Childhood Asthma: Part I. General aspects and Oral Features

Abstract:

Asthma is defined as a chronic inflammatory condi­tion characterised by variable and reversible episodes of airflow obstruction and bronchospasm. Asthma is the commonest chronic disease in childhood. Pediatric asthma is a common chronic condition with wide-ranging implications for children’s health, their families, and the health care system. The majority of asthmatic patients will require a form of long-term ‘preventive’ medication usually in the form of inhaled corticosteroids in order to prevent exacerbation of their symptoms. There is a consensus in the literature that this disease causes an impact that directly affects the quality of life of an individual, not only due to the respiratory alterations, but also the behavioural, functional, and physical losses, as exemplified by children’s school absenteeism. This paper consists of part I providing an overview of the Definitions, Prevalence, Incidence, Classification, Medications and Oral Manifestations in Children with Asthma.

Introduction

Medically-necessary care (MNC) is the reasonable and essential diagnostic, preventive, and treatment services (including supplies, appliances, and devices) and follow-up care as determined by qualified health care providers in treating any condition, disease, injury, or congenital or developmental malformation to promote optimal health, growth, and development [1]. Pediatric dentists have traditionally been viewed by the dental community as the specialty group best prepared to treat children with special health care needs [2].Dental caries, periodontal disease, dentoalveolar trauma, and other pathological orofacial conditions, left untreated, can limit substantially an individual’s development and quality of life. Therefore, an individual should be considered to have a dental disability if orofacial pain, infection, or pathological condition and/or lack of functional dentition affect nutritional intake, growth and development, or participation in life activities [1]. Health care for individuals with special needs requires specialized knowledge, as well as increased awareness and attention, adaptation, and accommodative measures beyond what are considered routine [1].

Definitions

Asthma is defined as a chronic inflammatory condi­tion characterised by variable and revers­ible episodes of airflow obstruction and bronchospasm. Symptoms include wheez­ing, shortness of breath, chest tightness and coughing, often in response to an identifi­able trigger. Asthma is a cause of consider­able morbidity worldwide. It is estimated, however, that as much as 75% of hospital admissions for asthma are avoidable and as many as 90% of deaths are preventable. Worldwide prev­alence is estimated at 300 million, a preva­lence that continues to increase [3].

Asthma is the commonest chronic disease in childhood. Pediatric asthma is a common chronic condition with wide-ranging implications for children’s health, their families, and the health care system [4]. Due to the various different phenotypes of childhood asthma, it has been difficult to agree on a clear definition of the condition and instead an operational description is used: ‘Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment (Global Initiative for Asthma, 2012). However, in children <5 years of age, clinical symptoms of asthma are variable and nonspecific, and a symptoms-only approach that defines various wheezing phenotypes has been recommended [5].

Asthma Classification

The diagnosis may be relatively straightforward for the child with characteristic symptoms, triggers, and response to therapy, but there are other less common presentations that can make the diagnosis challenging. Diagnosing asthma in a toddler with recurrent wheezing can be particularly difficult. Treating asthma in a step-wise fashion usually reduces symptom frequency and improves asthma control. Asthma exacerbations and poor outcomes from acute exacerbations remain an area in which we have room for improvement. This article provides an overview of the diagnosis and management of childhood asthma for the primary care provider [4]. Historically, asthma was classified according to severity of symptoms, but more recently the Global Initiative for Asthma (GINA) has classified asthma both according to disease severity and adequacy of symptom control. This represented a shift in asthma classi­fication and indicates the recognition that asthma severity is both a manifestation of underlying disease severity and responsive­ness to medication. GINA classifies asthma as controlled, partly controlled or uncontrolled [3]

Prevalence and incidence, and changing patterns of asthma with age

Asthma is a common condition which is managed in many countries and in millions of children and adolescents according to regional, national, and international guidelines. In the United States, besides dental caries, asthma is the most common chronic disease. The prevalence, causes and clinical presentation of asthma all vary with age. Many children first develop symptoms during infancy, but many cease wheezing in early childhood. The prevalence of childhood asthma increased markedly in Europe in the second half of the 20^th century. The increase was initially most marked in Western Europe. The questionnaires developed for the International Study of Asthma and Allergy in Childhood (ISAAC) have provided a common tool for assessing the prevalence of asthma and wheezing disorders in children. In the ISAAC study performed in 1997, the highest prevalence of childhood asthma in Europe was found in the British Isles, with the prevalence of ‘asthma ever’ (lifetime prevalence of asthma) ranging from 1.6% in Albania to 20.7% in the UK for 13–14-year-old children, and from 1.4% in Estonia to 22.9% in the UK among 6–7-year-olds, with markedly increasing rates across Europe from East to West (Figure 1)[5].

