ASTHMA IN CHILDREN AND ADULTS – WHAT ARE THE DIFFERENCES AND WHAT CAN THEY TELL US ABOUT ASTHMA?

EDITED BY : Steve Turner and John W. Upham PUBLISHED IN : Frontiers in Pediatrics

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# ASTHMA IN CHILDREN AND ADULTS – WHAT ARE THE DIFFERENCES AND WHAT CAN THEY TELL US ABOUT ASTHMA?

Topic Editors: Steve Turner, University of Aberdeen, United Kingdom John W. Upham, University of Queensland, Australia

Citation: Turner, S., Upham, J. W., eds. (2020). Asthma in Children and Adults – What are The Differences and What Can They Tell us About Asthma?. Lausanne: Frontiers Media SA. doi: 10.3389/978-2-88963-727-0

# Table of Contents

Li Ping Chung and James Y. Paton

Michelle Trivedi and Eve Denton

Eva Morales and David Duffy

# Editorial: Asthma in Children and Adults – What Are the Differences and What Can They Tell Us About Asthma?

Steve Turner 1 \* and John W. Upham2

1 Child Health, University of Aberdeen, Aberdeen, United Kingdom, 2 Faculty of Medicine, The University of Queensland, Princess Alexandra Hospital, Brisbane, QLD, Australia

Keywords: asthma, child, adult, difference, similarity

#### **Editorial on the Research Topic**

#### **Asthma in Children and Adults – What Are the Differences and What Can They Tell Us About Asthma?**

In the 1970s, asthma was an enigmatic condition with no agreed definition or diagnostic test, but which was nonetheless diagnosed and treated every day. Fast forward 50 years and the situation is mostly unchanged. Uncertainty about what asthma is has hampered development of new treatments. The care for other non-communicable diseases such as diabetes, leukemia, epilepsy, and inflammatory bowel disease has leapt ahead, whilst most patients with asthma are receiving the same treatment their parents were prescribed a generation ago, i.e., short acting beta agonists and inhaled corticosteroids. New treatments options have emerged for severe asthma treatment, but these impact on a relatively small proportion of people with asthma.

The subjective nature of asthma diagnosis causes both under- and over- diagnosis. This uncertainty results in preventable morbidity firstly due to treatment side effects where "asthma" is not present and secondly where effective treatment is not given.

It is now widely accepted that what is currently recognized as "asthma" is a syndrome (1) which describes a range of different pathologies which share common symptoms (i.e., wheeze, shortness of breath and cough) and common physiology (i.e., reversible airway obstruction). Over the years attempts to prise apart these different facets of asthma by stratifying have proven unhelpful; examples of well-meaning but ultimately unhelpful categorizations include atopic vs. non-atopic asthma, intrinsic vs. extrinsic asthma and intermittent vs. persistent asthma. Well-crafted efforts to describe asthma (or wheeze) phenotypes have proved convenient but ultimately flawed. For example, terms such as viral wheeze, multi trigger wheeze and the Asthma COPD Overlap Syndrome have been used to try and capture the potential overlap between "asthma" and other wheezing syndromes which are present early and later on in the life course. In children, viral wheeze and multi trigger wheeze are unstable phenotypes (2) (i.e., over time individuals viral wheeze develop multitrigger wheeze and vice versa) and in adults the "Dutch hypothesis" (3) remains hotly debated. The observation that viral wheeze (aka wheezy bronchitis) and asthma are both risk factors for COPD (4) further dampens enthusiasm for these phenotypes.

One phenotype which seems durable and appears in most attempts at cracking the asthma puzzle is childhood onset asthma (5–7). From a genetic perspective there are different variants associated with childhood onset asthma compared to other phenotypes (8) or adult onset asthma (9). "Childhood onset" is generally considered to include up to age 12 years but the persistently low lung function trajectory associated with asthma is present by 6 years of age (10, 11), and this

#### Edited and reviewed by:

Anne B. Chang, Charles Darwin University, Australia

> \*Correspondence: Steve Turner<EMAIL_ADDRESS>
#### Specialty section:

This article was submitted to Pediatric Pulmonology, a section of the journal Frontiers in Pediatrics

Received: 09 March 2020 Accepted: 11 March 2020 Published: 01 April 2020

#### Citation:

Turner S and Upham JW (2020) Editorial: Asthma in Children and Adults – What Are the Differences and What Can They Tell Us About Asthma? Front. Pediatr. 8:141. doi: 10.3389/fped.2020.00141

**4**

suggests that "childhood onset" might be refined to onset by 5 years of age. Further recognition that asthma may be different between adult and children is seen in asthma guidelines which have different approaches to diagnosis and management of asthma in children and adults. When adult chest physicians and pediatric pulmonologists meet at international conferences, local educational events and transition clinics, there are often differences in approaches for adults and children. For example, adult physicians believe that they can improve asthma symptoms with treatment for rhinitis and gastro esophageal reflux, but this is not clearly seen in children. Aspirin-sensitive asthma is almost exclusively seen in adults. Children inhale lots of environmental exposures at school but do not demonstrate an equivalent of occupational asthma. Steroid-resistant asthma is much more commonly seen in adult than in children and severe asthma in preschool children is very uncommon (and likely to be a manifestation of something other than asthma). Adult-onset, eosinophilic asthma with nasal polyps in the absence of atopy is a well-recognized entity in adults, but is rarely seen in children.

Has the elusive first key to unlocking the asthma conundrum been staring us in the face all along? Could childhood-onset asthma vs. adult onset asthma(s) be the obvious first way to start dissecting asthma?

We challenged experts in asthma from around the world to compare and contrast asthma in adults and children. The author's challenge was not to simply reproduce the many guidelines for asthma diagnosis and management. Each article compared and contrasted asthma in adults and children within the following 11 domains: epidemiology (causation) (Dharmage et al.); epidemiology (life-course) (Trivedi and Denton); genetics (including gene environment interactions) (Morales and Duffy); diagnosis (Saglani and Menzie-Gow); monitoring (Gallucci et al.); treatment (chronic symptoms) (Chung and Paton); treatment (acute symptoms) (Chavasse and Scott); dysfunctional breathing (Connett and Thomas); severe asthma (Fleming and Heaney); primary care (Kaplan et al.); and transition (Withers and Green). Authors of each article included an adult chest physician and a pediatric pulmonologist (with the exception of primary care). After submitting their article, authors were asked to give a "score of similarity" from the perspective of their article using the following scale:

TABLE 1 | This describes the 11 domains of asthma in which each article associated with this article compared and contrasted asthma in adults and children.

The table also states the nationality of authors and the authors "score of similarity" which rates the overlap between asthma in adults and children from the perspective of their article (higher score indicating greater overlap, see text for definition of score). \*A score was not available. † A score was not sought since the age range at transition is

The resulting scores ranged between 4 and 8, **Table 1**. The domains of epidemiology (life-course), genetics and severe asthma were rated as having only 40–50% overlap between childhood and adult asthma. In contrast, all other domains which were scored were considered to have 70–80% overlap.

So do these different perspectives give us any insight into how we can start to solve the asthma enigma? Well yes and no. The international experts who considered adult and childhood asthma from these different perspectives are consistent in believing that there are some areas of common ground, but also a clear distance between adult and childhood asthma; the experts differ on how much clear distance there is. If asthma is perceived as a single entity which is treated with the same medications as guidelines advocate (12, 13), then there will be an inevitable bias for diagnosis and treatment to be considered mostly homogenous across all ages. Similarly, it is not unexpected that childhood and adult asthma will be considered more heterogenous conditions when perceived from a life course perspective. Perhaps the notable differences are genetics and severe asthma. Hereditary factors are considered to explain up to 70% of asthma causation (14), so from a purely genetic perspective childhood and adult asthma are more different than similar. Severe asthma, as evidenced by persistently poorly controlled asthma despite adequate medication, is vanishingly rare in preschool children

so narrow.

and 70% of asthma deaths occurred in individuals whose diagnoses was made in adulthood (15). Recent years have seen the development of targeted therapies such as monoclonal antibodies that are transforming severe asthma management in adults (16).

Perhaps adult and child asthma may be the most useful (or least useless) method of phenotyping asthma. At the time of writing, 3 months after the last article was published, there have been almost 42,000 views of the articles, so the perspectives seem to have struck a chord. Looking forwards, endotypes, and using non-hypothesis driven artificial intelligence may prove more

#### REFERENCES

accurate means to tease apart the strands we know are within the heterogenous entity we call asthma. A uniform definition of asthma and a diagnostic test would be very helpful. In the meantime, we carry on diagnosing and managing asthma across the life course, but in the hope that we can do it better in the near future.

#### AUTHOR CONTRIBUTIONS

ST wrote the first draft. ST and JU made meaningful contributions to the final manuscript.

