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Despite significant advances in asthma research and care, the burden of asthma remains high. This article will review a number of different aspects of asthma care that impact the pediatrician.
Despite significant advances in asthma research and care, the burden of asthma remains high. On a daily basis, asthma leads to: 68,000 missed school days or workdays; 36,000 asthma attacks and 4800 emergency department visits; 1250 hospital admissions; and 11 deaths.1 This article will review a number of different aspects of asthma care that impact the pediatrician.
A link between lifestyle, obesity and asthma has been discussed in the medical literature for some time.2,3 In 1 long-term study, decreased levels of physical activity and increased screen time were associated with obesity. In turn, obesity in the 4th to 6th grades was associated with asthma and decreased lung function in a dose-dependent manner.4
Adult studies have demonstrated that weight loss can, in fact, improve lung function.5 As a result, office interventions targeting activity levels may impact asthma or its severity. Further, this evidence demonstrates additional benefit of the pediatrician targeting healthy weight loss and maintenance beyond traditional cardiovascular and endocrine targets that are well known.
Control of asthma in the pediatric years has a tremendous impact on the patient in adulthood. In the Melbourne Asthma study that examines the natural history of asthma, results demonstrate that lung function as well as clinical outcomes are predicted by asthma severity in childhood.6 Poorly controlled asthma in childhood can result in significant respiratory morbidity into adulthood, and poor control in childhood represents a significant risk of morbidity as children transition into their adult lives.
Fractional exhaled nitric oxide (FeNO) is a relatively recent, point-of-care diagnostic tool used to identify T-helper cell type 2 (Th2)-driven allergic inflammation, which is present in up to 80% of children and 50% of adult asthma patients.7 Elevated FeNO levels are indicative of airway inflammation that is likely to respond to inhaled steroids. Additionally, FeNO-based management of asthma symptoms is associated with less asthma exacerbations compared with management based on clinical parameters alone.
However, what is considered a meaningful difference in FeNO measurement still is under debate, and not all experts believe FeNO is useful in managing pediatric asthma. It also should be noted that use of FeNo is limited in patients with asthma phenotypes not characterized by inflammation. There is 1 FeNO measurement device approved by the US Food and Drug Administration (FDA) and available for use in clinical practice-the Nioxx Vero.7
The 2007 Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma8 recommends a short course of oral corticosteroids if increased doses of a short-acting beta agonist (SABA) do not lead to improved control of asthma symptoms. A recent practice guideline, Management of acute loss of asthma control in the yellow zone: a practice parameter,9 provides additional treatment options based on research published since the 2007 report.
The report emphasizes the importance of quick relief, but discourages scheduled SABA as the only treatment because this strategy fails to prevent progression into the red zone consistently.9 The guideline offers several options including:
1. Increase inhaled steroid doses by 4-fold by increasing either the frequency or dose of medication.
2. Dynamic dosing in which the patient uses his/her controller medication each time the SABA is used. In this way, the amount of steroids received is in proportion to the severity of the asthma symptoms.
These enhanced yellow-zone strategies should be continued for 14 days to ensure symptoms resolve and lung function improves.9 The guideline emphasizes that the strategies be tailored to the individual patient and that clinicians make changes to the action plan based on how well it performs with each episode of poor control.
Many parents like the ease and simplicity of a montelukast or other leukotriene inhibitors compared with an asthma inhaler. Although labeling was added in 2009 outlining risk for neuropsychiatric events, the FDA Pediatric Advisory Committee (PAC) recently recommended strategies to increase awareness with health providers and parents.10
Montelukast was discussed as part of a routine PAC pediatric safety review in September 2014.11 Public testimony by parents outlined that although the FDA has attempted to communicate these risks to clinicians, many are not aware or fail to communicate this risk to parents.
The prescribing information for montelukast includes the following:10
“Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking [montelukast sodium]. Postmarketing reports with [montelukast sodium] use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details of some postmarketing reports involving [montelukast sodium] appear consistent with a drug-induced effect.”
In the very young pediatric patient who is not able to fully communicate (montelukast is approved in children aged as young as 6 months), detection of these adverse effects can be very difficult. Similarly, some of these adverse effects can be easily attributable by a parent or pediatrician as part of adolescence in older children. As a result, it is only increased awareness that can identify this problem. Providers should educate parents and then follow up specifically after starting therapy.11
The most common adverse effects of montelukast are not serious and symptoms generally resolve with cessation of treatment.
For the longest time, Xolair has been the only biologic available for patients with poorly controlled moderate-to-severe asthma. Importantly, long-term follow-up studies (median follow-up of 5 years) have now demonstrated rates of cancer are similar between patients treated with Xolair and those not receiving Xolair. There are now other biologic options available to the pediatrician.3
Mepolizumab, a monoclonal anti-IL-5 antibody, was recently approved by the FDA as an add-on therapy for patients aged 12 years and older with severe asthma.12 Administered via injection once per month, the drug lowers eosinophil levels. Studies demonstrated decreased hospitalization and decreased steroid use but not improvements in lung function.2,3
Headache, injection-site reactions, back pain, and weakness were common adverse effects in clinical trials.12 Less-common but serious adverse effects included swelling of the face, mouth, and tongue; dizziness; hives; breathing problems; and rash, and herpes zoster infections also can occur.