Mortality: Asthma mortality in children is low and over recent years it has decreased in most European countries. Historically, mortality was highest among the youngest children, lower during school age, and then increased from puberty to adulthood.

Morbidity: Asthma morbidity is a major burden for the child, his/her family and the community. Asthma attacks are very frightening for the child and due to the resulting disruption of life and reduced physical ability there is an emotional, as well as economic, impact of the disease. The social burden of asthma is considerable, not only on the sick child but also on parents, siblings and the household in general [5].

Causes/pathogenesis

• Environmental: Asthma results from an interaction between different environmental and genetic factors. The environmental influences begin during pregnancy: allergic sensitization has been described before birth, and several studies have demonstrated reduced lung function in newborn infants of smoking mothers compared to those of nonsmoking mothers. Smoking increases the risk of both asthma and poorer lung function throughout childhood. All children should have the right to an environment free from tobacco smoke products both before and after birth. Respiratory virus infections are the major cause of acute bronchiolitis in infancy and of acute asthma attacks among older asthmatic children. Allergens may be encountered both outdoors and indoors, and house dust mites and animal dander are particularly important perennial indoor allergens. Occupational agents play a minor role during childhood, but several types of allergy may influence the choice of education in relationship to later working life. Kindergartens and schools are the working environment of children, and the need for a healthy indoor environment in such institutions should be emphasized. Special consideration should be given to the increased risk of respiratory infections, especially in kindergartens. In schools, precautions may be taken to reduce allergen exposure for allergic asthmatic children. Emphasis should also be put upon mastering exercise induced asthma in gymnastic lessons and physical training [5].
• Genetic: Asthma, and one of its major causes, allergy, have strong hereditary traits. During recent years, much effort has been put into genetic family studies in order to identify genetic markers. A large number of markers with possible relationships to asthma and airway inflammation have already been identified, but these vary between populations. There has also been increased focus upon epigenetics: the finding that environmental influences may cause DNA methylation and histone formation, and thus change and inactivate the influence of specific genes, has given insight into how the environment may interact with genes, and has shown that this interaction may even be transferred from mother to child. Furthermore, hereditary traits have been found to influence the response to asthmatic drugs. Examples include β2-receptor sensitivity and responsiveness to inhibitors of leukotriene synthesis [5].
• Exercise: Throughout childhood, but increasingly during school age, exercise is an important cause of asthma exacerbations (exercise-induced asthma). It has been reported that 30% of all asthmatic children suffer from restriction of physical activity and it is very important to teach asthmatic children to master exercise, by education, advice related to ‘warming up’ and medical treatment [5].

Asthma and Medications

Modern guidelines for treating childhood asthma distinguish between controlling and relieving treatment. Among the controlling treatments, inhaled corticosteroids are the most important drugs and enable most children and adolescents with asthma to lead a normal life. The treatment of asthma can be divided into two phases: the first is to control the symptoms of the acute phase, such as bronchospasm, with the use of bronchodilator medicines. The second phase is to prevent new acute events through maintenance treatment, by using inhaled or systemic steroids and bronchodilators of long duration [7].

The majority of asthmatic patients will require a form of long-term ‘preventive’ medication usually in the form of inhaled corticosteroids (ICS) in order to prevent exacerbation of their symptoms. Sustained bronchodilatation may be achieved by the use of inhaled long-acting beta‑2 ago­nists. Recently, an inhaled corticosteroid has been introduced as a pro-drug, which depends for its effect on enzymatic activation in the respiratory epithelium. The lack of systemic side-effects makes such agents particularly suitable for childhood asthma [5].