**Conflict of Interest:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2020 Turner and Upham. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Dysfunctional Breathing in Children and Adults With Asthma

Gary J. Connett\* and Mike Thomas

University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom

Asthma occurs across the life course. Its optimal treatment includes the use of personalized management plans that recognize the importance of co-morbidities including so-called "dysfunctional breathing." Such symptoms can arise as a result of induced laryngeal obstruction (ILO) or alterations in the mechanics of normal breathing called breathing pattern disorders. Whilst these two types of breathing abnormalities might be related, studies tend to focus on only one of them and do not consider their relationship. Evidence for these problems amongst childhood asthmatics is largely anecdotal. They seem rare in early childhood. Both types are more frequently recognized in the second decade of life and girls are affected more often. These observations tantalizingly parallel epidemiological studies characterizing the increasing prevalence and severity of asthma that also occurs amongst females after puberty. Exercise ILO is more common amongst adolescents and young adults. It should be properly delineated as it might be causally related to specific treatable factors. More severe ILO occurring at rest and breathing pattern disorders are more likely to be occurring within a psychological paradigm. Dysfunctional breathing is associated with asthma morbidity through a number of potential mechanisms. These include anxiety induced breathing pattern disorders and the enhanced perception of subsequent symptoms, cooling and drying of the airways from hyperventilation induced hyperresponsiveness and a direct effect of emotional stimuli on airways constriction via cholinergic pathways. Hyperventilation is the most common breathing pattern disorder amongst adults. Although not validated for use in asthma, the Nijmegen questionnaire has been used to characterize this problem. Studies show higher scores amongst women, those with poorly controlled asthma and those with psychiatric problems. Evidence that treatment with breathing retraining techniques is effective in a primary care population including all types of asthmatics suggests the problem might be more ubiquitous than just these high-risk groups. Future challenges include the need for studies characterizing all types of dysfunctional breathing in pediatric and adult patient cohorts and clearly defined, age appropriate, interventional studies. Clinicians caring for asthmatics in all age groups need to be aware of these co-morbidities and routinely ask about symptoms that suggest these problems.

Keywords: asthma, dysfunctioal breathing, paradoxical vocal fold motion, hyperventilation, breathing pattern disorders, inducible laryngeal obstruction, exercise inducible laryngeal obstruction, breathing retraining exercises

#### Edited by:

Steve Turner, University of Aberdeen, United Kingdom

#### Reviewed by:

Jean-Paul Praud, Université de Sherbrooke, Canada Yusei Ohshima, University of Fukui, Japan

> \*Correspondence: Gary J. Connett<EMAIL_ADDRESS>
#### Specialty section:

This article was submitted to Pediatric Pulmonology, a section of the journal Frontiers in Pediatrics

Received: 13 September 2018 Accepted: 07 December 2018 Published: 20 December 2018

#### Citation:

Connett GJ and Thomas M (2018) Dysfunctional Breathing in Children and Adults With Asthma. Front. Pediatr. 6:406. doi: 10.3389/fped.2018.00406

**7**

## INTRODUCTION

For most of the time breathing occurs sub-consciously. A network of brain stem neurones at the level of the medulla and pons forms the respiratory center which initiates rhythmic contraction of the respiratory muscles whilst co-ordinating these movements with other activities, such as speaking and swallowing (1). As humans we are able to override this otherwise automatic process, for example by breath holding to dive underwater or to forcefully blow out candles. Breathing can also be impacted upon by emotions. For example, bouts of laughter can harmlessly interrupt normal respiration. However, in some people physiologically inappropriate hyperventilation, in response to feelings of agitation and anxiety, can lead to disabling symptoms and become a chronic problem (2). In others abnormal dysfunctional breathing patterns, such as trying to breath through an obstructed larynx, rapid, shallow breathing, irregular breathing and predominant upper-chest breathing might also lead to troublesome symptoms with or without associated hypocapnia. Identifying such problems as a co-morbidity complicating asthma can be difficult as there is considerable overlap in the types of symptoms that occur and a complex interrelationship (3).

In this article we will review how the asthma phenotype might be impacted upon by dysfunctional breathing problems throughout the life course.

## DEFINITIONS AND TERMINOLOGY

Dysfunctional breathing might usefully be regarded as an overarching term that is inclusive of problems that are either thoracic or laryngeal in nature (4). Whilst both types are reported as occurring amongst asthmatics, there are no studies addressing the extent to which they both occur within individual patients. This is despite prevalence studies suggesting that both are common and that therefore there should be considerable overlap. Unfortunately the use of the term dysfunctional can be stigmatizing for patients and especially in children where it might have inappropriate connotations about dysfunctional families and elements of abuse or neglect. To address such issues, breathing pattern disorders is a recently recommended term describing functional abnormalities in the mechanics of the diaphragm and intercostal muscles that result in inefficient breathing. Similarly, a joint task force addressing upper airway problems has recommended the term inducible laryngeal obstruction (ILO) rather than laryngeal dysfunction or paradoxical vocal cord motion to denote extrathoracic airway problems. ILO usefully encompasses obstruction occurring at supraglottic as well as glottic (vocal fold) levels as characterized at laryngoscopy (5).

The most commonly recognized breathing pattern disorder and the first to be described was hyperventilation in adults (6). More recently however, breathing pattern disorders have come to encompass a wider spectrum of breathing abnormalities. These include periodic deep sighing, thoracic dominant breathing, forced abdominal expiration and thoracic-abdominal asynchrony (7, 8). The extent to which these other problems occur amongst asthmatics is unknown.

## PATHOPHYSIOLOGY

The pathophysiology of dysfunctional breathing disorders is incompletely understood. It has been suggested that the occurrence of a characteristic complex of symptoms that can include breathlessness, chest tightness, sighing, yawning, chest discomfort, general fatigue, anxiety and abdominal bloating, might usefully be regarded as a learnt conditioned response to some sort of emotional distress that has taken on physical manifestations (9). Those affected often do not recognize that their symptoms are arising in this way and that they might be "catastrophising" their health fearing serious underlying illness. The resulting interference with normal automatic control probably occurs at a sub-conscious level.

Somatisation symptoms typically resemble those of an illness the affected person is aware of, has, or has had in the past. In this context, it is well-recognized that those patients presenting with acute hyperventilation, commonly also have undetected co-existing asthma (10). Amongst known asthmatics however, the situation is far more complex because of the difficulties distinguishing true asthma from asthmatic symptoms induced by dysfunctional breathing. Hyperventilation for example, occurs in the vast majority of acute asthma attacks as demonstrated by low arterial carbon dioxide tensions (11). The mechanism whereby this happens might include stimulation of irritant and stretch receptors, anxiety mediated effects on cholinergic bronchosconstriction (12) and a hyperventilatory response to the perception of increased airways resistance (13). Hyperventilation per se might then further worsen true asthma through bronchosconstrictive cooling and airway dehydration.

ILO, the involuntary narrowing of the upper airway during inspiration, is similarly complex and multifactorial. Anxiety and psychological disorders are thought to be major contributory factors in the majority of adults who are affected and particularly when symptoms occur spontaneously at rest (14). Amongst younger asthmatics, exercise induced laryngeal obstruction (EILO) is more common and should usefully be regarded as a separate condition. It can co-exist with exercise-induced asthma and psychological co-morbidities are less predominant than in ILO. Causal factors include the aerodynamic effects of high inspiratory flow rates, neurally mediated laryngeal hyperreactivity and environmental factors, such as inhaling cold air. Gastro-esophageal reflux has been implicated but this is very common in unaffected individuals of all ages and a causal relationship has not been proven (15). Upper airway symptoms of rhinitis and post-nasal drip might also be a contributory precipitant of upper airway closure but is also unproven (16).

## EPIDEMIOLOGY

The findings of the main studies to determine the presence of hyperventilation in asthmatics are summarized in **Table 1**. These studies have used the Nijmegen questionnaire (**Table 2**). This

TABLE 2 | The Nijmegen Questionnaire, Please circle the number in the column that best represents what you have felt recently\* .

\*A total score of 23 or more has been used to screen for dysfunctional breathing in a UK community setting (17). Cut-off scores to detect "abnormality" will depend on a comparison with normal values in the same setting and culture in which the questionnaire is used.

was originally developed as a screening tool for symptomatic hyperventilation syndrome and subsequently used as a continuous measure of the benefits of interventions to regulate breathing through capnographic feedback methods (24). Although the questionnaire has not been validated for use in adults with asthma (27) or in children, it does appear to be able to detect a cluster of symptoms that can be characterized as relating to the breathing-related effects of stress and anxiety.

