Decayed teeth ≥2 Missing teeth ≥2 Filled teeth ≥2 Toothbrushings ≥2 per day Toothbrushings ≥1 min Use of toothpaste always Use of mouthwash always 0.5
1 Odds ratios
1.5
0.5
1 Odds ratios
1.5
Reference 1.041 (0.956–1.129) 1.180 (1.065–1.309)
Discussion
a
Reference 1.012 (0.956–1.071) 1.106 (1.030–1.188) 0.692 0.006 0.011 0.101
aOR (95% CI) ¼ odds ratio adjusted by the other variables in the model (confidence interval at 95%). Number of filled teeth and use of toothpaste were always excluded from the final regression models. In males, use of mouthwash was also excluded from the model.
0.343 0.002 0.040 0.166
0.963 (0.953–0.974) 1.030 (1.005–1.055) 50.001 0.02 0.037 0.029 0.968 (0.957–0.979) 1.046 (1.018–1.076) 50.001 0.001 0.032 0.045 50.001 0.001 0.036 0.032
Number of decayed teeth Number of missing teeth Use of mouthwash Never Sometimes Always
Variables in the regression modela
p
0.965 (0.957–0.972) 1.033 (1.014–1.052)
p b-coefficients aOR (95% CI) p
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b-coefficients
aOR (95% CI)
b-coefficients
Males (n ¼ 99 405) All (n ¼ 210 517)
Table 4. Dental status and oral health and their relationship with asthma, as assessed by multiple logistic regression, in high school and college students.
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aOR (95% CI)
M. H. Vargas et al.
Females (n ¼ 111 112)
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In the present study, a large database with responses to a selfcompletion questionnaire in subjects 14–24 years of age who initiated high school or college courses was analyzed with the aim of identifying factors related to asthma, mainly those concerning oral hygiene and dental status. Asthma is currently considered a disease that is primarily driven by immune cells, including TH2 cells in the classic eosinophilic, allergic-type phenotype and TH17 cells in the severe neutrophil-predominant phenotype. Thus, exploration of factors capable of modulating the immune response is important. Undoubtedly, the interaction between microorganisms and the immune system is one of the most powerful stimuli determining the type of immune response, and this interaction might occur with some specific microorganisms or with microbiota as a whole [14,19]. Our study unveiled some associations between asthma and dental status, inasmuch as subjects having current caries had a lesser probability of having asthma. Paradoxically, in the scientific literature, a number of studies have concluded that caries are directly related to asthma (reviewed by Alavaikko et al. [20]), which at first glance appears to be contradictory with our results. However, the majority of these studies defined caries employing the usual composite index of decayed, missing and filled teeth (dmf, DMF), as proposed by the World Health Organization [21]. In this index, only the first condition (decayed) truly refers to current caries, while the latter two variables are indicators of ‘‘past’’ caries. These three conditions could exert different effects on oral microbiota. For example, children with one or more carious teeth had higher salivary S. mutans levels than control children with healthy teeth, but these levels returned to control values after restoration of carious lesions [22]. Workers who attended regular dental appointments had fewer active caries and lower salivary levels of S. mutans [23]. Finally, number of teeth appeared to be related to levels of periodontopathic and cariogenic bacteria [24–26]. Thus, it is probable that microbiota in the mouth differs in subjects with and without current caries, and according to the hygiene hypothesis, the higher number and/or the different type of microorganisms found in subjects with active caries could be exerting a protective role against asthma. Following the same line of thought, it is reasonable to speculate that having missing and/or filled teeth is indicative that the subject receives professional and/or personal dental care more often than those who continue to have active caries. This opens the possibility that their oral microbiota might be different from that found in subjects