2022 Year in Review: Pediatric Asthma

Abstract

Asthma is the most common chronic disease in children. Asthma is a heterogeneous disease characterized by variable, reversible airway obstruction and hyper-responsive airways. There is a high economic burden due to a child having poorly controlled asthma with one or more asthma exacerbations resulting in an emergency department visit or hospitalization in a year. Publications on diagnosis, treatment, and management of pediatric asthma are ongoing with over 2,549 papers published from January–November 2022. The intent of this paper is to summarize 8 key topics that have prompted discussions with local, regional, and national asthma experts due to a shift in clinical practice or lessons learned from the recent pandemic that may have future application.

Introduction

Asthma is the most common chronic disease of childhood, with one in 12 children in the United States under the age of 18 years having a diagnosis of asthma.¹ Asthma is a heterogeneous disease characterized by variable, reversible airway obstruction and hyper-reactive airways. The average health care cost for a child with asthma ranges from $3,279–$13,612 per year, which is significantly higher than a child without asthma.² Higher health care costs are associated with emergency visits and hospitalizations due to poorly controlled asthma and asthma exacerbations. An estimated 50% of children under the age of 18 years report having poorly controlled asthma, and at least 42.7% of children report having at least one asthma exacerbation a year.^3,4

It is important health care clinicians stay current with the latest literature on treatment and management of children with asthma. There are more than 2,000 peer-reviewed scientific publications and review articles regarding pediatric asthma published in 2022. Due to the vast number of other publications, this review will focus on 8 key topics that have prompted frequent discussions with local, regional, and national asthma experts because of a shift in clinical practice or lessons learned from the recent pandemic that may have future application.

Methods

A PubMed full-text search was conducted to determine the number of papers published between January–November 2022 on pediatric asthma. The search resulted in 2,549 publications. A refined search including pediatric asthma and the following key words “recurrent wheezing in young children,” “phenotypes,” “COVID-19,” “heated high flow,” “social determinants,” intermittent inhaled corticosteroids,” and “single maintenance and relief therapy” resulted in 616 publications. Twenty manuscripts were selected based on 8 key topics based on frequent discussions with asthma experts because of a shift in out-patient and in-patient clinical practice or lessons learned from the recent pandemic that can be integrated into daily practice and potentially have future application. A summary of each of the 8 key topics and recent publications are included below.

Review of Literature

Recurrent Wheeze and Asthma

The first few years of life children have a higher rate of acquiring a respiratory viral infection (RVI).⁵ Peak outbreaks of RVIs in infants and young children have a direct correlation to children returning to school from vacations or breaks.⁶ Short-term morbidity and economic burden are high during these peak RVI outbreaks.⁷ Symptoms of an RVI usually present as a mild cold (runny nose, cough, decreased appetite, fever), but for children < age 2, it can be more serious due to respiratory viruses being the common cause of bronchiolitis.⁸ Bronchiolitis is inflammation of the bronchioles and is the most common respiratory tract infection in children < age 2 y, causing wheezing.⁹ At least 50% of children will have an episode of wheezing before the age of 6 y, and 80–90% of those episodes are triggered by an RVI.¹⁰ Approximately 22% of infants and young children have recurrent wheezing due to an RVI.¹¹ The association between recurrent wheezing with RVI and asthma is discussed within several studies.^12–14 These studies suggest asthma may be a consequence of airway epithelium and immune system alterations in response to an RVI and allergies causing chronic airway obstruction and remodeling.^12–14 Respiratory syncytial virus, enterovirus, and rhinovirus viral species are more commonly associated with the development of asthma.^15–17 Children with a history of eczema, increased eosinophilia, family history of allergies, and hospitalizations for RVI are more likely to progress into asthma.^18–20 Asthma can be difficult to distinguish from wheezing with illness of childhood because wheezing in younger children is heterogeneous and does not always indicate asthma.²¹ The asthma predictive index is a tool used by clinicians to aid in predicting the risk of asthma development in preschool children by looking at parental history of asthma, provider-diagnosed atopic dermatitis and allergic rhinitis, wheezing without colds, and blood eosinophil levels.^22,23 The tool is validated, simple, inexpensive, and noninvasive to serve as a proxy for providers in diagnosing asthma in young children with recurrent wheeze within the first 3 years of life.^24,25 Clinicians should monitor trends of RVI to better understand future changes to wheezing and asthma prevalence that can aid in determining timing of preventive measures.²⁶