Hyperventilation, as identified with this tool, is recognized as being common and occurs across the whole spectrum of asthma severity. It is more common in those with more severe disease and those with poor control (19, 26). Those studies that have investigated psychological co-morbidities, report that stress and the increased perception of more typical asthma symptoms occur more commonly in hyperventilators (21, 23). Such patients were also more likely to have acute asthma attacks.

All studies report that hyperventilation is more common amongst females vs. males and this sex difference tends to increase through childhood into early adult life. The only study in which asthma was more common amongst boys included a younger age group but, as in all other studies, the percentage of girls with asthma who also had hyperventilation was much higher than boys with asthma and hyperventilation (25).

It is not clear whether hyperventilation is more common in adults. A school study from Italy (25) produced comparable data to that in adult primary care, but a secondary care study from the Netherlands found far less dysfunctional breathing compared with adult data (26). Societal differences in reporting might be an important factor limiting the extent to which the Nijmegen questionnaire identifies abnormalities globally and might also limit the generalisability of such findings (28).

EILO is more common in adolescents and younger adults. It has been described in 26.9% of pediatric referrals to secondary care respiratory services, who were thought to have exercise induced asthma (29). Two population based studies suggest that it can occur in between 5.7 and 7.5% of none asthmatic adolescents (30, 31). Most studies also suggest a female predominance (15).

Adult studies have characterized a very severe phenotype of ILO in which symptoms typically occur without provocation. Amongst a hospital based series of 95 cases, 56% were diagnosed as also having asthma and 28% had suffered episodes needing endotracheal intubation to control symptoms (32). Two studies of adult asthmatics attending secondary care services report prevalences of 19 and 50% (33, 34). The study in which half of the asthmatics had this problem were identified using a novel computerized tomography imaging technique to none invasively assess laryngeal movements.

Poor discrimination between exercise induced inspiratory symptoms and exercise induced bronchoconstriction in adolescents and young adults, might be contributing to the over diagnosis of asthma in these age groups.

### DIAGNOSTIC CONSIDERATIONS (SEE TABLE 3)

Symptoms relating to dysfunctional breathing need to be differentiated from symptoms due to other causes. These include undiagnosed respiratory, cardiac or metabolic diseases associated with breathlessness, a lack of physical fitness, panic disorders whereby symptoms are more obviously a part of direct manifestations of anxiety, simply reaching physiological limits when exercising and the less common occurrence of wilfully fabricated or induced illness either by the patient or by proxy during childhood.

Increasing breathing difficulties with prolonged inspiration, throat tightness, stridor and wheeze in the cervical region is highly suggestive of ILO in all age groups. A lack of response to more conventional asthma treatment is also indicative. Clinical clues suggesting the possibility of breathing pattern disorders include chest pain or discomfort with no other obvious cause, very short expiratory breath-holding times (e.g., <20 s), feelings of not being able to take a deep breath, the abrupt onset of breathlessness with no obvious cause and the recognition that getting anxious is a trigger of respiratory symptoms (7).

Lactic acidosis after high doses of beta-2-agonists can of itself cause hyperventilation and further complicate a picture of acute asthma made worse by associated tremor and tachycardia which might compound feelings of anxiety (35).

Unfortunately there is no agreed diagnostic work up for this group of conditions. Screening tools for ILO have been suggested but these have largely been developed to distinguish ILO from asthma rather than recognize the two conditions as co-morbidities (36, 37). The medical history can be usefully TABLE 3 | Dysfunctional breathing in asthma: adults vs. children.

informative about EILO. Although psycho-social stressors are less of a feature amongst young people with this condition compared with those who have unprovoked symptoms, they are typically "A" grade individuals, high performing athletes and commonly striving to fulfill parental or peer group expectations. Symptoms crucially peak during exercise or just after stopping, whereas exercise induced bronchospasm typically comes on 3– 15 min after exercise. Whilst abnormal spirometry might be indicative of upper airway problems, it is poorly sensitive and should not be used in isolation for diagnosis (38). Typically there is inspiratory flow limitation, but there might also be a plateau in the expiratory flow rate (39). Laryngoscopy, performed during increasing levels of exercise to provoke symptoms, is regarded as the gold standard test, but diagnostic facilities are not widely available and can be difficult to perform in younger age groups (40).

Getting patients to perform voluntary over breathing challenge tests were recommended as a means of reproducing symptoms to support a diagnosis of hyperventilation (41). Initially, this was thought to occur through induced hypocapnia. However, subsequent studies have suggested that, in the majority of patients, alterations in feelings of anxiety and their central effects on neuro-muscular control of breathing are more important determinants of symptoms than respiratory alkalosis and such tests are no longer in common use (42, 43).

Hyperventilation is commonly screened for in asthma clinics using the Nijmegen questionnaire. The questionnaire matches up fairly well with more sophisticated diagnostic testing, such as graded exercise challenge tests (21). The creators of the questionnaire suggest that when used in clinical practice, it should be in conjunction with more objective measures of assessment (44). However, breathing assessments can be difficult as the use of mouthpieces and breathing circuits can directly alter breathing patterns. New technologies, such as structured light plethysmography, might help to better define breathing patterns in the future (45).

In an out-patient setting, there is usually little to find on clinical examination. If symptoms are present, it might be possible to differentiate upper from lower airway obstruction, but this can be difficult. Observing an abnormal breathing pattern might also be usefully informative, but young children in particular commonly breathe in strange ways when their chest is auscultated. Getting the patient or their family to use a mobile phone to capture episodes of abnormal breathing can sometimes be useful (4, 46).

### TREATMENT

An essential pre-requisite to treating dysfunctional breathing is to ensure optimal control of underlying asthma. This can be challenging given how similar respiratory symptoms occur in both problems and the need to contain the over use of medication.

Once problems, such as EILO and hyperventilation are identified, a clear explanation and reassurance about the nature of the problem can sometimes be effective in ameliorating symptoms. In the case of EILO, recordings of the larynx at endoscopy or direct visual feedback at the time of the procedure can be highly effective in explaining the cause of symptoms and the use of measures to overcome them (15). The optimal approach to ongoing treatment of (E)ILO is unclear (47). Many interventions have been suggested, but have only been studied in small, uncontrolled trials (48). The prognosis is also far from clear with conflicting case reports although those who have symptoms with no identifiable physical triggers (ILO) appear to do poorly (49). Most reviewers recommend the input of speech therapy services that have developed an interest and expertise in treating this problem and the use of inspiratory muscle training exercises. One retrospective study including adults and children suggested the benefits of inhaled anticholinergic agents in preventing exercise related problems (50). Laser supraglottoplasty has been used in highly selected cases with favorable results (40).

The intervention most commonly used for breathing pattern disorders is breathing retraining exercises. Pediatric studies are limited to reports of case series (51), but a large adult clinical trial in which asthmatics were taught by a trained physiotherapist or used a self-help online programme, reported significant improvements in quality of life scores compared to placebo (52). A smaller randomized controlled trial also reported positive results (53). A number of adult studies evaluating yoga and including yoga breathing techniques have shown small improvements in quality of life in unselected populations of asthmatics (54).

A pediatric service has reported a case series using individualized field testing protocols to characterize exercise related breathing problem in asthmatics and included the use of laryngoscopy to identify EILO as well as breathing pattern disorders thus facilitating individually tailored care plans (55). A pediatric respiratory physiotherapist led clinic designed to specifically address dysfunctional breathing problems has reported significant improvements in quality of life outcomes in support of this approach to treatment (56).

Whilst there is a good scientific rationale for psychological interventions to treat dysfunctional breathing, it is difficult to carry out well-designed studies in this area and there is little supporting evidence for this approach in any age group (57, 58). Suggestion therapy has been shown to be highly effective in young children with habit cough using a bed sheet as a bandage to strap and heal the chest, but a similar device has not been used for dysfunctional breathing in asthma (59).

Evaluating how psychotherapy might impact on dysfunctional breathing is compounded by the many ways in which environmental stressors might result in airway symptoms and associated confounders, such as poor adherence and poor lifestyle choices. These problems typically increase during adolescence and continue into early adult life. Stress increases the individual sensitivity to changes in airway caliber (60). It has also been shown to induce clinically significant bronchoconstriction in up to 40% of asthmatics under experimental conditions and asthmatics have been shown to develop increased indices of airway inflammation as a direct result of stress inducing challenges (61, 62). Research into psychological interventions in adults with asthma is inconclusive (63), but there are suggestions that interventions, such as cognitive behavioral therapy and mindfulness based stress reduction might improve both anxiety

### REFERENCES

scores and asthma control. There is even less evidence for this type of psychological intervention in children and adolescents and high quality clinical studies with clearly defined outcomes are needed in this area (64).