Inhaled β2-agonists are important reliever medication, for both acute and chronic asthma. Combination treatment consisting of an inhaled corticosteroid and an inhaled long-acting β2-agonist has proved to be very effective in adult asthma care, but in childhood asthma and especially in pre-school children, the treatment response has not been as good.

Inhaled corticosteroids are commonly pre­scribed as a preventive medication and side effects are principally local, compared with the oral or parenteral route. However, sys­temic effects are seen with high-dose ther­apy. These adverse effects may include the suppression of the hypothalamo-pituitary-adrenal axis, thinning of the skin, stunted growth in children, ophthalmic effects and osteoporosis [8]. Children should be monitored carefully to assess the response to treatment, and treatment that proves to be ineffective should be stopped. Anticholinergic therapy, in particular ipratropium bromide, is also effective as a bronchodilator in children and may have an additive effect to inhaled β2-agonists. Anticholinergic treatment seems to have a special place as pre-medication before exercise in children with exercise-induced asthma and in treatment of asthmatic adolescents with an athletic career. The anti-immunoglobulin (Ig) E monoclonal antibody omalizumab has proved effective for some patients with severe allergic asthma, but, again, some fail to respond, emphasizing the need for careful follow-up. Other novel treatments are currently being investigated. Asthma care involves much more than just pharmacological treatment, although this is a very important part of the treatment plan. Participation in physical activity is of prime importance in childhood asthma and should be encouraged [5].

Asthmatic patients may be at an increased risk of significant adverse reactions to com­monly used medications. It has been reported that 7% of patients with asthma and 14% of patients with severe asthma have aspirin-exacerbated respiratory disease. In severe cases the reactions can lead to intense bron­chospasm and fatal anaphylaxis [9].

Cross-sensitivity has been noted between aspirin and other non-steroidal anti-inflam­matory drugs (NSAIDs) and, therefore, therapy with NSAIDs should be avoided in asthmatic patients with a history of aspi­rin or other NSAID sensitivity. Equally, it should be administered cautiously in all patients with pre-existing asthma, whether or not they have a history of sensitivity [10]. Aspirin desensitisation has been shown to be effective and can lead to patients over­coming their allergy to aspirin and NSAID drugs, with a subsequent reduction in res­cue courses of oral corticosteroids to control their symptoms [11]. Due to the above indications, paracetamol is the drug of choice for pain relief in asthmatic patients. Opiate drugs are also contra-indicated in severe asthmatic patients as they can lead to respiratory depression and histamine release, therefore precipitating a severe attack [12].

Dental antibiotic prescribing in asth­matics has not been found to have many contra-indications and most antibiotics do not interfere with asthma treatment. Patients taking theophylline-containing asthmatic medications should avoid erythromycin and other macrolide antibiotics as they interfere with theophylline metabolism and can lead to toxic levels of methylxanthines in the blood [13].

This is treated with vita­min D and calcium supplementation, bis­phosphonate therapy or the administration of monoclonal antibodies. Patients on bis­phosphonate therapy may be at an increased risk of bisphosphonate related osteonecro­sis of the jaw (BRONJ), especially those on intra-venous bisphosphonates. These patients require careful treatment plan­ning and liaison with the patient’s physi­cian, particularly if dental extractions are required [14].

Prognosis

Childhood asthma most often starts before school age. During puberty, many children – especially boys – experience improvement, but later in life the symptoms of asthma often recur. During early life, boys more frequently have asthma; after 10 years of age, however, girls more frequently develop asthma, often with greater severity. However, with modern asthma treatment and care, most asthmatic individuals are able to lead a normal, healthy life. The lifetime risk of asthma is approximately 35%, with most cases occurring early in life, and many requiring lifelong medical follow-up and medication, and thus having an impact on health costs. Early childhood asthma and, in particular, severe childhood asthma increase the risk of chronic airway obstruction in adult life[5].

Oral Manifestations

There is a consensus in the literature that this disease causes an impact that directly affects the quality of life of an individual, not only due to the respiratory alterations, but also the behavioural, functional, and physical losses, as exemplified by children’s school absenteeism [15]. In addition, there is a growing body of evidence from clinical or epidemiological studies suggesting a significant increase in oral diseases in asthmatic children, including increased prevalence of caries, enamel defects, malocclusion, erosion, oral candidiasis, and changes in salivary composition and flow, which worsens in children who do not have access to dental care [16, 17].