with sound teeth or in subjects with decayed teeth. Thus, in previous studies the use of composite dmf or DMF indexes may have blurred the true role carried out by active caries in asthma. In this context, our findings strongly suggest that in future studies, each of the three elements of dmf and DMF indexes needs to be evaluated separately. In our analysis, the strength of the association between active caries and development of asthma may have been underestimated. Anti-asthma medication itself may contribute to dental caries and periodontal disease due to, for example, a beta-2 agonist-induced decrease of salivary
Dental status, oral hygiene and asthma
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DOI: 10.3109/02770903.2014.974816
protein secretion and flow rate, and reduced pH of saliva and plaque, among other mechanisms [27]. Thus, even though a putative causal relationship between active caries and protection from asthma may exist, once a patient becomes asthmatic, then the use of medication may increase the risk of caries. Interestingly, our results showed that women who nearly always use mouthwash as part of their oral hygiene were more likely to have asthma than those never using these products. Active ingredients of mouthwashes vary greatly among commercial solutions, but often include alcohol, essential oils (eucalyptol, menthol, thymol, methyl salicylate, eugenol, etc.), fluoride, cetylpyridinium, triclosan, hydrogen peroxide and/or chlorhexidine. Many of these compounds possess antimicrobial effect against bacteria commonly found in the mouth [28–31]. Thus, a potential mechanism accounting for the association of oral rinse with asthma could be modification of microbiota of the mouth, with derangement of its modulatory role in the immune status. On the other hand, some case reports have informed about the development of allergic reactions, including asthma exacerbations, due to mouthwash ingredients such as menthol and eugenol [32,33]. The cooling sensation elicited by menthol and eucalyptol is due to the activation of transient receptor potential melastatin 8 (TRPM8) receptors, which are thermo-sensors located in dorsal root and trigeminal afferent neurons [34]. However, TRPM8 receptors are also present in airway epithelial cells and mastocytes, and their activation is followed by the release of mediators [34,35]. Thus, an additional mechanism linking essential oils and asthma could be the secondary release of pro-inflammatory cytokines due to TRPM8 receptors activation in non-neuronal cells once menthol is inhaled or absorbed. We fully acknowledge that in our study, the effect size of oral hygiene and dental status on asthma was relatively small, and that additional research is required to corroborate and contextualize our results. In addition, we must bear in mind that asthma is a multifactorial disease, and thus associations found in our study must be viewed from the perspective that many other genetic and environmental factors are interacting to favor or prevent the development of asthma. Therefore, at present it is not possible to recommend modifications to the individual’s customary oral care. Furthermore, a major drawback of the study was its inevitable cross-sectional design, which precludes elucidation of the temporal relationship of variables. Unfortunately, the questionnaire does not include more details about questions listed in Table 1, which precludes drawing further associations or temporal assessments. Thus, although we are postulating that asthma presentation could be influenced by oral hygiene and conditions leading to current dental status, the reverse association could also be possible. In consequence, our results should merely be considered as hypothesis-generating findings, and further studies to confirm and clarify these associations are warranted. In conclusion, we identified oral hygiene and dental status as novel factors associated with asthma, inasmuch as having decayed teeth appeared to protect from asthma, while number of missing teeth and use of mouthwash was associated with the disease, especially among female subjects.