### CONCLUSIONS

The diagnosis and treatment of dysfunctional breathing has mostly evolved through observational experience and a growing realization about the importance of this problem in all age groups. Further studies might usefully identify the extent to which the increasing emergence of this clinical problem is impacting on asthma morbidity and in particular during adolescence and early adult life. Recent epidemiological studies have characterized how asthma becomes more prevalent and severe after puberty and particularly in women (65). These changes parallel the emergence of dysfunctional breathing as an increasing problem in asthmatics.

Further studies are needed to help define the optimal approach to treatment in all age groups and to clearly delineate the long-term outcomes for different types of dysfunctional breathing across the lifecourse. Controlled trials have shown that many adults with asthma can benefit from breathing retraining programmes, most probably as a result of correcting breathing pattern disorders. Similar trials are urgently needed to assess the effectiveness of such interventions in children and adolescents.

### AUTHOR CONTRIBUTIONS

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

comparison study examining the accuracy and inter-rater agreement of flowvolume loops as a diagnostic tool. Prim Care Respir J. (2013) 22:306–11. doi: 10.4104/pcrj.2013.00067

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**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2018 Connett and Thomas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Use of Symptoms Scores, Spirometry, and Other Pulmonary Function Testing for Asthma Monitoring

Marcella Gallucci 1 , Paolo Carbonara2 , Angela Maria Grazia Pacilli 2 , Emanuela di Palmo1 , Giampaolo Ricci 1 \* and Stefano Nava2

*1 Department of Pediatrics, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy, 2 Department of Specialistic, Diagnostic and Experimental Medicine (DIMES), University of Bologna, Alma Mater Studiorum, Bologna, Italy*

Asthma is a global problem affecting millions of people all over the world. Monitoring of asthma both in children and in adulthood is an indispensable tool for the optimal disease management and for the maintenance of clinical stability. To date, several resources are available to assess the asthma control, first is the monitoring of symptoms, both through periodic follow-up visits and through specific quality of life measures addressed to the patient in first person or to parents. Clinical monitoring is not always sufficient to predict the risk of future exacerbations, which is why further instrumental examinations are available including lung function tests, the assessment of bronchial hyper-reactivity and bronchial inflammation. All these tools may help in quantifying the future risk for each patient and therefore they potentially may change the natural history of asthmatic disease. The monitoring of asthma in children as in adults is certainly linked by many aspects, however the asthmatic child is a future asthmatic adult and it is precisely during childhood and adolescence that we should implement all the efforts and strategies to prevent the progression of the disease and the subsequent impairment of lung function. For these reasons, asthma monitoring plays a crucial role and must be particularly close and careful. In this paper, we evaluate several tools currently available for asthma monitoring, focusing on current recommendations emerging from various guidelines and especially on the differences between the monitoring in pediatric age and adulthood.

Keywords: asthma, guidelines, asthma monitoring, lung function tests, children, adults

## INTRODUCTION

Asthma is one of the most widespread diseases in the world and affects about 300 million patients (1). Despite the high prevalence of asthma in industrialized countries, overall asthma control is still not completely satisfactory. In Europe, only 15% of patients under steroid treatment achieve adequate disease control (2, 3). These findings highlight the importance of optimizing the asthma management in order to improve disease control. Asthma monitoring is an essential step of disease management, which cannot disregard the understanding of the asthma pathogenesis. The main goals of an effective management is the achievement of an optimal control and the prevention of serious exacerbations and impairment of lung function. Achieving control is ensured by monitoring.

#### Edited by:

*Steve Turner, University of Aberdeen, United Kingdom*

#### Reviewed by:

*Bruno Balbi, Fondazione Salvatore Maugeri, Veruno (IRCCS), Italy Yusei Ohshima, University of Fukui, Japan*

> \*Correspondence: *Giampaolo Ricci<EMAIL_ADDRESS>
#### Specialty section:

*This article was submitted to Pediatric Pulmonology, a section of the journal Frontiers in Pediatrics*

Received: *30 November 2018* Accepted: *11 February 2019* Published: *05 March 2019*

#### Citation:

*Gallucci M, Carbonara P, Pacilli AMG, di Palmo E, Ricci G and Nava S (2019) Use of Symptoms Scores, Spirometry, and Other Pulmonary Function Testing for Asthma Monitoring. Front. Pediatr. 7:54. doi: 10.3389/fped.2019.00054*

**15**

The tools for monitoring asthma include the assessment of frequency and severity of symptoms (patient/parents reported or through specific scores) and the use of objective measurements such as spirometry, airway hyper-responsiveness and inflammatory markers.

During the pediatric age, the asthma monitoring must take into account that children are "growing subjects" with the need for continuous treatment adjustments related to the different stages of development not only physical but also psychorelational. Moreover, healthcare providers do not face a patient but a family unit that must take care of the problem, with all the implications related to school and sports activities.

All guidelines recommend periodic follow-up visits, the interval between visits depends on initial assessment and treatment. Despite the availability of several asthma guidelines, detailed recommendations on asthma monitoring in children and young people (aged 5–16) are poorly defined.

The 2007 American National Asthma Education and Prevention Program (NAEPP) guidelines focuses their attention on the concepts of "impairment and risk" to determine the levels of asthma control and severity, assessed through symptom frequency and measures of lung function among children 5–11 years of age (4). NAEPP guidelines introduced a categorization of asthmatic patients defining them as having "persistent asthma" if they have experienced two or more exacerbations treated with oral corticosteroids (OCS) in the previous 6 months, with a consequent increased future risk. More recently, GINA guidelines state that a previous severe exacerbation in the last 12 months, a history of access into an intensive care or intubation are major independent risk factors for exacerbations (4, 5).

Others factors that increase the future risk in children and adults include the following: socioeconomic or psychological problems, comorbidities such as obesity, chronic rhino-sinusitis, food allergy, exposure to smoke or allergens, low FEV1, higher bronchodilator reversibility, high SABA use, inadequate treatment, sputum or blood eosinophilia and elevated FeNO (5).

The latter two performed before and after the preventive therapy are useful in the assessment of response to medical treatments.

Therefore, the need to quantify the "future risk" for each patient, led the scientific community to search for specific indicators of future exacerbations, such as biomarkers, individual characteristics and genetic factors. These indicators could play a crucial role in asthma monitoring, although some methods are not yet standardized or used in clinical practice.

Scottish Intercollegiate Guidelines Network (SIGN) recommends the monitoring of asthma in children mainly through the assessment of symptoms, number of exacerbations, school absences, evaluation of therapy adherence and inhaler technique, measurement of height, and weight at least annually (6).

A close monitoring of asthma should include also an early detection of the impairment in lung function as well as the presence of bronchial hyper-responsiveness and bronchial inflammation. These findings are even more relevant in patients at risk, especially in those at high risk of exacerbations or with poor/inadequate disease control (7).

Ideally, a successful management should minimize both daily symptoms and risk factors for exacerbations/complications.

As recommended by the most recent published guidelines (GINA, NICE, SIGN/BTS) the follow up of asthmatic patients should be centered on continuing patients self-monitoring and periodical ambulatory visits for the assessments of the clinical status and lung function parameters (5, 6, 8).

The frequency of follow-up visits depends on asthma severity and the need of treatment adjustments. According to GINA recommendations, the lung function should be recorded at diagnosis, 3–6 months after starting treatment and "periodically" thereafter.

Among pediatric population, an adequate parents training can have a role in reducing the frequency of follow-up visits (9–11).

The main purpose of this article is to compare recommendations of various guidelines about asthma monitoring but also highlighting the differences between recommendations for pediatric and adult patients. In particular, we focus our attention on the availability of clinical tools for assessment of frequency and severity of symptoms, the use of lung function tests and inflammatory markers and the early detection of comorbidities and risk factors for severe asthma.

Monitoring asthma also means investigating the causes of poor medication adherence as well as comprising practical difficulties in using inhaler devices and understanding therapeutic plans especially in adult patients with comorbidities. The lack of awareness and detailed information regarding the importance of treatment adherence, avoidance of triggers, proper inhaler technique significantly contributes to the poor disease control.

Many tools are currently available for clinical and instrumental asthma monitoring, some of these can be performed by patients or caregivers (e.g., PEF), others (such as FeNO, spirometry, or asthma scores) can be made by general practitioners and/or by pulmonologists while some other (such as sputum analysis and oscillometry) only by pulmonologists.

In this paper, we will analyze each of these tools by evaluating different applications in the disease monitoring and comparing different guidelines.

### CLINICAL TOOLS

#### Asthma Control Scores

The clinical history is crucial to assess the asthma control and should include simple key questions and specific asthma scores to collected information about exacerbations, limitations of daily activities, nocturnal awakenings and reliever medication use.

For young children, asthma control should be determined with help from the child's parent through.