Intermittent Inhaled Corticosteroids in Young Children

The National Asthma Education and Prevention Program (NAEPP) Expert Panel Working Group and Global Initiative for Asthma (GINA) report both suggest young children (0–5 y of age) with 3 or more episodes of wheezing in their lifetime or 2 wheezing episodes triggered by respiratory viral illness in the past year with a lack of wheezing symptoms in between may benefit from a short course (7–10 d) of inhaled corticosteroids (ICSs) and as-needed inhaled short-acting bronchodilators (SABAs).^27,28 Several studies show starting medium to high-dose ICS at the first onset of respiratory viral illness can reduce symptom duration and severity, days of SABA use, the frequency of oral steroids, health care utilization, and negative effect on quality of life.^10,29–31 Buendía, Patiño, and Ramirez³² recently release findings intermittent ICS with SABA during respiratory viral illness was cost-effective. To achieve optimal outcomes from intermittent ICS and SABA in young children with recurrent wheeze with respiratory viral illness, it is important for clinicians to select the best delivery device that is easy for parents/caregivers to administer and age appropriate for the young child. Nebulizers and pressurized metered-dose inhalers (pMDIs) with spacer (+mask) have been found to be equally effective in young children when administered correctly.^33–35

Intermittent Inhaled Corticosteroids in Adolescents

Daily ICS is the maintenance therapy of choice in mild asthma because of the noted improvement in FEV₁, FVC, FEV₁/FVC, and peak expiratory flow, reducing the need for SABA.³⁶ However, medication adherence to daily maintenance therapy is 18–65% in children, with the majority being < 50%.³⁷ Poor medication adherence increased health care costs and mortality and decreases quality of life.³⁸ Common causes for poor medication adherence can include hectic schedules, social stigma, separate households, medication costs, inadequate health literacy, lack of understanding of the disease, not integrating shared decision, complex medication regimen, and multiple medications to be taken daily.^39,40 The NAEPP Expert Panel Working Group released updates to the asthma management guidelines that has 2 preferred treatment choices for mild persistent asthma in ≥ 12 y.²⁷ The first is daily low-dose ICS with as needed SABA, which is associated with better daily asthma control. The second is as needed concomitant ICS and SABA at the first sign of asthma symptoms.²⁷ For those who are not willing or able to consistently take daily medications, concomitant ICS and SABA taken at the first sign of asthma symptoms has been found to decrease the severity of an asthma exacerbation and worsening of the disease compared to SABA alone, while being cost-effective and potentially decreasing the need for systemic steroids.^41–44 The NAEPP suggests individuals who have low perception of symptoms are more likely to have more severe asthma exacerbations should be placed on daily ICS rather than concomitant.²⁷ Clinicians should consider concomitant ICS and SABA in adolescents and adults who have mild persistent asthma with good recognition of their symptoms but are not compliant with their daily maintenance therapy.

COVID-19 and Pediatric Asthma

In the United States, there have been 101 million cases of COVID-19 and 1.1 million deaths resulting from this disease.⁴⁵ Children with COVID-19 were more likely to be asymptomatic or the illness was less severe, and prognosis was better than adults.^46,47 Mask wearing and social distancing were implemented during the pandemic as public health measures to reduce the transmission of COVID-19.⁴⁸ When children returned to in-person learning, there was ongoing controversy that children with asthma should not return to in-person learning due to risks of them having an asthma exacerbation because of mask wearing. Abrams, Jordan, and Szefler⁴⁹ found there was no evidence mask wearing exacerbated asthma and children could safely attend in-person school with no increased risk of morbidity or mortality from asthma due to mask wearing. Furthermore, Boechat, Wandalsen, and Delgado⁵⁰ found if health care providers focused on asthma control, risk of stratification, and medication adherence it could reduce the risk of the child having severe COVID-19 and better asthma control will allow children to safely return to school. Although society no longer needs to wear masks and maintain social distancing in the face of COVID-19 pandemic, there is always a risk society will need to revert back to mask wearing in an effort to minimize future pandemic outbreaks.⁵¹ It is important for clinicians to be aware of findings during the COVID-19 pandemic and the minimal risk of asthma exacerbations with mask wearing.