A systematic review and meta-analysis concluded, based on a study of 25 articles from 1950 to 2010, that asthma significantly increases the risk of caries in the deciduous and permanent dentition. One of the predisposing factors is possibly the medication taken, which acts on saliva secretion and the content of immunoglobulin A [18]. On the other hand, another literature review based on the study of 27 articles found that, although recent studies show little evidence of a relationship between asthma and dental caries, most show that the severity of the disease and its pharmacotherapy (types of drugs) are factors for an increased risk of caries [16]. Moreover, we highlighted that most of the published studies was developed in hospital context, and this study provides evidence to primary health care setting. Therefore, the increase in caries in asthmatics seems to be more associated with the treatment, especially the use of salbutamol, than with the disease itself, which is according findings in this study, in a primary health care setting [19].

Dental Caries

There are many factors related to dental caries etiology, such as diet, salivary flow, salivary components, host defenses, and socioeconomic conditions. Considering the importance of an early identification of populations at risk of dental caries, this study intended to evaluate whether the asthmatic population needs special dental attention in the form of prevention programs.  There is some controversy in the scientific community about the relationship between asthma and caries, and regarding the different methodologies used to study these diseases. In this study, widely known indexes and methodologies-were used, that allowed comparison between groups with or without asthma. The risk of dental caries in people that use asthma medications regularly has been well documented and its occurrence is mainly due to alterations in salivary parameters [20].

There has been considerable debate in the literature regarding the caries risk of asth­matic patients. Studies have demonstrated higher caries prevalence in both the primary and permanent dentitions of children with asthma [21, 22]. Conversely, alternative research has failed to demonstrate an association between dental caries and asthma. A recent systematic review has concluded that asthma doubles the risk of dental caries in both the primary and permanent dentition [18].

Numerous theories have been postulated to explain this increased caries risk includ­ing increased medication effects, increased prevalence of mouth-breathing, increased consumption of sugary drinks and the risk of parental overindulgence. Therefore, it is likely that the aetiology is multifactorial [23]. 

Saliva has a beneficial effect on caries reduction through four main actions: physi­cal cleansing, antibacterial effect, buffering capacity and super saturation with calcium phosphate. Prolonged use of a beta‑2 ago­nist can significantly reduce salivary flow. Ryberg et al. reported that overall salivary flow decreased by 26% and parotid flow reduced by 36% in asthmatic groups on medication, when compared with controls [24]. This group also determined that asthmatic patients have a reduced salivary output per minute of amylase, lysozyme, salivary peroxidase and secretory IgA in stimulated salivary flow. Therefore, reduced quantity of saliva, combined with a reduced quality of secreted saliva may significantly increase caries risk for asthmatic patients [25].

In addi­tion, Kargul et al. described a decrease in salivary and plaque pH to below the criti­cal value of 5.5, 30 minutes after the use of agonist (salbutamol 400 mcg) and inhaler corticosteroid (fluticasonepropionate 250 mcg) [26].

This has been confirmed in a study by Tootla et al., who found that dry powder inhalers consistently produce a pH below 5.5 indicating their cari­ogenic potential. Certain inhalers contain fermentable carbohydrates in the form of lactose. This aims to mask the bitter medica­tion taste and improve patient tolerance, but may contribute to an increased caries risk. Asthmatic patients have also been found to show increased counts of the cariogenic bac­teria Streptococcus mutans [25, 27].

Decreased salivary flow as a result of regu­lar beta-2 agonist inhalation, combined with consistent mouth breathing, can create a feeling of thirst. To compensate for this oral drying, asthmatic patients may drink regu­larly. The continual masking of the bitter medication taste and thirst quenching with carbonated drinks, combined with reduced salivary protection and increased prevalence of enamel defects, may be a major contrib­utor to caries amongst these patients. The long-term use of sugary medications, includ­ing antibiotics and analgesics, which may occur in the asthmatic population has been shown to be deleterious to dental health [3, 28].