**Abbreviations:** NAEPP, American National Asthma Education and Prevention Program; BDR, bronchodilator reversibility; BHR, bronchial hyperresponsiveness; GINA, Global Initiative for Asthma; FeNO, fractional exhaled nitric oxide; IOS, impulse oscillometry; FOT, technique of forced oscillations; COPD, Chronic Obstructive Pulmonary Disease.

Both in adult and children, GINA guidelines distinguishes between controlled, partly controlled and poorly controlled asthma based on level of symptoms during the past 4 weeks (5).

This categorization take into account the presence of daily symptoms (>2 per week), any night awakenings, reliever needed (>2 per week) and any activity limitation due to asthma, therefore, controlled asthma is defined by minimal daily symptoms and need of short acting bronchodilator, no nocturnal symptoms and no limitation of activities.

Further and more specific tools to assess the asthma control include quality-of-life measures such as questionnaires applicable in both adults and children (**Table 1**).

The Asthma Control Test (ACT) and the Asthma Control Questionnaire (ACQ) are recommended by all Guidelines and have been studied and extensively validated for both adults and children (the childhood ACT for children 4– 11 years of age and the ACQ for children older than 5 years).

ACT includes 5 questions, 3 related to symptoms, 1 related to medication use, and 1 about overall control during the past 4 weeks with separate sections for parent and child; a score ≤ 19 indicate a poor symptoms control (15–17).

The C-ACT include seven items and it is divided into two parts. The first part is addressed to the child and consists of four questions on perception of asthma control, limitation of activities, coughing and awakenings at night. The second one is completed by parents and consists of three questions (daytime complaints, daytime wheezing and awakenings at night) with six response options. The score ranges from 0 (poorest asthma control) to 27 (optimal asthma control). ACT and ACQ are useful to assess the response to longerterm treatment.

The ACQ includes 7 questions, 5 related to symptoms, 1 on rescue treatment use and 1 on FEV1 finding; the control is assessed over the preceding week. For children with normal FEV1 a version of five-point questionnaire is preferable (12).

Other available scores include the Mini Asthma Quality of Life Questionnaire, validated for adults (its counterparts for patients 7–17 years of age is the Pediatric Quality of life Questionnaire) and the Royal College of Physicians 3 Questions (13, 14). The first values the control over the preceding 2 weeks and could be used to assess response to longer-term treatment trials. The latter although not well validated in both adults and children, could be used in day-to-day clinical practice thanks to his simplicity.

In the pediatric setting, GINA guidelines also include the Test for Respiratory and Asthma Control in Kids (TRACK) and the Composite Asthma Severity Index (CASI) both including the assessment of exacerbations. The TRACK is the first validated questionnaire designed to assess asthma control exclusively in young children (<4 years). This score may be more sensible in children since it reflects the changes in asthma control over a short follow up period and take into account the assessment of exacerbations (18, 19). Nevertheless, children may experience more exacerbations during one season vs. another while most of the clinical scores investigate trends over the last month, so they may not be totally indicative of asthma control in children with seasonal wheezing (20).

SIGN guidelines also recommend the use of the Pediatric Asthma Quality of life Questionnaire (PAQLQ) to assess healthrelated QoL in children with asthma and including 23 questions that investigate 4 domains (symptoms, activity limitations, emotional function, and environmental stimuli), validated for the age range 7–17 years (21, 22).

A further questionnaire is the Asthma Therapy Assessment Questionnaire (ATAQ), a 20-item parent-completed questionnaire, developed to assist clinicians to identify children at risk for adverse outcomes of asthma and including 4 different domains on symptom control, behavior and attitude barriers, self-efficacy barriers, and communication gaps (23).

TABLE 2 | Positive test threshold of objective tests in children (aged 5 years and over) and adults.

*Comparison between the different guidelines. n/a, not applicable; n/i, not included.* \**Calculated from twice-daily readings (best of each time): (HighestPEF-LowestPEF)/mean of the day's highest and lowest PEF, and averaged over 1–2 weeks.* \*\**School children using a threshold of 9% change.* \*\*\**Monitor peak flows for 2–4 weeks.* ◦*PC20: provocative concentration of methacholine causing a 20% fall in FEV1.*

A new score defined Severe Asthma questionnaire (SAQ) is being validated in adults; it can be used to detect the impact of both asthma symptoms and treatment on quality of life (24).

Usually, in daily practice, the possibility of using asthma control questionnaires and above all quality of life measures is significantly higher in the pediatric clinical routine.

Certainly, in the pediatric age the supervision of parents ensures a further control and makes these scores more reliable than those compiled by asthmatic patients. Moreover, in the adulthood comorbidities play an important role in the care management, often with reduced time to apply these clinical tools by healthcare professionals.

Concluding, we believe that asthma control scores are simple and useful monitoring tools, but the most of these refer to a short previous period and are often influenced by the subjective (or caregivers') symptom perception, for this reason they should be combined, when possible, with more objective tests such as pulmonary function tests or a careful clinical follow-up.

#### Patients and Parents Self-Monitoring

Patients as well as parents should be encouraged to keep track of symptoms consequently healthcare practitioners should adequately train them on this issue.

As recognized by several guidelines, many patients can benefit from a written action plan in which, according to the disease control, the patient is instructed to recognize the need for action (e.g., to step up therapy or seek medical advice) (5, 25).

A detailed education program for both adults and pediatric patients should cover: training on treatment adherence and correct use of medication, recognition and avoidance of triggers and risk factors for exacerbations or worsening of symptoms (such as exposure to allergens, influenza virus or rhinoviruses, smoke both active and passive or other environmental factors, including workplace related factors) (25, 26).

Among adults, educational programs have been repeatedly proven effective in improving symptoms control, quality of life and treatment compliance therefore they potentially can prevent or reduce severe exacerbations conducive to urgent visits and hospital admissions (4, 5).

A recent prospective randomized controlled trial including 160 adults with asthma showed that a single 10 min, educational session provided by a respiratory specialist, could substantially improve asthma control determined by the ACT score after 3 months. The educational program included basic information about asthma treatment and instructions on inhalation technique for about 10 min (27).

More recently, new tools for the self-assessment of asthma control are available such as applications for smartphones, often produced by respiratory societies, which can often be obtained for free (28, 29).

These applications enable patients to enter in their profile daily data such as symptoms and their frequency, ACT, PEF values etc. The app can therefore calculate the level of asthma control. Some apps have up to date pollen maps and calendars, or have personalized acoustic memos to remind patients to take the inhaled therapy (30).

Vasbinder et al. in their randomized controlled trial e-MATIC (e-Monitoring of Asthma Therapy to Improve Compliance in children), proposed the use of the "real-time medication monitoring (RTMM)" for improving adherence to inhaled corticosteroids. The study failed to prove a significant improvement in asthma control, quality of life or asthma exacerbations with high costs in the intervention group, although RTMM with tailored SMS reminders improved adherence to ICS (31).

Nevertheless, e- devices may be precious tools for monitoring, especially in adolescence. Teenagers, in particular, may experience age-related difficulties as they accept responsibility for self-management from their parents; the negative impacts of asthma are largely preventable if adolescents engage in self-management behaviors, including symptom prevention as treatment adherence and trigger avoidance or symptom monitoring. It has been proved that the use of "asthma apps" can positively influence adolescents' self-management behaviors through increased self-observation, self-judgment and increased self-efficacy (32).

The availability of these new promising resources certainly opens up new possibilities in the management and monitoring of asthma, even though a recent Cochrane meta-analysis (including 21 studies in adults and children), concluded that tele-healthcare for asthma did not seems to improve QoL or reduce exacerbation rate in children (33). Therefore, further evidences and studies will be needed to routinely recommend the use of these tools in the clinical practice.

### LUNG FUNCTION TESTS AND INFLAMMATORY MARKERS

#### Spirometry

The functional hallmark of asthma is a reversible airway obstruction and its detection is often required for the diagnosis of the disease. The severity of obstruction is a known risk factor for exacerbations, therefore functional monitoring is essential in order to achieve optimal control.

Moreover, severity of obstruction does not always correlate with symptoms: a significant bronchial obstruction may be present also in asymptomatic children and adults. It has been shown that children with chronic obstruction are less likely to perceive the symptom of dyspnea than children with an acute obstruction (34). For this reason, children with poor perception of chronic obstruction are at risk of developing severe exacerbations, associated with poor lung function. Therefore, a regular assessment of lung function is crucial.

The spirometry is the main test for detecting and measuring airway obstruction in children over 5 years old and adults and it has some precision for predicting future attacks.

Reference values of the lung function tests suggested by several guidelines are reported in **Table 2**.

The presence of expiratory airflow limitation should be valued at diagnosis or at the beginning of treatment (in order to evaluate increase in treatment dose), after 3–6 months of controller therapy and then periodically depending on clinical course, although SIGN and GINA guidelines do not indicate clear recommendations on monitoring FEV1 in children (5, 6).

