asthma exacerbation | Exacerbation of asthma in children

 Exacerbation of asthma in children

Exacerbation is a significant component of asthma in children

 

Exacerbation is a significant component of asthma in children


1. Introduction
Asthma is the most common pediatric chronic respiratory disease that affects 7.4% of children in central Taiwan, 19.7% in northern Taiwan, and up to 32.6% in the western world.

Exacerbation is a component of asthma that has a significant impact on the child and family. An exacerbation is often the initial event that precedes the diagnosis of this disease and constitutes the majority of acute care events in children. Despite advances in the treatment of asthma and the introduction of specific guidelines for pediatric asthma, acute exacerbations continue to occur and impose considerable morbidity in pediatric patients, and cause considerable pressure on health care resources, as well as in the lives of affected children and their families.

In the Asia-Pacific region, a survey conducted in 2006 showed persistently poor control in asthmatic children. Compared to the results of a survey conducted in 2000, there has been no subsequent decrease in emergency care due to exacerbation of asthma (44% in 2000 vs. 43% in 2006), including visits to the emergency department (DE) (19% vs. 19%) and hospitalization (15% vs. 17%). The rate of emergency care in patients with asthma can be as high as 43%. Real-world surveys conducted in the US and Europe also revealed a considerable burden for patients and health professionals associated with the exacerbation of asthma.

The current guidelines for evaluating asthma control are based on two main aspects: clinical control and future risk. The presence of an exacerbation has proven to be equivalent to altering the level of control. However, the two domains are not necessarily concordant. Patients can be well controlled in the deficiency domain and be receiving optimal medications, and still experience a severe exacerbation. Current interest in this aspect of asthma is reflected in numerous recent publications that evaluated exacerbations from various points of view. In addition, the International Collaboration in Asthma, Allergy and Immunology (International Collaboration in Asthma, Allergy and Immunology - iCAALL), has recently proposed an International Consensus on Pediatric Asthma (ICON) in 2012 and emphasizes the treatment of exacerbations as a major consideration, regardless of chronic treatment. iCAALL considers "the best treatment for the exacerbation of asthma" as "an important need not met", so it recommends conducting a central investigation in order to develop "new medications and / or strategies." The objective of the present study was to provide a review of the latest reports on clinical practice in asthma / wheeze exacerbations, with special emphasis on research highlighting results that have not yet been fully discussed in current guidelines.The latest research on new therapeutic modalities is not included in this review.

2. Definition of asthma exacerbation
The exacerbation of asthma, also called "attack" or "episode" of asthma, is a very common condition in pediatric practice. Although a detailed assessment of the severity and treatment of the exacerbation was first proposed in the guidelines years ago, the definition of exacerbation of asthma remains controversial.

In the most recently published consensus of pediatric asthma in 2013, asthma exacerbation was defined as an acute or subacute episode of progressive increase in asthma symptoms associated with bronchial obstruction. The most common results of the exacerbation include the need for systemic corticosteroids, urgent non-scheduled ED care, or emergency care (UC) and admissions for asthma.

In young children, recurrent wheezing is a challenge in the diagnosis of asthma. In the PRACTALL consensus report published in 2008, the "phenotypes" of "persistent wheezing," "intermittent severe wheezing," and "non-atopic wheezing" (mainly caused by viral infection) were proposed. exacerbation of asthma in young children It is difficult to diagnose asthma in young children and infancy, however, several publications have given useful results in the prevention of severe and future wheezing attacks in this age group, especially in those with a high rate of asthma prediction (IPA).


3. Burdens in the exacerbation of asthma
In the United States in 2007, there were 0.64 million ED visits related to asthma in children and 157,000 admissions related to pediatric asthma. A survey of 753 children with asthma in seven European countries revealed that 36% of the children required an unscheduled emergency care visit in the last 12 months. Eighteen percent of children required one or more emergency room visits for asthma in the last year. In the Asia-Pacific area, the costs of unscheduled care (CU) were responsible for 18-90% of the total direct cost per patient. In general, the total direct costs per patient were equivalent to 13% of the gross domestic product per capita and 300% of the health expenditure per capita, which did not include the indirect social / economic costs. In Taiwan, the percentages of hospitalizations and emergency room visits of patients for asthma were estimated at 12% and 25% per year, respectively, equivalent to 1.2 days of hospitalization and 0.59 visits to the ED per patient. and year, respectively.