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The mechanisms underlying these associations deserve further investigation.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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ORIGINAL ARTICLE
Oral hygiene and dental status as factors related to asthma in high school and college students Mario H. Vargas, MD, MSc1,2, Francisco Macedo-Sa´nchez, MD3,4, Cuauhte´moc Solı´s-Torres, CPA, MSc3, Horacio Rubio-Monteverde, MD3, and Marı´a E.Y. Furuya, MD, PhD1
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1
Unidad de Investigacio´n Me´dica en Enfermedades Respiratorias, Hospital de Pediatrı´a, Centro Me´dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Me´xico DF, Mexico, 2Departamento de Investigacio´n en Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias, Me´xico DF, Mexico, 3Direccio´n General de Servicios Me´dicos, Universidad Nacional Auto´noma de Me´xico, Me´xico DF, Mexico, and 4 Servicio de Consulta Externa, Instituto Nacional de Enfermedades Respiratorias, Me´xico DF, Mexico Abstract
Keywords
Objective: Considering that oral microbiota might modulate immune responses, we explored if customary oral care procedures might influence immune-driven diseases such as asthma. Methods: This was a retrospective, cross-sectional analysis of responses to a self-completion medical questionnaire applied to subjects entering into college and high school programs during 2006–2011. Results: Responses from 329 780 students aged 14–24 years (97.6% of the original population) were analyzed. The prevalence of lifetime asthma was 4.01%. Subjects with asthma were slightly older, taller and heavier than subjects without asthma, and these differences were equally present in males and females. Subjects currently having two or more decayed teeth had asthma less frequently than those with one or none decayed tooth, with an odds ratio (OR) ¼ 0.86 and 95% confidence interval (95% CI) 0.83–0.89. In contrast, asthma was reported more frequently among students having two or more missing or filled teeth [OR ¼ 1.1 (95% CI 1.04–1.17) and OR ¼ 1.05 (95% CI 1.01–1.09), respectively]. From 2008 onwards, subjects also responded questions about oral hygiene incorporated into the core questionnaire. In these subjects, the use of toothpaste as well as the frequency and duration of toothbrushing were unrelated to asthma; regular use of mouthwash was associated with asthma in women [OR ¼ 1.16 (95% CI 1.07–1.25)], but not in men [OR ¼ 1.04 (95% CI 0.96–1.13)]. Results of multiple logistic regressions were in line with these findings. Conclusions: Our results suggested that oral hygiene and dental status could be novel factors influencing asthma development, and thus further studies to confirm and clarify this association are warranted.
Caries, dental care, DMF index, oral microbiota, oral rinse, toothpaste
Introduction Scientific knowledge about mechanisms involved in the pathogenesis of asthma has greatly improved over the last decades, but the primary causes of this complex disease remain questionable. The so-called hygiene hypothesis postulates that reduced exposure to microorganisms or their products favor the development of allergic-type, TH2-driven responses of the immune system [1]. Although basic research and epidemiological studies provide support for this hypothesis, the specific microorganism(s) whose absence promotes the allergic process remain uncertain. Contrary to the hygiene hypothesis, the colonization of airways by some specific infecting agents such as syncytial respiratory virus, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Correspondence: Dr. Mario H. Vargas, Unidad de Investigacio´n Me´dica en Enfermedades Respiratorias, Hospital de Pediatrı´a, Centro Me´dico Nacional Siglo XXI, IMSS. Av. Cuauhte´moc 330, CP 06720, Me´xico DF, Mexico. Tel: +55-56276900. E-mail: mhvargasb@ yahoo.com.mx
History Received 31 July 2014 Revised 18 September 2014 Accepted 5 October 2014 Published online 5 November 2014
Streptococcus pneumoniae, Hemophilus influenzae, and/or Moraxella catarrhalis, has been postulated as favoring the development of asthma [2–4]. More recently, a wider panorama of the potential role of microorganisms in the development of asthma is emerging. In this regard, the characterization of microbial diversity in the airways through metagenomic techniques has unveiled notable differences between asthmatic and non-asthmatic airways. The majority of studies exploring the airways microbiota coincided in that patients with asthma possess significantly greater bacterial diversity, with overrepresentation of bacteria belonging to the Proteobacteria phylum [5–8]. Interestingly, in 2011, Charlson et al. reported that the composition of airway microbiota in healthy subjects was indistinguishable from microbiota present in the oropharynx, although in progressively lower amounts as more distal was the airway sampled [9]. The authors speculated that the oropharynx was the source of the tracheobronchial microbiota, most likely by microaspiration. The oral cavity contains a vast array of different microorganisms that make up its