NICE guidelines specify to perform a spirometry for monitoring asthma at each visit or at least after 3 or 6 months from the beginning of therapy and then every 1–2 years (8).

Spirometer parameters should be adjusted according to sex, age, and ethnicity. According to GINA guidelines, the FEV/FVC ratio cut-off of normality is 0.90 in children and 0.75–0.80 in adults (5). Different guidelines often diverge in the choice of this cut-off (according to NICE guidelines, it is 0.70 in both pediatric and adult age) (8) (**Table 2**).

In general, a fixed threshold might lead to an overestimation of obstruction in elderly patients and an underestimation in young ones (35).

In **Table 3** we reported the main lung function tests used in our clinical setting in monitoring asthma.

FEV1 is the most widely used functional index in the asthma follow up; in particular, among asthmatic children a FEV1 <60% is a risk factor for exacerbations and its decrease is associated with increasing asthma severity (36). Children with FEV1 <60% of the predicted seem to have a double risk of asthma exacerbations in the following year compared to those with FEV1> 80% (4, 37).

In order to compare spirometry findings in children, Global Lung Initiative recommend that the spirometry values should be expressed in z score, even though these recommendation is poorly applied worldwide (5).

Adults with an accelerated FEV1 decline (>30 ml/year) may be either steroid-resistant/difficult-to-treat asthmatics or not adequately treated principally due to under-perception or poorly adherence to maintenance therapy (38).

Some authors have argued that other indices, such as FVC, should be also considered, as some patients with severe obstruction respond to bronchodilators with a significant increase in FVC but not FEV1 (39).

In order to compare spirometry findings in children, Global Lung Initiative recommend that the spirometry values should be expressed in z score, even though these recommendation is poorly applied worldwide (8).

It is well known that the confirmation of the diagnosis requires a positive reversibility test (according to GINA guidelines improvement in FEV1 ≥12 in children, ≥12% together with an increase in volume ≥200 ml in adults). American Thoracic Society recommendations define a significant bronchodilator response (BDR) as an increase in FEV1 ≥12% and/or 200 ml in both adults and children (40).

+*, dubious role in asthma monitoring;* ++*, potentially useful in asthma monitoring.*

Some studies showed that in children, this cut-off may be too high and then less sensitive to assess airway obstruction, suggesting that a lower cut-off (8%) should be used to improve the diagnosis of asthma (41).

The assessment of bronchodilator reversibility (BDR) can be useful not only to confirm the diagnosis but also in the asthma monitoring. In severe pediatric asthma, the spirometry should be always performed with a bronchodilator test to detect airway obstruction and its reversibility since it has been shown that these children have an increased bronchodilator response that may be associated with higher risk of impairment of lung function (42, 43). A persistent BDR may also be associated with poor therapy compliance or wrong inhaler technique and seems to correlate to some indices of airway inflammation, such as the exhaled nitric oxide fraction (FeNO), therefore it might be predictive for a positive response to inhaled corticosteroids (ICSs) (44).

Regarding the most appropriate setting to perform lung function tests, although spirometry performed in the primary care setting may be a useful tool in asthma monitoring, concerns have been raised about the quality and standardization of this procedure compared to hospitalbased or laboratory spirometry. The spirometry provides objective data of lung function, but the outcome is often dependent on the operator. Therefore, in our opinion, expert personnel that spurs the patient to an optimal execution should perform it.

### Peak Expiratory Flow

Home monitoring of peak expiratory flow (PEF) may be use as an additional functional test in the monitoring of asthma. There is still lack of evidence that PEF monitoring over time might result in better disease control. PEF measurement can be used to document the variability of bronchial obstruction in asthma even if PEF is not related to FEV1 values and may underestimate the degree of airflow limitation and air trapping. Moreover, PEF values vary depending on the meter used therefore it is advisable to compare its measurement with the best personal value (obtained during the disease control phase or during maximum treatment) using the same meter. PEF "personal best" has proved to be useful in improving the progression of asthma, but the patient needs to be adequately trained since measures are effort dependent (45, 46).

According with most of the guidelines, PEF measurement should not be routinely used to monitor asthma in children, unlike in adults where it is recommended for subjects with severe asthma or with poor perception of airflow limitation (5, 6, 8). Certainly, PEF measurements do not give information about the obstruction characteristics (obstructive or restrictive) or site. Nevertheless, NICE guidelines recommend a monitoring of peak flow variability for 2–4 weeks in children and young people (aged 5–16) if there is "diagnostic uncertainty after initial assessment with a normal or obstructive spirometry, irreversible airways obstruction (negative BDR) and a FeNO level of 35 ppb or more" (8). NICE guideline also recommend considering a value of more than 20% variability as a positive test. Even GINA guidelines in the diagnostic assessment of asthma include the use of diurnal PEF variability calculated from twice daily over 2 weeks; for children diurnal variability >13% is considered excessive [unlike in adult where the cut-off of PEF variability is >10% (5)] (**Table 2**).

The ease of execution even in pediatric age and the possibility of being performed at home and during acute phase make this test easy to handle and reproducible, even though its monitoring does not improve asthma control in addition to clinical scores in adults and children (6, 47). For this reason, PEF assessment is not recommended in pediatric age in asthma monitoring.

### Impulse Oscillometry, Forced Oscillations Technique, and Expiratory Flow Limitation

During childhood, impulse oscillometry (IOS) and the technique of forced oscillations (FOT) may be used as an alternative technique to assess lung function, since measurements are made from tidal breathing and younger children are able to comply compared to spirometry. IOS measures respiratory resistance and reactance by analyzing responses to pressure waves of different frequency. The assessment of airflow resistance can be an indirect indicator of airway caliber, while spirometry mainly reflects airflow characteristics. IOS is easily performed during tidal breathing therefore it only need a partial collaboration of small patients, even though it is not available in all centers and in some cases, it is difficult to interpret. ERS/ATS guidelines give practice information about the test modality and its analysis (48).

Several studies showed a significant association between findings of the IOS and those of spirometry. In asthma, IOS has been used to assess the bronchodilator response and the therapeutic response to different treatments. In studies utilizing both IOS and spirometry, the first one has proved to be more useful than spirometry in early detection of asthmatic children from normal cohorts (49).

Many evidence showed that peripheral airways (PAW) in children as in adults are the initial site of inflammation and obstruction in asthmatic disease (50).

IOS can evaluate peripheral airways more accurately than spirometry identifying a PAW impairment before symptoms and spirometric abnormalities occur. For these reasons, it could be used to guide an early therapeutic approach to prevent clinical symptoms and further lung damage (51).

In adulthood, excluding patients with severe chronic asthma and marked airway obstruction, an expiratory flow limitation (ELF) at rest is seldom observed, unless under severe and prolonged bronchoconstriction.

One way to value EFL is by the forced oscillation technique (FOT) through the application of negative pressure at the mouth during tidal expiration (NEP).

When the oscillatory pressure applied at the mouth does not reach alveoli during expiration due to a flow-limiting segment in the bronchial tree, the reactance signal, instead of reflecting the mechanical properties of the lung parenchyma and airways, is influenced only by those of the airways and becomes much more negative with a clear distinction between inspiration and expiration.

This application of the FOT is useful to identify flow limitation during tidal breathing, but the closure of intrathoracic airways eventually occurring at end expiratory lung volume (EELV) must be considered as an important limiting factor of this technique, since the distortion of the reactance signal is similar (52, 53).

In addition, when EFL originates in the peripheral airways, it is mainly due to the viscous, density-independent, flowlimiting mechanism, while the speed wave, density-dependent, flow-limiting mechanism is substantially involved when the EFL originates in the central airways.

Despite several potential applications of FOT and oscillometry, larger longitudinal studies will be needed to confirm the usefulness of these techniques as routinely monitoring tools in asthma.

### Blood and Sputum Eosinophils

As indicated in the recent ERS/ATS guidelines, the assessment of asthma phenotype (eosinophilic or noneosinophilic) may play a crucial role in the management of patients with severe disease (54). The ideal tool for this purpose is represented by the cell count on BAL during bronchoscopy. The invasive nature of the procedure has obviously limited the number of subjects studied, therefore the scientific community has sought surrogates that allowed the identification of different asthma phenotypes such as eosinophils count in induced sputum and the peripheral eosinophilia.

Based on the sputum analysis, patients with asthma can be grouped in four different inflammatory phenotypes: eosinophilic asthma, neutrophilic asthma, mixed granulocytic asthma, and paucigranulocytic asthma. Eosinophilic asthma defined as a sputum eosinophil count of 2–3% or higher, represents almost half of the asthmatic population (55).