Some authors found that asthmatic subjects could have higher caries risk, paying special attention to the medication used. Increased caries experience was associated with prolonged use of bronchodilators, which leads to reduced salivary flow [24]. Reduced salivary flow is accompanied by a concomitant increase in cariogenic microorganisms, lactobacilli and Streptococcus mutans in the oral cavity, which are contributing factors for higher caries rates. In addition, antiasthmatic medications containing fermentable carbohydrates and sugars can indirectly decrease oral pH, another factor that can contribute to the development of the disease [29]. However, other authors did not observe the same results [30].

Asthma itself was considered a risk factor for dental caries by some authors [31, 32] or the medication used for asthma treatment was blamed [25, 29, 31, 33]. But there are other authors who did not find a correlation between asthma and/or the medication used and an increased caries risk [30].

An increase in the salivary levels of Streptococus Mutans, correlated with asthma treatment duration, which can be attributed to a decrease in salivary flow and, therefore, an indirect effect of medication [33]. The salivary flow rate of subjects was investigated by Paganini et al., 2011 [20]. They found that children with moderate or severe asthma showed reduced salivary flow, as seen by Shashikiran et al., 2007 [33].

The asthmatic through either its disease status or its pharmacotherapy carries several factors for an increased caries risk. pH values of most inhalant powders are less than 5.5. A decrease of the salivary and plaque pH has been detected in asthmatic children after use of these inhalers. This low pH value associated with a reduced salivary flow rate (caused by beta-adrenergic agonists and by anti-histaminic medication) makes asthmatics more susceptible to caries and erosion. There are only a few studies that take into account that asthma is a disease with a large diversity of severity and duration. This approach could help to clarify some variability in caries risk. A dose-response study conducted to examine the oral health status of asthmatic children and to compare the oral health condition and oral health habits within different groups of asthmatic children [34].

There are only few studies reporting its impact on the oral cavity. Children with chronic conditions such as asthma require an oral and dental preventive program as part of their interdisciplinary care [35].

In conclusion, asthmatic children and adolescents presented greater caries prevalence in permanent teeth after 10 years of age, as well as poor oral hygiene and greater Mutans streptococci salivary levels, an important bacterial group involved in the etiology of caries. Besides other important factors that should be evaluated, our results suggest that asthmatic children and adolescents should receive special dental attention for the prevention of caries [22, 30].

Dental Erosion

It has been suggested that asthma medica­tion and its side effects contribute to dental erosion. Saliva is the main neutraliser of daily dietary acids in the oral cavity. This increased risk of dental erosion may be attributed to the reduction in salivary flow as mentioned previously [25].

Tootla et al. meas­ured the erosive potential of inhalers. Those with a higher titratable acidity are consid­ered to have a higher erosive potential for dental tissues. Despite the fact that asthma inhalers, particularly lactose-based inhalers, produce a low oral pH, their titratable acid­ity has not been shown to have an erosive potential for dental tissues [27].

An increased risk of dental erosion may be explained by the increased incidence of gastro-oesophageal reflux disease (GORD) amongst asthma sufferers. GORD occurs when gastric acid within stomach contents escapes into the oesophagus. The most com­mon symptoms include heartburn and acid regurgitation, but consequences of reflux may be more extensive. An association between GORD and asthma has been accepted for over a century since Osler’s comment that ‘severe paroxysms of asthma may be induced by overloading the stomach. GORD is 75% more prevalent in asthmatic patients when compared with controls [36].

However, it is unclear whether there is a causal relationship between asthma and GORD, or alternatively, whether this represents a chance association between two common childhood conditions. There are a number of possible explanations for this increased prevalence. The ‘reflux theory’ suggests that the bronchial tree is damaged as a result of occult acid inhala­tion, whereas the ‘reflex theory’ postulates that bronchospasm is precipitated by acidic stimulation of vagal nerve endings in the oesophagus [37].

 A significant association between asthma and GORD has been reported in the literature, although the direction of causality remains unclear [38].

As there is a strong association between asthma and GORD, all dentists must be proactive at making appropriate referrals if tooth erosion is noted [3].