There has been a great deal of interest and research in recent years into diet and patterns of asthma. Current evidence points to a “Mediterranean diet” decreasing asthma risk while a “Western diet” increases risk. The Western diet (increased amounts of refined grains and saturated fats with low amounts of fruits and vegetables) is proinflammatory and increases risk of asthma while the Mediterranean diet (limited amounts of refined grains and saturated fats but increased amounts of fruits and vegetables) is anti-inflammatory and decreases asthma risk. However, evidence for specific anti-inflammatory foods is still lacking to the point that the supplementation can be recommended.2 This has led to multiple studies looking at the relationship between specific foods or supplements and how they might be related to or treat asthma.
Previous evidence has noted increases in allergic disease and asthma in places where vitamin D is deficient, and more severe exacerbations of asthma with exposure to a trigger such as a viral respiratory tract infection.13 However, the Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma (VIDA) trial failed to demonstrate more rapid tapering of inhaled steroids or improved asthma control when vitamin D-deficient patients were supplemented or given a placebo.14
Despite animal models of vitamin A deficiency being significantly associated with airway inflammation and evidence of vitamin A deficiency being proinflammatory in adults, there is little evidence to support if vitamin A impacts asthma.15 In the Danish National Birth Cohort,16 maternal vitamin A intake did not impact asthma in the first 7 years of life. Other studies have failed to demonstrate any impact on the development or treatment of asthma with vitamin A supplementation in early life.16,17
Although the results for vitamin C supplementation are more promising, the evidence still appears insufficient to make a recommendation that supplementation improves asthma.15
Similarly, there is not enough current evidence to suggest that vitamin E supplementation in pregnancy prevents respiratory disease in early childhood despite animal models that support the concept.15 Recent randomized trials also have not demonstrated a positive impact of supplementation with vitamin E on asthma.
Like with studies in cancer and other diseases that appear amenable to dietary intervention, research appears to be at a crossroads in regard to diet and its association with asthma. Is it better to look at more general diets (eg, Mediterranean diet) or should researchers continue to go down a path examining specific components looking for some sort of magic bullet? There is at least some evidence that trying to encourage better diets may have an impact. In a Spanish study, children who ate an overall high-antioxidant diet were less likely to experience an asthma episode compared with children consuming lower levels of antioxidants.16
Future research hopefully will provide an answer, but there is a definite benefit from a reasonable diet that encourages weight loss in the obese and overweight or maintenance of a healthy weight.
Depending on what one reads and how one defines adherence, compliance ranges somewhere between 22% and 78%. Adherence is poor in asthmatic patients for a number of different reasons including parental concern about adverse effects, the complexity of asthma regimens, cost, and a whole host of other factors. Interventions that can improve adherence will likely improve asthma control and decrease asthma costs.19
Research recently began looking at whether today’s increasingly “plugged-in” society might help improve asthma control. One study looked at more than 1000 children in the Kaiser Permanente Colorado health maintenance organization and the impact of speech recognition on asthma adherence.19
Speech recognition phone calls were made to intervention parents when inhaled steroid refills were due or overdue.19 Although adherence overall in both the intervention arm and the standard care arm was poor, adherence was 25% greater in the intervention group as measured by a possession ratio over 24 months. Interestingly, urgent care visits did not differ between the 2 groups. Low-cost interventions such as the one described have the potential for significant improvements in adherence and subsequent asthma control and potential cost savings.
In another adherence study, the target was adolescents and delivering messages to their ever-present smartphones to help improve compliance.20 Using a web-based application, patients sign up and request med reminder delivery messages. In addition to improvements in adherence, improvements in self-efficacy and quality of life also were seen.
There are a number of different smartphone applications offering free (Medisafe [www.medisafe.com/]; MedActionPlan [www.medactionplan.com/]; MyMeds [http://my-meds.com]) and paid (Rx Remind Me [https://itunes.apple.com/us/app/rx-remind-me/id972766049?mt=8]) apps and plans that allow one to enter a medication to receive text or e-mail reminders. For some patients, this type of reminder system may significantly improve compliance and potential control.20
Despite being used in clinical practice for more than 100 years, immunotherapy remains underused in clinical practice related to asthma.21 As healthcare moves toward more personalized medicine, immunotherapy holds great promise-identification of specific subsets of patients that will be identified from a specific therapy.
Increasingly, available molecular diagnosis tools will allow for better identification of patients who will benefit from particular immunotherapies. As an example, 2 recent studies have demonstrated decreased need for inhaled steroids among patients sensitized to house dust mites and started on a targeted oral immunotherapy.22,23
1. American College of Asthma, Allergy, and Immunology. Asthma facts. Available at: http://acaai.org/news/facts-statistics/asthma. Accessed February 18, 2016.