Phenotypes in Pediatric Asthma

Asthma is a heterogeneous disease involving several different phenotypes. Phenotypes are clinical characteristics of asthma: wheezing patterns, symptom triggers, atopic features, lung function, disease severity, and response to treatment.^52,53 Identifying phenotypes can aid in predicting the development or diagnosis of asthma and assist in individualizing treatment and management.

Three major inflammatory phenotypes have been identified in children with asthma: eosinophilic, neutrophilic, and paucigranulocytic.^54–57 Eosinophilic asthma is the most common, characterized by airway inflammation, blood eosinophils > 2–3%, elevated immunoglobulin E (IgE) levels, and fractional exhaled nitric oxide levels.^58–60 Eosinophilic asthma typically responds well to ICSs.⁶⁰ Neutrophilic asthma has no clear definition but is characterized with sputum neutrophilia ≥ 61% or blood neutrophil levels ≥ 73% or in children neutrophils in bronchial lavage ≥ 5%, with increased numbers reflecting increased severity.^60,61 A recent study found neutrophilic asthma has been associated with airway colonization of Haemophilus influenza and Moraxella catarrhalist.⁶² Neutrophilic asthma tends to be associated with early recurrent childhood wheeze, more severe disease, air flow limitation, and poor response to coritcosteroids.^63,64 Paucigranulocytic asthma is defined as blood level neutrophils ≥ 76% and elevated blood eosinophils levels < 3% with no evidence of elevated sputum eosinophils or neutrophils.^60,65 Paucigranulocytic asthma has good response to treatment but if the patient remains poorly controlled despite optimal treatment may require further evaluation.⁶⁵

Approximately 5–10% of individuals have poorly controlled asthma despite appropriately prescribed medication, resulting in a higher incidences of emergency department visits and hospitalizations.⁶⁶ Evaluation of phenotypes in poorly controlled asthma can help direct more advanced therapy such as biologics because more biologics are becoming available and/or under investigation showing promise.^59,67 Biologic therapy is laboratory-produced antibodies designed to target specific cytokines or antibodies.⁶⁸ There are currently 5 approved biologics therapies in the United States. Omalizumab, mepolizumab, and dupilumab are approved for children ≥ 6 y of age with moderate to severe asthma. Benralizumab and tezepelumab are approved for adolescents ≥ 12 y of age.⁶⁹ There are other biologic treatments in the United States market but currently not approved for patients < 18 y of age. Omalizumab is used as add-on therapy in moderate to severe allergic asthma where IgE antibodies are elevated.⁷⁰ Mepolizumab, dupilumab, and benralizumab are used as add-on therapy for severe eosinophilic asthma.⁷¹ Tezepelumab is the only biologic approved for severe asthma with no phenotype or biomarker limitations.⁷²

Biologics have been found to improve lung function, quality of life, decrease asthma exacerbations, reduce the need for corticosteroids, and improve asthma control.⁶⁹ However, the cost for biologic therapy is prohibitive in the United States. In 2018, wholesale purchase for a unit of biologics can range from $879 to $4,750.⁷³ This does not include facility and provider fees or indirect costs to the family for taking time off from school or work to attend a clinic visit for administration of the biologic therapy. Dupilumab is the only biologic approved for at-home administration, decreasing some costs to families.