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permanent microbiota. Around 280 bacterial species have been cultured from the mouth, but this number rises to nearly 700 by additionally using culture-independent methods such as 16S rRNA gene-based molecular cloning [10]. Up to 96% of mouth-related taxa are contained in six major phyla: Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Spirochaetes and Fusobacteria [10]. Although the majority of bacteria usually found in the mouth maintain a commensal relationship with the host, under certain circumstances some of these may become pathogenic and cause diseases such as dental caries [11]. The bacteria most frequently associated with human caries are those belonging to a group of phenotypically similar microorganisms, the so-called mutans streptococci, from which Streptococcus mutans and Streptococcus sobrinus, are the major pathogens. These bacteria are transmitted to the child from primary caregivers (mainly the mother) [12,13]. At present, it is fully acknowledged that microbial communities living on body surfaces (skin and mucosal membranes) profoundly influence the development and shape of the immune system [14], and this modulatory role has been also ascribed to oral microbiota [15]. Thus, it is reasonable to speculate that subtle modifications of microbiota of the mouth due to procedures commonly employed in oral hygiene such as toothbrushing with toothpaste and the use of mouthwash [16–18], might modulate immune responses, hence promoting (or protecting from) the development of asthma. The Universidad Nacional Auto´noma de Me´xico is the largest educative institution in Mexico, and each year it accepts 65 000 students for entry into high school or college courses for the first time. Every student entering formal courses must fill out a self-completion automated medical questionnaire, which includes questions about lifetime asthma, current dental conditions and usual dental care. Thus, the objective of the present study was to analyze responses to this questionnaire with the aim to investigate at the individual level the potential relationships between asthma and dental status or oral hygiene.
Population and methods Study design In this retrospective and cross-sectional study, responses to the automated medical examination applied between 2006 and 2011 to students aged between 14 and 24 years were
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analyzed. The questionnaire-based, automated medical examination is composed of three modules that include 210 multiple-choice items related to current or past illnesses and with major factors that confer risk or protection on the student’s health. In 2008, a fourth module comprising 13 items on oral hygiene was added to the core questionnaire. Specific questions and possible responses that were taken into account for the present report, as well as the proportion of missing data, are listed in Table 1. The protocol was approved by the institutional research boards of the Instituto Mexicano del Seguro Social (approval No. R-2012-785-010) and the Instituto Nacional de Enfermedades Respiratorias (approval no. E01-12). Data management Associations between asthma and other variables were analyzed through the chi-square test and the odds ratio (OR) with a 95% confidence interval (95% CI). Multiple logistic regressions were used to assess the potential influence of selected variables on the risk for asthma. Data analyses were performed using the IBM SPSS Statistics v19.0 software (IBM Corporation, Somers, NY). Statistical significance was set at p50.05 bimarginally.
Results Between 2006 and 2011, a total of 337 875 students filled out the automated medical examination questionnaire. All students aged between 14 and 24 years were initially selected for inclusion into the study, comprising 330 982 subjects. After excluding individuals not responding to the question about asthma, a final population of 329 780 subjects (97.6% of the original population) was included in the analysis. This population included a slightly higher proportion of females (53.0%) than males. The percentage of subjects who responded affirmatively to the question about asthma was 4.35% among males and 3.70% among females (p50.001), for a global prevalence of 4.01%. Although anthropometric differences between subjects with and without asthma were rather small, they reached statistical significance (p50.01 in all comparisons). Thus, subjects with asthma were slightly older (16.97 versus 16.85 years of age), taller (165.67 versus 164.64 cm in height) and heavier (weight, 63.14 versus 61.67 kg; body mass index [BMI], 22.92 versus
Table 1. Selected questions included in the medical questionnaire regarding asthma, dental status and oral hygiene. Question Of the following health problems, which have you had? Asthma With respect to your permanent teeth How many have you lost? How many have caries? How many are obtruded? How many times do you brush your teeth in a day?a How much time do you spend on your toothbrushing?a Which of these oral health helpers do you use?a Toothpaste Mouthwash a
Questions available from 2008 onwards.