Enamel Defects

The prevalence of developmental defects of enamel is reported to be increased in the asthmatic patient with its consequent risk of caries. Guergolette et al. estimated an 11-fold increased risk of enamel defects compared with controls. This correlated with increased disease severity and earlier symptomology. The occurrence of dental enamel defects (enamel opacity) correlated with greater asthma severity [39].

The prevalence of enamel defects found was 53.2% in asthmatics and 48.1% in the non-asthmatic group, without statistical differences between groups, and the same occurred for the type of asthma and types of medications used [40].

A recent systematic review including 25 studies on the aetiology of MIH found, in several studies, an association of early childhood illnesses, such as asthma, as an aetiological factor for MIH, but the results were conflicting regarding the use of medications [40].

A study with Danish children from 6 to 8 years of life assessed the presence of marked opacities in the permanent first molars in asthmatic children, both those taking and not taking medication. Children who used inhaled medications (β2-agonists and corticoids) before age 3 had marked opacities and hypoplasia, and those who did not use oral or inhaled medications for asthma control also presented alterations to the dental enamel. In brief, the authors concluded that the use of asthma medications before age three did not present an increased risk for the development of marked opacities in the first molar, if compared with children that did not take medications, but had a greater chance of developing hypoplasia [41]. In agreement with this study, it is possible to observe that enamel defects were not related to the medications used for asthma control in patients aged 6-12 years who presented with intermittent and mild persistent asthma in a Primary Health Care (PHC) setting. As limitations of this study, it can highlight the cross-sectional analysis and the fact that the patients evaluated were cared for by physicians and dentists in their health units, and their oral and overall health was properly controlled. According to another study, there was no evidence for an association between asthma, caries, erosion, and enamel defects in children aged from 6 to 12 years in a PHC setting. Nevertheless, there was a relationship between caries prevalence and use of salbutamol, regardless of asthma type and severity, and erosion with high frequency of oral hygiene [19].

There is no consensus in the literature over the relationship between asthma and the occurrence of caries, enamel defects, and erosion; therefore, longitudinal studies need to be carried out to establish a possible cause-effect relationship between asthma and oral alterations in children [19].

Periodontal Diseases

Studies investigating the association between asthma and periodontal disease have shown equivocal results [17]. It has been suggested that the relationship between the two may be attributed to either the side effects of the asthma medication, pathological activation of the inflammatory and immune process or a combination of the two. The protective mechanisms within saliva balance the interactions between bacterial and immunological factors and help maintain periodontal health. A decrease in salivary flow and secretory IgA, caused by long term use of asthma medication, reduce its protective qualities and therefore place the patient at greater risk of developing periodontal disease. In addition to this, studies have reported that gingival tissues of asthmatic patients have markedly elevated IgE levels, which are responsible for periodontal destruction [42].

Oral hygiene has been shown to be poor in the asthmatic population. McDerra et al. reported higher plaque deposits in 4–10-year-old asthmatic children, compared with controls. This was not replicated in the 11–16 year group. Increased levels of gingivitis and calculus levels have also been demonstrated in asthmatic children. This may be exacerbated by chronic mouth breathing secondary to sinupulmonary disease [43].

Candida

The long-term use of ICS is strongly associated with increased incidence of oral candidal infection, in particular, pseudomembranous candidosis [44].

This presents as white, plaque-like lesions on the oral mucosal surface, which can be wiped off to reveal an erythematous mucosa. The soft palate and buccal mucosa are commonly affected. Only 10–20% of inhaled corticosteroids are delivered to the lower respiratory tract. The remainder is deposited in the oropharynx. Asthmatic patients have increased incidence of oral candidal infection, which can be attributed to the generalised immunosuppressive and anti-inflammatory effects of the corticosteroids. In addition, many dry powdered inhalers contain lactose monohydrate. The elevated oral glucose levels provide an encouraging environment for candidal adhesion and proliferation in the oral cavity, thus elevating the risk of mucosal infection in the asthmatic patient. As mentioned previously, the use of beta-2 agonists reduces salivary flow, which may further predispose the asthmatic patient to candidal infection [17].

To be followed by Childhood Asthma: Part II. Dental treatment.