An analysis of the data obtained from the National Health Insurance Research Database of Taiwan in 2002 showed that the overall health expenditure in pediatric patients with asthma was 2.2 times higher than in patients without asthma, and a quarter of the cost in asthmatic children was attributed to hospitalization and UC.



4. Factors associated with exacerbations
4.1. Poor control of asthma
Poor asthma control can lead to severe exacerbations. In a study from a Severe Asthma Research Program of the National Heart, Lung and Blood Institute, the percentage of asthmatic patients with three or more exacerbations a year was 5% in the mild group, 13% in the moderate group and 54% in the severe group, suggesting that frequent exacerbations are related to the severity of the disease. In terms of asthma control, in a survey of 1,003 patients in the United States with uncontrolled asthma, 70% had an unscheduled visit to a doctor's office, 36% had a visit to the ED, and 14% had a hospitalization in the last year. Even among patients with controlled asthma, 43% had an unscheduled visit to a doctor's office, 10% had a visit to the ED, and 3% had had an inpatient visit in the previous year. Appropriate management of persistent asthma includes treatment with control medications such as inhaled corticosteroids (IC) and leukotriene receptor antagonists (ARLs), which have consistently shown to reduce the risk of severe exacerbations of the disease. Poor adherence to medications is an important factor contributing to poor asthma control. A recent study showed that children with low adherence to IC had a 21% increase in emergency room visits and a 70% increase in hospitalization.4.2. Serious exacerbation in the previous year
One or more severe exacerbations in the previous year have been shown to be an independent risk factor for future exacerbation. Asthmatic patients, especially children, who require a visit to the ED or hospitalization are significantly increasing the risk of future exacerbations regardless of demographic and clinical factors, severity and control of asthma. In a multivariate model, the severe recent exacerbation was the strongest predictor for a severe future exacerbation with an odds ratio (OR) of 3.08: 95% CI = 2.21 - 4.28. On the basis of recommendations from the GINA guidelines, frequent exacerbations in the last year are also a factor associated with future risk.

4.3. Virus
Viral infections have been implicated in the majority (> 80%) of asthma exacerbations in children. Viral infections of the upper respiratory tract have been recognized as a factor in exacerbation events, especially in children. Such infections are sometimes referred to as the "epidemic September" because of their seasonal pattern. Khetsuriani and colleagues conducted a study that included children from 2 to 17 years of age using a panel of PCR assays. The researchers compared children who experienced an exacerbation with those who had well-controlled asthma. Viral respiratory infection was associated with exacerbation in 63.1% of patients compared to 23.4% in individuals with well-controlled asthma (OR 5.6, 95% CI = 2.7-11.6). Although several viruses have been found in asthmatics, rhinovirus has been the virus most frequently identified in exacerbations of asthma due to viral infection in children aged 6 to 17 years (55%) and in infants and preschoolers (33%). Other viruses detected and associated with the exacerbation of asthma include respiratory syncytial virus, enterovirus, coronavirus and human metapneumovirus.

4.4. Allergic sensitization
Allergic sensitization, especially when there are more than three allergen triggers, is also associated with exacerbation of asthma (OR 2.05, 95% CI = 1.31 - 3.20). Simpson and colleagues observed that the majority of children classified as atopic using conventional definitions were grouped into four different classes: multiple early, multiple late, dust mite, and not dust mite. Only the multiple early class, which comprised approximately a quarter of the atopic children, was significantly associated with the risk of hospitalization for asthma. Because PRACTALL has proposed that an asthma phenotype is induced by allergens, highlighting the heterogeneity of these disorders, a more detailed interpretation of allergen sensitization may provide a better prediction of the exacerbation.

4.5. Allergic-viral interactions
A growing body of evidence supports the idea that viral infection and allergy interact to increase the risk of an exacerbation. Murray and colleagues observed the synergistic interaction in children, which was even greater than the effect in adults. In their study, neither sensitization to allergens nor viral infection were independently associated with hospital admission. It was the combination of the presence of virus and sensitization with high allergenic exposure that increased the risk of hospitalization (OR 19.4, 3.5 - 101.5, p <0.001).

4.6. Smoking
The relationship between passive smoking and asthma morbidity in children is also well recognized. In the United States, more than 200,000 episodes of childhood asthma per year have been attributed to parental smoking.