2. Carr TF, Kraft M. Update in asthma 2014. Am J Respir Crit Care Med. 2015;192(2):157-163.
3. Siracusa CM, Brewington JJ, Brockbank JC, Guilbert TW. Update in pediatric lung disease 2014. Am J Respir Crit Care Med. 2015;192(8):918-923.
4. Chen YC, Tu YK, Huang KC, Chen PC, Chu DC, Lee YL. Pathway from central obesity to childhood asthma. Physical fitness and sedentary time are leading factors. Am J Respir Crit Care Med. 2014;189(10):1194-1203.
5. Al-Alwan A, Bates JH, Chapman DG, et al. The nonallergic asthma of obesity. A matter of distal lung compliance. Am J Respir Crit Care Med. 2014;189(12):1494-1502.
6. Tai A, Tran H, Roberts M, et al. Outcomes of childhood asthma to the age of 50 years. J Allergy Clin Immunol. 2014;133(6):1572.e3-1578.e3.
7. Mummadi SR, Hahn PY. Topics in practice management: update on exhaled nitric oxide in clinical practice. Chest. December 12, 2015. Epub ahead of print.
8. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma–Summary Report 2007. J Allergy Clin Immunol. 2007;120(5 suppl):S94-S138. Erratum in: J Allergy Clin Immunol. 2008;121(6):1330.
9. Dinakar C, Oppenheimer J, Portnoy J, et al; Joint Task Force on Practice Parameters; Practice Parameter Workgroup; American Academy of Allergy, Asthma, and Immunology; American College of Allergy, Asthma, and Immunology. Management of acute loss of asthma control in the yellow zone: a practice parameter. Ann Allergy Asthma Immunol. 2014;113(2):143-159.
10. US Food and Drug Administration. Singulair (montelukast) briefing materials for the PAC meeting, September 23, 2014. Available at: http://www.fda.gov/ScienceResearch/SpecialTopics/PediatricTherapeuticsResearch/ucm434555.htm. Updated August 7, 2015. Accessed February 18, 2016.
11. Scudder L, Seymour S, Torjusen E. Montelukast's underrecognized adverse drug events. Available at: http://www.medscape.com/viewarticle/840302. Published March 2, 2015. Accessed February 18, 2016.
12. Jenco M. FDA approves drug for severe asthma. Available at: http://www.aappublications.org/news/2015/11/05/AsthmaDrug110515. Published November 5, 2015. Accessed February 18, 2016.
13. Beigelman A, Zeiger RS, Mauger D, et al; Childhood Asthma Research and Education (CARE) Network of the National Heart, Lung, and Blood Institute. The association between vitamin D status and the rate of exacerbations requiring oral corticosteroids in preschool children with recurrent wheezing. J Allergy Clin Immunol. 2014;133(5):1489-1492,1492.e1-1492.e3.
14. Castro M, King TS, Kunselman SJ, et al; National Heart, Lung, and Blood Institute’s AsthmaNet. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial. JAMA. 2014;311(20):2083-2091.
15. Han YY, Blatter J, Brehm JM, Forno E, Litonjua AA, Celedón JC. Diet and asthma: vitamins and methyl donors. Lancet Respir Med. 2013;1(10):813-822.
16. Rodriguez-Rodriguez E, Ortega RM, González-Rodriguez LG, Peñas-Ruiz C, Rodriguez-Rodriguez P. Dietary total antioxidant capacity and current asthma in Spanish schoolchildren: a case-control control study. Eur J Pediatr. 2014;173(4):517-523.
17. Maslova E, Hansen S, Strøm M, Halldorsson TI, Olsen SF. Maternal intake of vitamins A, E, and K in pregnancy and child allergic disease: a longitudinal study from the Danish National Birth Cohort. Br J Nutr. 2014;111(6):1096-1108.
18. Kiraly N, Balde A, Lisse IM, Eriksen H, Aaby P, Benn CS. Vitamin A supplementation and risk of atopy: long-term follow-up of a randomized trial of vitamin A supplementation at six and nine months of age. BMC Pediatr. 2013;13:190.
19. Bender BG, Cvietusa PJ, Goodrich GK, et al. Pragmatic trial of health care technologies to improve adherence to pediatric asthma treatment: a randomized clinical trial. JAMA Pediatr. 2015;169(4):317-323.
20. Johnson KB, Patterson BL, Ho YX, et al. The feasibility of text reminders to improve medication adherence in adolescents with asthma. J Am Med Inform Assoc. December 11, 2015. Epub ahead of print.
21. Canonica GW, Bagnasco D, Ferrantino G, Ferrando M, Passalacqua G. Update on immunotherapy for the treatment of asthma. Curr Opin Pulm Med. 2016;22(1):18-24.
22. de Blay F, Kuna P, Prieto L, et al. SQ HDM SLIT-tablet (ALK) in treatment of asthma-post hoc results from a randomised trial. Respir Med. 2014;108(10):1430-1437.
23. Mosbech H, Deckelmann R, de Blay F, et al. Standardized quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while maintaining asthma control: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2014;134(3):568-575.e7.
Dr Bass is chief medical information officer and associate professor of medicine and of pediatrics, Louisiana State University Health Sciences Center–Shreveport. The author has nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.