Note: This research is part of 2019-1-RO01-KA202-063820 Erasmus+ Project „Oral Special Care Academic Resources” (OSCAR)

Conflict of interests: None

References

1. AAPD. Policy on Medically-Necessary Care. Pediatr Dent 2018; 40(6):22-7.
2. Baens-Ferrer C, Roseman MM, Dumas HM, Haley SM. Parental perceptions of oral health-related quality of life for children with special needs: impact of oral rehabilitation under general anesthesia. Pediatr Dent 2005; 27(2):137-42.
3. Harrington N., Prado N. and Barry S. Dental treatment in children with asthma – a review. BDJ 2016;220; 6: 299-302.
4. Hoch HR, Houin PR, Stillwell PC. Asthma in Children: A Brief Review for Primary Care Providers. Pediatr Ann 2019; 48(3):103–9.
5. ERS European Respiratory Society. The European Lung White Book 
6. Gulledge L, Beard S. Asthma management. Aspen publication inc. Maryland, 1999. p 38.
7. Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology, ed 5. Edinburgh, Churchill Livingstone, 2003.
8. Chee C, Sellahewa L, Pappachan JM. Inhaled Corticosteroids and Bone Health. Open Respir Med J 2014; 8: 85–92.
9. Rajan JP, Wineinger NE, Stevenson DD, White AA. Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature. J Allergy Clin Immunol 2015; 135: 676–81.
10. Stevenson DD, Hougham AJ, Schrank PJ, Goldlust MB, Wilson RR . Salsalate cross-sensitivity in aspirin-sensitive patients with asthma. J Allergy Clin Immunol 1990; 86: 749–58.
11. Berges-Gimeno MP, Simon RA, Stevenson DD. Long-term treatment with aspirin desensitization in asthmatic patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 2003; 111: 180–6.
12. Claramunt Lozano A, Sarrión Perez MG, Gavaldá Esteve C. Dental considerations in patients with respiratory problems. J Clin Exp Dent 2011; 3: e222–e227.
13. Little JW, Falace DA. Pulmonary disease. In: Dental Management of the Medically Compromised Patient. 4th ed., St Louis: Mosby, 1993. p 235–41.
14. Sigua-Rodriguez EA, da Costa Ribeiro R, de Brito AC, Alvarez-Pinzon N, de Albergaria-Barbosa JR. Bisphosphonate-related osteonecrosis of the jaw: a review of the literature. Int J Dent 2014; doi:10.1155/2014/192320.
15. Guergolette RP, Dezan CC, Frossard WTG, Ferreira FBA, Cerci Neto AFK. Prevalence of developmental defects of enamel in children and adolescents with asthma. J Bras Pneumol 2009;35: 295‐300.
16. Turkistani JM, Farsi N, Almushayt AAS. Caries experience in asthmatic children: a review of literature. J Clin Pediatr Dent. 2010; 35:1‐8.
17. Thomas MS, Parolia A, Kundabala MVM. Asthma and oral health: a review. Aust Dent J. 2010; 55: 128‐33.
18. Alavaikko S, Jaakkola MS, Tjäderhane LJJ. Asthma and caries: a systematic review and meta-analysis. Am J Epidemiol. 2011; 15:631‐41.
19. Rezende G, Dos Santos NML, Stein C, Hilgert JB, Faustino-Silva DD. Asthma and oral changes in children: Associated factors in community of southern Brazil. Int J Paediatr Dent. 2019; 29(4):456-63.
20. Paganini M, Dezan CC, Bichaco TR, de Andrade FB, Neto AC, Fernandes KB. Dental caries status and salivary properties of asthmatic children and adolescents. Int J Paediatr Dent 2011; 21: 185–91.
21. Stensson M, Wendt LK, Koch G, Oldaeus G, Birkhed D. Oral health in preschool children with asthma. Int J Paed Dent 2008; 18: 243–50.
22. Botelho MPJ, Maciel SM, Neto AC, Dezan CC, Fernandes KBP, de Andrade F B. Cariogenic microorganisms and oral conditions in asthmatic children. Caries Res 2011; 45: 386–92.