Mackay et al. Showed an annual reduction of 18.2% in the rate of hospitalizations related to asthma in children after the application of the smoking ban in public places in Scotland. Prior to its implementation, hospitalization for asthma was increasing at an average rate of 5.2% per year.4.7.

Pollution
Acute exposure to specific pollutants contributes to the symptoms and increases the severity of asthma exacerbations, although their effects are not as pronounced as those of viruses and airborne allergens. In children with asthma, exposure to NO2 is associated with an increase in respiratory symptoms and the personal increase in NO2 level is associated with a greater severity of virus-induced exacerbations.

4.8. Genes
Several simple nucleotide polymorphisms (PNSs) are reported as related to asthma exacerbations. The PNSs of the T allele of the IL-13 promoter gene were associated with an increased risk of exacerbations among those receiving CI. Three PNSs of the low affinity IgE receptor gene (FCεR2) were significantly associated with a high IgE level, and each was associated with an increase in severe exacerbations in white children.

Racial differences should be taken into account in genetic studies. In Taiwan, Chen and colleagues also reported a common variant of a gene coding for 10 kDa Cala cell protein as a candidate determinant of asthma severity and response to corticosteroids in Chinese asthmatic children.

More recently, Bisgaard and colleagues investigated variants of genes associated with asthma and exacerbation in early childhood. The variation in the locus 17q12-q21 was associated with approximately double risk of recurrent wheezing, asthma exacerbations and bronchial hyperreactivity from early childhood to school age, but without conferring risk of eczema, rhinitis, or sensitization to allergens.

This report adds to the growing evidence of genetic variation in susceptibility to exacerbations, particularly in non-atopic asthma, and also supports the existence of an independent presence of exacerbations. In general, the finding of genetic variations that affect severe exacerbation demonstrates the need to consider the interaction of genes with other known factors in the evaluation of children with frequent exacerbations.



5. Strategies for preventive management
The management of the prevention of exacerbation can be considered from two main perspectives in order to: (1) reduce the severity of the exacerbation, and (2) prevent future exacerbations after the current episode. In this article, updated strategies were examined to achieve these two objectives in patients with different conditions.

5.1. Intermittent asthma
It was reported that a leukotriene receptor antagonist (ARLT) reduces the exacerbation of asthma in patients with mild intermittent asthma. A multicentre, double-blind, parallel group study demonstrated that the use of montelukast every 4 or 5 mg for 12 months significantly reduced the exacerbation rate, the median time of the first exacerbation and the rate of IC use. An Australian randomized control trial (RCT) conducted in children with mild intermittent asthma, demonstrated that a short treatment with montelukast, administered by the parents during the first signs of an episode of asthma for at least 7 days until 48 hours after resolution Total symptoms, resulted in a significant reduction in the utilization of acute medical care resources, symptoms, time away from school, and time of absence of parents at work. However, no significant effects were observed in the hospitalization rate, the duration of symptoms, or the use of bronchodilators and systemic corticosteroids. The effect on future episodes of exacerbation has not been investigated in this study.
5.2. Intermittent wheezing in preschoolers
At preschool age, the diagnosis of asthma is a difficult task, and often a long follow-up period is required to define the pattern of wheezing in young children. However, during the course of follow-up, there are often severe episodes of wheezing that occur intermittently, especially when there is a respiratory tract infection. The PRACTALL consensus proposed the concept of "virus-induced asthma" in which colds are the most common precipitating factor, and which also explains how some children can be quite well between symptomatic periods.

With regard to adherence and the possible adverse effects of daily ICs, several studies have investigated the effects of intermittent therapy of this phenotype in recent years and the results have been instructive in pediatric clinical practice. For children aged 12 to 59 months with moderate to severe intermittent wheezing, the early use of budesonide or montelukast inhalation, in addition to albuterol for 7 days showed a moderate reduction in respiratory distress and interference activity compared with the placebo group, and the effects were particularly significant in those with positive predictive rates of asthma. The effects were comparable in these two groups. However, neither episodic budesonide (1 mg twice daily, through a nebulizer), nor montelukast (4 mg daily) showed differences in event-free day, use of oral corticosteroids, use of health care , quality of life, or linear growth compared to the placebo group. Another study conducted in Canada recruited children aged 1 to 6 years with at least 3 episodes of previous wheezing and at least one moderate to severe episode in the last 6 months in order to investigate the preventive use of inhaled fluticasone for wheezing induced by viruses. The study group received 750 μg of fluticasone twice a day at the start of upper respiratory tract infection and continued for up to 10 days. In the study period of 6 to 12 months, the fluticasone group showed a decrease in the use of rescue systemic steroids (OR 0.49, 95% CI = 0.3 - 0.83), but they suffered less gain in height and weight. Therefore, its long-term benefits require future clarification.