Possible responses
Missing data (%)
Yes/No
0.4
0/1/2/3/4/5/6/7/8/more 0/1/2/3/4/5/6/7/8/more 0/1/2/3/4/5/6/7/8/more 1/2/3 or more/none 30 s/1 min/1–3 min/3 min or more
1.8 2.3 2.0 3.7 3.8
Always/Sometimes/Never Always/Sometimes/Never
3.7 3.8
Dental status, oral hygiene and asthma
DOI: 10.3109/02770903.2014.974816
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22.67 kg/m2) than subjects without asthma (Table 2). These differences were equally present in both males and females. As can be observed in Table 3, in the whole population subjects having two or more decayed teeth had asthma less frequently than those with one or no decayed tooth [OR ¼ 0.86 (95% CI 0.83–0.89)]. In contrast, asthma was reported more frequently among subjects having two or more missing or filled teeth [OR ¼ 1.10 (95% CI 1.04–1.17) and OR ¼ 1.05 (95% CI 1.01–1.09), respectively]. From 2008 onwards, a subpopulation of 225 716 students responded to a questionnaire about oral hygiene. In these subjects, use of toothpaste as well as the frequency and duration of toothbrushing were not associated with asthma, but regular use of mouthwash was more often found among subjects with asthma. Analysis by gender corroborated that relationships between asthma and current caries, missing teeth or filled
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teeth occurred equally in both genders (Figure 1). However, regular use of mouthwash was associated with asthma in women [OR ¼ 1.16 (95% CI 1.07–1.25)], but not in men [OR ¼ 1.04 (95% CI 0.96–1.13)]. Results of the multiple logistic regression analysis (Table 4) were in line with the previously mentioned findings, i.e. in the whole population, the prevalence of asthma was lower according to the number of decayed teeth [adjusted OR ¼ 0.965 (95% CI 0.957–0.972)] or higher according to the number of missing teeth [adjusted OR ¼ 1.033 (95% CI 1.014–1.052)], and this was true when male and female students were evaluated separately. In addition, everyday use of mouthwash was also associated with a higher prevalence of asthma [adjusted OR ¼ 1.106 (95% CI 1.030–1.188)], but this tendency was solely observed among women [adjusted OR ¼ 1.180 (95% CI 1.065–1.309)].
Table 2. Anthropometric characteristics of the study population, and their relationship with asthma. All a
Males a
a
Females a
a
Characteristic
Asthma (n ¼ 13218)
No asthma (n ¼ 316562)
Asthma (n ¼ 6753)
No asthma (n ¼ 148380)
Asthma (n ¼ 6465)
No asthmaa (n ¼ 168182)
Age (years) Height (cm) Weight (kg) BMI (kg/m2)
16.97 ± 0.02** 165.67 ± 0.08** 63.14 ± 0.12** 22.92 ± 0.04**
16.85 ± 0.004 164.64 ± 0.02 61.67 ± 0.02 22.67 ± 0.007
17.06 ± 0.03** 171.45 ± 0.09** 67.56 ± 0.17** 22.93 ± 0.05**
16.96 ± 0.006 170.77 ± 0.02 66.48 ± 0.04 22.73 ± 0.01
16.89 ± 0.03** 159.63 ± 0.08** 58.54 ± 0.14** 22.92 ± 0.05**
16.75 ± 0.005 159.23 ± 0.02 57.45 ± 0.03 22.61 ± 0.01
BMI ¼ body mass index. Data correspond to mean ± standard error. **p50.01 versus the respective ‘‘No asthma’’ group.
a
Table 3. Association of asthma with dental status and oral hygiene in high school and college students.