Several studies have found higher levels of sputum eosinophils in uncontrolled asthmatics, therefore sputum analysis may be a useful method of objectively monitoring asthma (56). Moreover, the short-term response to inhaled corticosteroids depends on the amount of eosinophils present in the sputum therefore this technique may be a guide for modulating steroid therapy (57).

A recent study by Fleming et al. included 55 children with severe asthma and showed that incorporating the control of sputum eosinophils into the management algorithm reduce exacerbations in the short term even though did not significantly reduce overall exacerbations or improve asthma control (58).

It is difficult for children to collect sputum because they tend to swallow more than expectorate.

Among pediatric patients with bronchial hyperactivity, induced sputum, through stimulation with hypertonic saline, may allow to understand the type of inflammation, the presence of cells and lower respiratory tract mediators (59–61).

Several studies have evaluated the safety of sputum induced in asthmatic children aged 6 to 16, demonstrating how moderate bronchospasm occurs in 10% of children and resolves with the administration of the bronchodilator (62, 63).

In clinical practice, the use of these tools for the diagnosis and monitoring of asthma certainly has limitations, however among pulmonologists and also in our center these may be a precious help for the assessment of the type of inflammation, the diagnostic confirmation and the adjustment of the preventive therapy.

In asthma, blood eosinophil are considered a good surrogate marker for sputum eosinophil count (over 2–3% with a cut-off of 220 cells per mm3 or 3% among adults). High eosinophil count in peripheral blood is a recognized risk factor for disease severity and for future exacerbations (58, 64). During childhood, the asthma predictive index (API) also include blood eosinophils within minor criteria as predictor of future recurrent wheezing (65, 66).

Nadif et al. showed that patients with high blood eosinophilia (>250 cells per mm3 ) had lower FEV1 values and worse asthma control than those with eosinophils in normal range (67).

For these reasons, the bronchial and peripheral eosinophilia could be considered a potentially useful biomarker for the selection of patients who will respond to anti IL5 therapy, a monoclonal antibody used in patient older than 12 years with refractory eosinophilic asthma.

#### Fractional Exhaled Nitric Oxide (FeNO)

As already mentioned, the detection of different asthma phenotypes guided the scientific community searching for specific biomarkers that could guide and improve the disease monitoring and the therapeutic approach. The monitoring of asthma should also include the determination of minimally invasive inflammatory markers.

Fractional exhaled nitric oxide (FeNO) measurement correlates with eosinophilic airway inflammation and therefore with the most common asthma endotype, independently of gender, and age. FeNO levels are higher in asthmatic children compared to non-asthmatic children and in one study values rose further during exacerbations and rapid decline after oral steroid treatment (68–70). British guidelines recognize that a FeNO <20 ppb in children under 12 years may have a role in identifying patients who can step down corticosteroid treatment (5). This relationship is lost in adults smokers (superior cut off in children >35 ppb, in adults >50 ppb) (6) (**Table 3**).

Agency for Healthcare Research and Quality (AHRQ), recently conducted a systematic review (including 175 studies) about the role of FeNO in the diagnosis, treatment and monitoring of asthma. Both in adults and in children FeNO results can predict which patients will respond to inhaled corticosteroid therapy, therefore the use of this marker in long-term managing of treatments can reduce the frequency of exacerbations. Moreover, the review showed that FeNO diagnostic accuracy was modestly better in steroid-naïve asthmatics, children and non-smokers than the overall population. Nevertheless, regarding the asthma monitoring in preschooler children authors concluded that there is insufficient evidence supporting the use of FeNO in this category for predicting a future diagnosis of asthma (69).

Two recent Cochrane reviews, including both pediatric and adulthood studies, showed that tailoring asthma medications based on FeNO levels decreased the frequency of asthma exacerbations but did not impact on day-to-day clinical symptoms or inhaled corticosteroid dose (71–73).

In conclusion, FeNO role in asthma management has not been concretely proven due to incomplete evidence therefore it is not routinely recommended in all patients, at least in monitoring, even though it may be useful in subjects who respond poorly to inhaled corticosteroids (73).

Nevertheless, the use of biomarkers as tools for phenotyping asthma and personalizing therapy is certainly attractive but it has not yet entered clinical practice.

## AIRWAY HYPERRESPONSIVENESS

### Bronchial Provocation Tests

A hallmark feature of asthma is increased responsiveness of the airways to inhaled stimuli. The assessment of bronchial responsiveness through provocation tests can be useful for both research purposes and clinical practice. Bronchial provocation tests include the direct inhalation of different substances such as methacholine, histamine, mannitol, inhalation of allergens or the use of "stimuli" such as exercise, inhalation of cold air and hyperventilation with dry air (74).

Monitoring of bronchial hyper-responsiveness (BHR) is not routinely recommended in current guidelines, since its role is more typically confined to the diagnostic process.

However, some data seem to indicate a potential usefulness of BHR among asthmatic adults, as an indicator of exacerbation risk and inhaled corticosteroid response (75, 76).

Bronchial provocations tests are not usually performed in asthmatic children and several papers support this recommendation including one clinical trial (77). Nevertheless, BHR assessments could have a role in asthma monitoring among children with exercise limitations or with reduced perception of symptoms (78).

Within the pediatric population, the exercise test may be a precious tool for the evaluation of indirect BHR (79). A reduction in post-exercise FEV1 compared to the baseline is considered a sign of bronchial obstruction induced by exercise. GINA guidelines recognize that the exercise challenge may provide information about airway hyper-responsiveness but "only undertake a challenge if it is otherwise difficult to assess asthma control." A positive exercise challenge for children is considered for a fall in FEV1 >12% of predicted or PEF >15% (for adult a fall in FEV1 >10% and >200 ml from baseline).

NICE guideline clearly recommend of "do not use challenge testing to monitor asthma control," while SIGN group state that "regular monitoring of airway responsiveness not proven to improve asthma control in children" (6, 8) (**Table 2**).

### COMORBIDITIES AND RISK FACTORS

Both for adults and children, the detection of potentially modifiable risk factors for exacerbations may be useful in asthma monitoring and includes the exposure to specific allergens, smoking, high SABA use, poor adherence to therapy and incorrect inhaler technique. As already mentioned, GINA guidelines state that a previous sever exacerbation in last 12 months and a history of access into an intensive care or intubation are major independent risk factors for exacerbations (5).

Moreover, the asthma monitoring cannot be separated from an early identification and management of associated comorbidities (**Table 4**).

This term defines factors and/or pathological conditions, which can coexist with asthma, contribute to its severity and to poor control.

Comorbidities are obviously more frequent in adults and may significantly complicate the management of asthma throughout

#### TABLE 4 | Principal asthma comorbidities.

*–, not relevant;* ±*, some relevance;* ++*, relevant;* + + +*, very relevant.*

all its stages, from diagnosis to treatment. All guidelines present this point as relevant in the workup of asthma. The most frequent comorbidities among adult population include upper airway diseases (rhinitis, chronic rhinosinusitis), obesity, COPD, gastroesophageal reflux disease (GERD), bronchiectasis; in elderly patients, heart failure is very common.

From an epidemiological point of view, rhinitis, and rhinosinusitis are the most frequent comorbidities of asthma for all ages and the former seems to be associated with an increased risk of exacerbations (80). The presence of GERD is associated with worse asthma symptoms and poorer quality of life while obesity can worsen asthma by compromising lung function, inducing corticosteroid insensitivity and systemic inflammation (81–83).

All these conditions often exacerbate or simulate symptoms of asthma causing a poor response to treatment. For these reasons, it is essential to assess and carefully monitor these comorbidities also by implementing integrated care pathways.

Other conditions that may present with elevated blood eosinophilia and a clinical picture mimicking a severe refractory asthma, such as chronic eosinophilic pneumonia, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis (ABPA), should be taken into account during asthma monitoring (84).

Finally, a subset of adult patients (usually over 40 years of age) present a combination of both asthma and COPD features which is known as Asthma-COPD overlap syndrome (ACOS), likely resulting from different phenotypes of airway disease. They are often smokers, but may have allergies and a family or personal history of asthma with a not completely reversible airway obstruction (5).

Additional diagnostic findings include eosinophilic airway inflammation, a good response to corticosteroid therapy, and high concentrations of exhaled nitric oxide, which should be assessed in the monitoring of these patients (85). Since ACOS outcome is generally worse than asthma with higher treatment needs, the management should be especially careful therefore it might be advisable to refer these patients to specialized center.

#### ASTHMA ACTION PLAN

The asthma action plan helps asthmatic adults and/or caregivers recognize worsening asthma and gives clear instructions on what to do in response. Each asthmatic patient is different, so each action plan will be too.