Zeiger and colleagues compared intermittent and daily budesonide treatment to prevent severe exacerbation in children between the ages of 12 and 53 months who had positive values ​​of modified IPA, episodes of recurrent wheezing, and at least one exacerbation in the previous year. , but a low degree of deterioration. High doses (1 mg) and intermittent budesonide administered twice daily for 7 days, predefined at early onset during respiratory disease, showed an effect comparable to that of budesonide once daily (0.5 mg per day). night) with respect to the frequency of exacerbations (0.95 vs. 0.97 per patient years). There were also no significant differences between several other measures of asthma severity, including time to first exacerbation or adverse events. The mean exposure to budesonide was 104 mg less with the intermittent regimen than with the daily regimen. A meta-analysis of the Cochrane database also addressed this question in a study on the use of inhaled corticosteroids for episodes of viral wheezing in childhood. It was concluded that high doses of episodic inhaled corticosteroids provide a partially effective strategy for the treatment of episodes of mild viral wheezing in children. There is currently no evidence in favor of maintaining low doses of inhaled corticosteroids in the prevention and treatment of episodes of mild wheezing induced by viruses in childhood.

The early effects of oral corticosteroid use have also been evaluated in recent years, but the results have been inconsistent. For children with a previous episode of wheezing, a 5-day course of oral prednisolone was instituted on admission (10 mg per day for children between 10 and 20 months, and 20 mg per day for those between 20 and 20 months of age). 60 months). Compared to the placebo group, there were no differences in the duration of hospitalization, in the symptom score at 7 days, or in the use of albuterol.Another study of children aged 5 to 12 years with a history of recurrent episodes of acute asthma used the strategy of prednisolone initiated by parents when parents suspected the imminent onset of a severe asthma attack based on their previous experience or the absence of improvement of symptoms in a matter of 6 to 8 hours. Prednisolone was used at 1 mg / kg / day 3 to 5 days depending on the persistence or disappearance of your child's asthma symptoms. There was some reduction in asthma symptoms (p Z 0.023), the use of health resources (p Z 0.01), and school absenteeism (p Z 0.045). In general, current data suggest that early institution of oral corticosteroids is not recommended for the prevention of severe crisis.

In an investigation of wheeze attacks, Bisgaard et al. Assigned infants to a treatment group with a 2-week course of inhaled budesonide (400 mg / day), which started after a 3-day episode of wheezing, or for a placebo group that received conventional care. There was no decrease in the proportion of days without symptoms, percentage of persistent use of budesonide, or duration of acute episode compared with the placebo group during the 3 years of follow-up, and there was no decrease in bone height or bone mineral density in the study group

5.3. Persistent asthma
Patients with controlled persistent asthma have fewer exacerbations than patients with persistent uncontrolled asthma. However, even among asthma-controlled patients, 43% have an unscheduled visit to a doctor's office, 11% visit an emergency department, and 3% are hospitalized due to an exacerbation every year. Therefore, an additional regimen before or at the early stage of the exacerbation is a recommended strategy for better asthma control.

Bisgaard et al. Proposed maintenance and Symbicort relief therapy (SMART) as a new strategy in pediatric asthma in 2006. SMART involves the use of Symbicort 80 / 4.5 μg qd plus more additional doses as needed. In these 12 months, a double-blind, randomized study of 341 children between 4 and 11 years with uncontrolled asthma who received regular IC with a daily average dose of up to 320 μg of budesonide was performed. SMART showed reductions of 70% and 79% (p <0.001) in exacerbations compared to groups receiving budesonide in high doses (320 μg qd) plus 0.4 mg of terbutaline in rescue form and Symbicort 80 / 4.5 μg qd plus 0.4 mg of terbutaline in rescue form, respectively. The SMART regimen also reduced the days of mild exacerbations and night awakenings. The annual height growth was better than that of the budesonide group in high doses. The good result as a result, led to several tests using the SMART approach in several countries. In 2011, Cochrane published a meta-analysis of combined fluticasone and salmeterol versus fixed fixed doses of budesonide and formoterol for the treatment of chronic asthma in adults and children. In the present analysis, the SMART regimen did not find significant decrease in severe exacerbations. The conclusion of this meta-analysis was that imprecise estimates of the exacerbation indicate that future investigations are warranted. In fact, the most recent studies on the SMART regime have yielded different results.