As mentioned previously, medication adherence to daily maintenance therapy among children is < 50%.³⁷ As clinicians, it is important to align with NAEPP⁷⁴ and GINA²⁸ guiding documents by ensuring proper inhaled device technique and validating medication adherence before adding on biologic therapy to achieve the best outcomes for the cost. A study done by d'Ancona, Kavanagh, and Roxas et al⁷⁵ found subjects who had good medication adherence to ICSs and were treated with a biologic had noted improved quality of life, decrease in health care utilization, and decrease in oral steroids therapy, whereas those who had poor adherence to their daily ICS regimen did not experience as good of outcomes.

Social Determinants of Health in Children With Asthma

Social determinants of health have a major impact on health outcomes and have gained priority since COVID-19, when social and health disparities became more apparent. Healthy People 2030 defines social determinants of health as conditions in the environment where people are born, live, work, play, worship, and age affect people health, well-being, and quality of life.⁷⁶

Social determinants are divided into 5 domains: economic stability, education access and quality, health care access and quality, neighborhood and build environment, and social and community context.⁷⁶ Individual-level social determinants (no high school diploma, low income) and social vulnerability (living at below poverty level, poor air quality in non-Hispanic and Black communities, and younger/older age) result in children having poorer outcomes from recurrent wheeze, greater risk of developing asthma, and poorer asthma control despite access to health care.^77–79

Health care providers should incorporate ways to identify and address social determinants of health preventing patients/parents/caregivers from adhering to medication and following the plan of care.⁸⁰ Implementing a standard screening process to identify social barriers is an important first step. There are several different types of social screening tools available. Two of the most common social screening tools are Protocol for Responding and Assessing Patients' Assets, Risks, and Experiences tool⁸¹ and Accountable Health Communities Health-Related Social Needs Screening Tool.⁸² A couple of considerations when integrating a social screening tool into clinical practice. First, determine who should ask the questions. It should not be the sole responsibility of one single person. Second, integration should have minimal workflow impact to ensure the biggest buy-in from the health care team. Third, what is the process once a barrier(s) has been identified. It is important to engage various health care team members (social work, health navigators, school nurses, community partners, etc) to establish a short- and long-term resource support plan for the patient/parent/caregivers when social barriers have been identified with the goal of improving health outcomes.⁸³

Heated High-Flow Nasal Cannula in Pediatric Asthma

Heated high-flow nasal cannula (HFNC) has increased popularity in pediatric care over the past 10 years. HFNC is heated and humidified gas delivered at higher gas flows to wash out of nasopharyngeal dead space, exceeding inspiratory demand flow, and providing minimal end-distending pressure while decreasing inspiratory resistance and the need for mechanical ventilation.^84,85 Initially HFNC was used to treat bronchiolitis but has expanded to asthma, congenital heart disease, obstructive sleep apnea, and pneumonia.⁸⁶ HFNC improves work of breathing and reduces carbon dioxide retention during an asthma exacerbation.⁸⁷ Increase utilization of HFNC is due to ease of use, provides a lower level of support better tolerated in younger children, and does not require sedation.⁸⁷ There is no consensus on optimal flow settings in pediatrics. Several studies recommend flow of 1–2 L/kg/min with maximum liter flow based on the nasal cannula size and type.⁸⁷ There is no difference in mortality or stay with HFNC compared to noninvasive ventilation.⁸⁸