Variable Decayed teeth 2 Missing teeth 2 Filled teeth 2 Use of toothpaste alwaysb Toothbrushings 2 per dayb Toothbrushings 1 minb Use of mouthwash alwaysb
Asthmaa (n ¼ 13218) 7008 1342 4516 8804 8220 4942 1571
No asthmaa (n ¼ 316562)
(54.2)** (10.3)** (34.8)** (99.3) (92.6) (55.7) (17.7)**
179 202 29 434 104 430 206 840 192 987 116 235 33 993
OR (95% CI)
(57.9) (9.5) (33.7) (99.4) (92.7) (55.9) (16.4)
0.86 1.10 1.05 0.84 0.98 0.99 1.10
(0.83–0.89) (1.04–1.17) (1.01–1.09) (0.65–1.08) (0.91–1.07) (0.95–1.04) (1.04–1.16)
OR (95% CI) ¼ odds ratio (confidence interval at 95%). Data are expressed as number (percent) of subjects. Data from 225 716 students (2008–2011 period). **p50.01 as compared with their respective ‘‘No asthma’’ group by chi-square test.
a
b
Figure 1. Variables related to oral hygiene and dental status and their relationship with the presence of asthma. Symbols correspond to the odds ratios (circles) and confidence intervals at 95% (horizontal lines) for male (A) and female (B) subjects.
Protective
(A)
Risk
(B)
Protective
Risk
Decayed teeth ≥2 Missing teeth ≥2 Filled teeth ≥2 Toothbrushings ≥2 per day Toothbrushings ≥1 min Use of toothpaste always Use of mouthwash always 0.5
1 Odds ratios
1.5
0.5
1 Odds ratios
1.5
Reference 1.041 (0.956–1.129) 1.180 (1.065–1.309)
Discussion
a
Reference 1.012 (0.956–1.071) 1.106 (1.030–1.188) 0.692 0.006 0.011 0.101
aOR (95% CI) ¼ odds ratio adjusted by the other variables in the model (confidence interval at 95%). Number of filled teeth and use of toothpaste were always excluded from the final regression models. In males, use of mouthwash was also excluded from the model.
0.343 0.002 0.040 0.166
0.963 (0.953–0.974) 1.030 (1.005–1.055) 50.001 0.02 0.037 0.029 0.968 (0.957–0.979) 1.046 (1.018–1.076) 50.001 0.001 0.032 0.045 50.001 0.001 0.036 0.032
Number of decayed teeth Number of missing teeth Use of mouthwash Never Sometimes Always
Variables in the regression modela
p
0.965 (0.957–0.972) 1.033 (1.014–1.052)
p b-coefficients aOR (95% CI) p
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b-coefficients
aOR (95% CI)
b-coefficients
Males (n ¼ 99 405) All (n ¼ 210 517)
Table 4. Dental status and oral health and their relationship with asthma, as assessed by multiple logistic regression, in high school and college students.
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aOR (95% CI)
M. H. Vargas et al.
Females (n ¼ 111 112)
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In the present study, a large database with responses to a selfcompletion questionnaire in subjects 14–24 years of age who initiated high school or college courses was analyzed with the aim of identifying factors related to asthma, mainly those concerning oral hygiene and dental status. Asthma is currently considered a disease that is primarily driven by immune cells, including TH2 cells in the classic eosinophilic, allergic-type phenotype and TH17 cells in the severe neutrophil-predominant phenotype. Thus, exploration of factors capable of modulating the immune response is important. Undoubtedly, the interaction between microorganisms and the immune system is one of the most powerful stimuli determining the type of immune response, and this interaction might occur with some specific microorganisms or with microbiota as a whole [14,19]. Our study unveiled some associations between asthma and dental status, inasmuch as subjects having current caries had a lesser probability of having asthma. Paradoxically, in the scientific literature, a number of studies have concluded that caries are directly related to asthma (reviewed by Alavaikko et al. [20]), which at first glance appears to be contradictory with our results. However, the majority of these studies defined caries employing the usual composite index of decayed, missing and filled teeth (dmf, DMF), as proposed by the World Health Organization [21]. In this index, only the first condition (decayed) truly refers to current caries, while the latter two variables are indicators of ‘‘past’’ caries. These three conditions could exert different effects on oral microbiota. For example, children with one or more carious teeth had higher salivary S. mutans levels than control children with healthy teeth, but these levels returned to control values after restoration of carious lesions [22]. Workers who attended regular dental appointments had fewer active caries and lower salivary levels of S. mutans [23]. Finally, number of teeth appeared to be related to levels of periodontopathic and cariogenic bacteria [24–26]. Thus, it is probable that microbiota in the mouth differs in subjects with and without current caries, and according to the hygiene hypothesis, the higher number and/or the different type of microorganisms found in subjects with