With respect to the safety of the use of long-acting bronchodilators (BDAP) ​​in children, in recent years the guidelines recommend increasing the dose of IC in uncontrolled asthma instead of the addition of BDAP / LABA. The SMART regimen was first proposed in 2006, before the availability of specific guidelines for children, so even the "maintenance" component of SMART is not the first choice for children with persistent asthma. The development of monoclonal antibodies / mAbs directed against molecular targets identified as important in patients with allergic asthma have shown some early potential in the prevention of asthma exacerbations. In a randomized study of 6 to 12 years with multiple exacerbations despite IC treatment, a 43% reduction in clinically significant exacerbations was observed in the omalizumab-treated group over a 1-year period.

Based on this knowledge, a combined short course of CI + ARLs to prevent pediatric asthma / wheeze exacerbation has never been reported previously, although it was reported in a systematic review that the CI + ARLs combination could be superior to CI only for the prevention of future exacerbation.6. Education and full follow-up plan

Post-exacerbation care is a necessary component of exacerbation care. Many doctors believe that families need to be educated to recognize an impending exacerbation and to improve adherence to control medication. A Cochrane publication in 2009 found that educational programs significantly reduce the risk of subsequent ED visits and hospital admissions, as well as fewer unscheduled visits to the doctor compared to controls. They concluded that asthma education aimed at children (and their carers) who come to the emergency room for acute exacerbations may result in a lower risk of future presentation to the ED and admissions to the hospital. Schatz and colleagues also reviewed the evidence of the effectiveness of follow-up after acute episodes of asthma. Recommendations based on their findings are as follows: (1) Telephone appointment reminders should be used to improve the effectiveness of patient follow-up after the ED visit, and if possible, appointments should be made before leaving the office. FROM; (2) the severity of chronic patients must be characterized by elements of the asthma guidelines; (3) specific elements should be included in the follow-up visit, such as the controller, inhalation technique, self-monitoring, individualized asthma treatment plan, trigger identification, avoidance instruction, and even more of follow up; (4) Patients should be referred to a specialist when indicated.


7. Conclusion
One of the main objectives in the treatment of asthma is to minimize the severity and future risk of exacerbations, which also improves asthma control. Respiratory viruses are well accepted as the main trigger of these exacerbations, and rhinoviruses remain the most commonly detected pathogens. The interaction of viruses and sensitized allergens in asthma / wheezing in pediatric patients needs further clarification, which should include the role of genetic variation. Currently, modalities of treatment of early episodes provide some benefit, albeit to a limited extent, in reducing the impact of the exacerbation, but more research should be done, especially with regard to the identification of response subgroups. In a review of the literature by the authors, it is evident that patients with severe anterior exacerbation, predictive rates of positive asthma and sensitization to multiple allergens require special attention and need to be educated about these aspects of their disease. Pediatricians should be able to identify the signs and symptoms of patients with chronic asthma so that families can be educated to detect impending exacerbation and adhere to the asthma control plan. Referral to a pediatric allergy specialist is indicated in pediatric patients with recurrent seizures and persistent asthma.

Comment: Asthma is the most common chronic disease of the lower respiratory tract in childhood. Despite advances in the management of asthma, acute exacerbations continue to have a great impact on patients and their families and translate into a considerable burden on health systems. A severe exacerbation that occurs within a year is an independent risk factor. Respiratory viruses have become the most frequent precipitating factors of exacerbations in children. It is clear that there may be interactions between viruses and other triggers, such as allergens, which increases the likelihood of an exacerbation.

In this study, a summary of current knowledge about asthma exacerbations is provided,the impact on health systems and the associated factors. Discussion of the management of asthma preventionintermittent wheezing, as well as intermittent wheezing in preschool children and those with persistent asthma.The findings of this review support the importance of controlling persistent asthma, as indicated in current guidelines.In addition, it was remarked that early episodic intervention seemed to be crucial in the prevention of episodessevere and future exacerbations. In addition to the use of medication, family education afterexacerbation, along with a comprehensive plan in the follow-up is also of crucial importance.