There continues to be controversy on effectiveness of nebulized medication through the HFNC in children. Based on recent studies, there are several limitations to optimal inhaled medication delivery with HFNC.^89,90 The commercially available vibrating mesh nebulizer (VMN) (Aerogen Solo, Aerogen, Galway, Ireland) delivers 2–3 times greater medication with less residual drug remaining at the end of the treatment and does not introduce added flow into the HFNC circuit.^91,92 A standard jet nebulizer (JN) has been shown to have less medication delivery with more residual medication volume and requires at least 6 L/min of gas flow to effectively nebulize the medication. Adding additional flow to an HFNC circuit alters oxygen delivery, total flow, and pressure.⁹³ Medication deposition is higher with VMN placed at the inlet of humidifier and at lower flow (0.25 K/kg/min), but lower flows will likely not achieve optimal HFNC therapeutic effect.⁹⁴ Distressed breathing in an infant and toddler can slightly alter medication delivery.⁹⁴ The upper airway gets the majority of the medication compared to the lungs.^90,94 Inhaled dose is higher with intermittent administration than continuous regardless of HFNC flow.⁹⁵ Placing a JN with a mask or pMDI with spacer/mask for intermittent therapy over HFNC results in significantly lower aerosol delivery.^96,97 Continuous medication administration through HFNC provides a higher level of trans-nasal aerosol absorption of the medication.^94,98 Trans-nasal absorption occurs when medication is systemically diffused from the nasal mucosa. Trans-nasal absorption administration of medication for prolonged periods may be beneficial, which is why most ICUs will administer continuous albuterol with HFNC.⁹³ Further randomized controlled trails are needed to compare therapeutic response of nebulized medication through HFNC in pediatric asthma. It is important clinicians understand the limitation of inhaled medication administration via HFNC and work within their designated institution to determine what is the best clinical approach to treating and managing a child with asthma who is on HFNC while achieving the best possible outcomes.

Single Maintenance and Relief Therapy in Children

In 2020, the NAEPP Working Group published Focus Updates to the Asthma Management Guidelines recommending a single inhaler with an ICS and formoterol to be used as a daily controller and reliever medication for children ≥ 4 y with moderate to severe persistent asthma.²⁷ This preferred recommendation is similar to the preferred recommendation in the GINA 2022 strategy report, but their recommendations are for ≥ 6 y.²⁸ Formoterol is a long-acting β agonist with a rapid onset and longer duration.^27,28,99 There are currently only 2 combination inhalers with ICS and formoterol available in the United States market. Some patients and caregivers may find it more convenient to manage their asthma using single maintenance and reliever therapy (SMART) to reduce asthma exacerbation risks and lower maintenance dosing.^99,100 The NAEPP has maximum dosing of 8 puffs in a 24-h period for 4–11 y and 12 puffs in 24 h for ≥ 12 y.²⁷ There has been ongoing discussion and need for clarity on the strength of the ICSs, frequency of the daily dose, and dosing for as-needed therapy using SMART. Both NAEPP and GINA recommend one or 2 inhalations of low to medium strength of ICS to be taken once or twice daily.^27,28 As needed dosing for SMART should be one inhalation at the first sign of asthma symptoms, and if symptoms persist after a few minutes, a second dose can be taken until maximum dosing is reach for the day.¹⁰¹ This treatment strategy has been determined to be effective, safe, and easily adopted by patients and caregivers.¹⁰¹ Despite this new adoption of therapy, there continues to be several barriers in the United States. First, the FDA has not approved budesonide/formoterol (Symbicort) or mometasone/formoterol (Dulera) to relieve acute respiratory symptoms. Second, the NAEPP 2020 updates do not address pretreatment prior to exercise or increased activity with SMART. Third, several studies determined SMART was the efficient alternative compared to fixed combination inhaler or fixed dose of budesonide, yet health insurance payers typically do not find ICS-formoterol to be cost-effective when compared to SABA and currently do reimburse for more than one 30-d supply of a maintenance medication.^102,103 Patients who may run out of SMART due to an asthma exacerbation or need an additional inhaler for exercise pretreatment at school may need to pay out of pocket for a second inhaler. It is also important for clinicians to have a clear understanding of the asthma management guiding documents; establish a standardize way for integrating SMART into standards of care; develop education for other health care providers, patients, and caregivers about SMART; and add language in the asthma home management plan on SMART dosing that is clear to understand and follow.

Summary

In the past year, there have been thousands of publications addressing diagnosis, treatment, and management of pediatric asthma. Asthma care is constantly evolving as new therapies are researched and incorporated into clinical care. Recurrent wheeze in a young child, intermittent ICS therapy, COVID-19, phenotyping and biologic therapy, social determinants, aerosol delivery through heated HFNC, and single inhaler for maintenance and relief are some of the topics frequently discussed and debated by pediatric asthma experts. It is important respiratory therapists and clinicians continue to remain aware of new studies and publications that will influence future clinical practices and standards of care to achieve the best outcomes for children with asthma.