active caries could be exerting a protective role against asthma. Following the same line of thought, it is reasonable to speculate that having missing and/or filled teeth is indicative that the subject receives professional and/or personal dental care more often than those who continue to have active caries. This opens the possibility that their oral microbiota might be different from that found in subjects with sound teeth or in subjects with decayed teeth. Thus, in previous studies the use of composite dmf or DMF indexes may have blurred the true role carried out by active caries in asthma. In this context, our findings strongly suggest that in future studies, each of the three elements of dmf and DMF indexes needs to be evaluated separately. In our analysis, the strength of the association between active caries and development of asthma may have been underestimated. Anti-asthma medication itself may contribute to dental caries and periodontal disease due to, for example, a beta-2 agonist-induced decrease of salivary
Dental status, oral hygiene and asthma
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DOI: 10.3109/02770903.2014.974816
protein secretion and flow rate, and reduced pH of saliva and plaque, among other mechanisms [27]. Thus, even though a putative causal relationship between active caries and protection from asthma may exist, once a patient becomes asthmatic, then the use of medication may increase the risk of caries. Interestingly, our results showed that women who nearly always use mouthwash as part of their oral hygiene were more likely to have asthma than those never using these products. Active ingredients of mouthwashes vary greatly among commercial solutions, but often include alcohol, essential oils (eucalyptol, menthol, thymol, methyl salicylate, eugenol, etc.), fluoride, cetylpyridinium, triclosan, hydrogen peroxide and/or chlorhexidine. Many of these compounds possess antimicrobial effect against bacteria commonly found in the mouth [28–31]. Thus, a potential mechanism accounting for the association of oral rinse with asthma could be modification of microbiota of the mouth, with derangement of its modulatory role in the immune status. On the other hand, some case reports have informed about the development of allergic reactions, including asthma exacerbations, due to mouthwash ingredients such as menthol and eugenol [32,33]. The cooling sensation elicited by menthol and eucalyptol is due to the activation of transient receptor potential melastatin 8 (TRPM8) receptors, which are thermo-sensors located in dorsal root and trigeminal afferent neurons [34]. However, TRPM8 receptors are also present in airway epithelial cells and mastocytes, and their activation is followed by the release of mediators [34,35]. Thus, an additional mechanism linking essential oils and asthma could be the secondary release of pro-inflammatory cytokines due to TRPM8 receptors activation in non-neuronal cells once menthol is inhaled or absorbed. We fully acknowledge that in our study, the effect size of oral hygiene and dental status on asthma was relatively small, and that additional research is required to corroborate and contextualize our results. In addition, we must bear in mind that asthma is a multifactorial disease, and thus associations found in our study must be viewed from the perspective that many other genetic and environmental factors are interacting to favor or prevent the development of asthma. Therefore, at present it is not possible to recommend modifications to the individual’s customary oral care. Furthermore, a major drawback of the study was its inevitable cross-sectional design, which precludes elucidation of the temporal relationship of variables. Unfortunately, the questionnaire does not include more details about questions listed in Table 1, which precludes drawing further associations or temporal assessments. Thus, although we are postulating that asthma presentation could be influenced by oral hygiene and conditions leading to current dental status, the reverse association could also be possible. In consequence, our results should merely be considered as hypothesis-generating findings, and further studies to confirm and clarify these associations are warranted. In conclusion, we identified oral hygiene and dental status as novel factors associated with asthma, inasmuch as having decayed teeth appeared to protect from asthma, while number of missing teeth and use of mouthwash was associated with the disease, especially among female subjects.
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The mechanisms underlying these associations deserve further investigation.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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