23. McDerra EJ, Pollard MA, Curzon ME. The dental status of asthmatic British school children. Paediatr Dent 1998; 20: 281–7.
24. Ryberg M, Moller C, Ericson T. Effect of beta 2-adrenoceptor agonists on saliva proteins and dental caries in asthmatic children. J Dent Res 1987; 66: 1404–6.
25. Ryberg M, Moller C, Ericson T. Saliva composition and caries development in asthmatic patients treated with beta 2-adrenoceptor agonists: a 4-year follow-up study. Scand J Dent Res 1991; 99: 212–8.
26. Kargul B, Tanboga I, Ergeneli S, Karakoc F, Dagli E. Inhaler medicament effects on saliva and plaque pH in asthmatic children. J Clin Pediatr Dent 1998; 22: 137–40.
27. Tootla R, Toumba K, Duggal MS. An evaluation of the acidogenic potential of asthma inhalers. Arch Oral Biol 2004; 49: 275–83.
28. Barry S, O’Connor M, Fleming P. Prescribing sugar-containing medicine for children – Are we forgetting “Primum non Nocere”? Ir Med J 2009; 102: 298–300.
29. Reddy DK, Hedge AM, Munshi AK: Dental caries status of children with bronchial asthma. J Clin Pediatr Dent 2003; 27: 293–6.
30. Meldrum AM, Thomson WM, Drummond BK, Sears MR: Is asthma a risk factor for dental caries? Findings from a cohort study. Caries Res 2001; 35: 235–9.
31. Ersin NK, Gülen F, Eronat N, Cogulu D, Demir E, Tanaç R, Aydemir S. Oral and dental manifestations of young asthmatics related to medication, severity and duration of condition. Pediatr Int 2006; 48: 540–54.
32. Stensson M, Wendt LK, Koch G, Nilsson M, Oldaeus G, Birkhed D. Oral health in pre-school children with asthma – followed from 3 to 6 years. Int J Paediatr Dent 2010; 20: 165–72.
33. Shashikiran ND, Reddy VVS, Raju PK. Effect of antiasthmatic medication on dental disease: dental caries and periodontal disease. J Indian Soc Pedod Prev Dent 2007; 25: 65–8.
34. Eloot A, Vanobbergen J, Martens L. Oral health in asthmatic children: a dose-response study. Rev Belge Med Dent (1984). 2004; 59(2):130-7.
35. Ramos-Ríos JA, Ramírez-Hernández E, Vázquez-Rodríguez EM, Vázquez-Nava F. Asthma-associated oral and dental health repercussions in children aged 6 to 12 years. Rev Alerg Mex. 2017;64(3): 270-276.
36. Harding SM. Gastroesophageal reflux, asthma, and mechanisms of interaction. Am J Med 2001; 111 (Suppl 8A): 8S–12S.
37. Mansfield L E, Stein MR. Gastroesophageal reflux and asthma: a possible reflex mechanism. Ann Allergy 1978; 41: 224–226.
38. Havemann BD, Henderson CA, El-Serag HB. The association between gastro-oesophageal reflux disease and asthma: a systematic review. Gut 2007; 56: 1654–64.
39. Guergolette RP, Dezan CC, Frossard WT, Ferreira FB, Cerci Neto A, Fernandes KB. Prevalence of developmental defects of enamel in children and adolescents with asthma. J Bras Pneumol 2009; 35: 295–300.
40. Silva M, Scurrah K, Craig J, Manton D, Kilpatrick N. Etiology of molar incisor hypomineralization – A systematic review. Community Dent Oral Epidemiol. 2016; 44: 342‐53.
41. Wogelius P, Haubek D, Poulsen S. Prevalence and distribution of demarcated opacities in permanent 1st molars and incisors in 6 to 8-year-old Danish children. Acta Odontol Scand. 2008;66: 58‐64.
42. Hyyppa T. Gingival IgE and histamine concentrations in patients with asthma and in patients with periodontitis. J Clin Periodontol 1984; 11: 132–7.
43. McDerra EJ, Pollard MA, Curzon ME. The dental status of asthmatic British school children. Paediatr Dent 1998; 20: 281–7.
44. Geddes DM. Inhaled corticosteroids: benefits and risks. Thorax 1992 47: 404–7.