An accurate action plan should cover every of these points:

The asthma action plan should be based on symptoms trend or peak expiratory flow (PEF) measurements and is individualized according to the pattern of the patient's disease. In children, symptom-based plans are preferred.

Inclusion of PEF measurements in the asthma action plan can be beneficial for adults with more severe or difficult-to-control asthma and those with poor symptoms perception. When PEF is used, the asthma action plan should be based on personal best rather than on predicted values.

Regular review of the asthma action plan is an important part of asthma monitoring since the level of asthma severity and control may change over time (86, 87).

### CONCLUSION

An ideal asthma monitoring should provide a personalized approach for each asthmatic patient.

The personalized asthma care should use specific monitoring tools for different patients, preferably with different fields. This assumption therefore represent a fundamental part of comprehensive asthma management.

In light of reported evidences, it may be noted that some advice in monitoring of asthma may apply to both adults and children.

acute exacerbations and to detect an early impairment of lung function.

Ideally, the follow-up of asthmatic patients should have as its objective a responsible self-monitoring associated with a periodic outpatient check of the clinical status and lung function findings.

#### REFERENCES

As healthcare professionals, we should arouse awareness and self-management. Particularly among adolescents, we should implement a shared decision-making and find ways to connect with them effectively.

The use of new technologies in monitoring asthma is inevitable and may help us to provide great opportunities to monitor patients remotely and to improve the communication.

### DATA AVAILABILITY

All datasets generated for this study are included in the manuscript and the supplementary files.

### AUTHOR CONTRIBUTIONS

MG and PC performed the literature review. AP, SN, and EdP contributed to data collection and interpretation of the literature data. GR coordinated the writing group. All authors critically reviewed the manuscript, read and approved the final version.

southern china. Pediatrics. (2013) 131:e518–24. doi: 10.1542/peds.201 2-0946

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2019 Gallucci, Carbonara, Pacilli, di Palmo, Ricci and Nava. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# The Differences in Acute Management of Asthma in Adults and Children

Richard Chavasse1† and Stephen Scott 2,3 \* †

*1 Consultant Respiratory Paediatrician, St George's University Hospitals NHS Foundation Trust, St George's University of London, London, United Kingdom, 2 Consultant in Respiratory Medicine, The Countess of Chester Hospital NHS Foundation Trust, Cheshire, United Kingdom, 3 Chester Medical School, The University of Chester, Chester, United Kingdom*

Acute asthma or wheeze is a common presentation to emergency services for both adults and children. Although there are phenotypic differences between asthma syndromes, the management of acute symptoms follow similar lines. This article looks at the similarities and differences in approaches for children and adults. Some of these may be age dependent, such as the physiological parameters used to define the severity of the attack or the use of age appropriate inhaler devices. Other differences may reflect the availability of evidence. In other areas there is conflicting evidence between adult and pediatric studies such as a temporary increase in dose of inhaled corticosteroids during an acute attack. Overall there are more similarities than differences.

#### Edited by:

*Steve Turner, University of Aberdeen, United Kingdom*

#### Reviewed by:

*Giuseppe Pingitore, ASL Roma, Italy Yusei Ohshima, University of Fukui, Japan*

\*Correspondence: *Stephen Scott<EMAIL_ADDRESS>
*†These authors have contributed equally to this work*

#### Specialty section:

*This article was submitted to Pediatric Pulmonology, a section of the journal Frontiers in Pediatrics*

Received: *07 November 2018* Accepted: *18 February 2019* Published: *11 March 2019*

#### Citation:

*Chavasse R and Scott S (2019) The Differences in Acute Management of Asthma in Adults and Children. Front. Pediatr. 7:64. doi: 10.3389/fped.2019.00064*

Keywords: asthma, attack, adults, children, treatment

### INTRODUCTION

Asthma is the commonest chronic condition in the UK with a UK lifetime prevalence of patient-reported clinician-diagnosed asthma of 15.6%. In 1 year asthma results in 6.3 million primary care consultations and 93,000 hospital in-patient episodes. The costs of asthma are estimated at £1.1 billion 12% of which is accounted for by hospital care and 14% for primary care consultations (1). Many physicians in both adult and pediatric medicine across the whole healthcare economy will therefore be expected to manage patients who may present with an acute attack of their disease so knowledge of this area is very important for good patient care. Guidelines for the management of an acute asthma attacks are documented in a number of national and international publications (2–4). Management of an acute attack may start with treatment at home and may progress to treatment in primary care, the emergency department and on the hospital wards including intensive care. This article looks at similarities and differences in the management of acute management between adults and children of varying ages.

The definition of asthma is difficult and there is no gold standard, and it is increasingly recognized that asthma as a condition is made up of a number of phenotypes (5, 6). The use of phenotypic variations is more likely to inform and modify chronic management, rather than the acute management of a crisis at the present time. The first recognized presentation of asthma is not uncommonly an acute attack, particularly in children, and therefore may present a diagnostic challenge.

The British Thoracic Society and Scottish Intercollegiate Guidelines Network (BTS/SIGN) asthma guideline precis the definitions of asthma as the presence of more than one symptom of wheeze, breathlessness, chest tightness and cough associated with variable airflow obstruction. Other definitions of asthma, in both children and adults, include airway hyper-responsiveness

**27**

and airway inflammation as components of the disease (BTS/SIGN) (2). The National Institute of Clinical Effectiveness (NICE) have suggested a diagnosis should not be made without objective evidence of airway obstruction or inflammation (3).

In younger children, particularly those <5 years of age, the diagnosis of asthma (or phenotypes of wheeze) is difficult and often controversial (7). Acute wheeze is however a very common presenting complaint to both primary and secondary care and may frequently be recurrent and troublesome. Whilst the intricacies of diagnosis is beyond the context of this piece, recognition of this difficulty is important. Asthma diagnosis and phenotypes are subjects covered elsewhere in this series of articles. As is not uncommon, the evidence for different treatments are less well studied in the younger age groups. For the purpose of this review it will be assumed that the diagnosis of asthma is secure and we will be comparing / contrasting the differences in children and adult asthma.

#### DEFINITION OF ADULTS AND CHILDREN

The definition of an adult will be taken as a person over 18 years, accepting there is a considerable cross over in the adolescent age group. In most hospital emergency departments, adolescents under 18 are usually managed in the pediatric area, and if necessary by pediatricians, although it is recognized that different healthcare systems may have different policies. Guidelines and clinical trials vary in their cut off ages with many studies including adolescents over 12 in "adult" studies. Age cut offs are clearly not as relevant to provision of care in primary care and the home environment, however the age and maturity of the individual patient should be considered when agreeing a management plan. For children there are differences in the approach to the young, preschool child (<5 years) and there is very little evidence for the management of asthma symptoms in children under 1 year of age.

### DEFINITIONS & ASSESSMENT OF ACUTE ASTHMA

An acute asthma attack represents a deterioration in symptoms and lung function from the patient's normal status. Distinguishing between a lower respiratory tract infection and an asthma attack can be challenging, particularly in young children. This can include shortness of breath, wheezing, cough, and chest tightness (4). Attacks are marked by a decrease from baseline in objective measures of pulmonary function, such as peak expiratory flow rate and FEV1. Objective measures, such as FEV1 are less easy to perform in children and young persons, and PEFR can be unreliable in children and young persons if they have not used the technique before and are highly unlikely to be achieved in children <5 years of age (8). In some individuals, in particular those with poor adherence and/or more severe asthma, there can be a challenge in distinguishing between a mild asthma attack and long-standing poorly controlled asthma; the challenge in in part due to symptoms being common to both a mild asthma attack and poorly controlled asthma and in part due to guidelines not defining criteria for a mild asthma attack.

Pharmacological management is entirely dependent upon the severity of the attack which in turn is defined by a number of objective and subjective findings. These differ between adults and children, reflecting the age-related physiologic differences and the reliability of pulmonary function testing in children. Definitions from the BTS/SIGN and Global Initiative for Asthma (GINA) guidelines are outlined in **Table 1**.

### PRE-HOSPITAL MANAGEMENT OF ACUTE ASTHMA

Adults are encouraged to have a personalized asthma action plan (PAAP) in place which empowers them to increase treatments in response to increasing symptoms or decreasing PEFR (9). The PAAP should advise them when to seek medical assistance. In children PAAPs advice only recommends increasing short acting beta agonist. A Cochrane database systematic review of 4 clinical trials in children concluded that symptom-based PAAPs are superior to peak flow PAAPs for preventing acute care visits (10). There was insufficient data to firmly conclude how symptom-based PAAPs were superior of the two. For example the observed superiority of symptom-based PAAPs may have been due to greater adherence to the monitoring strategy, earlier identification of onset of deteriorations, higher threshold for presentation to acute care settings, or the specific treatment recommendations (10).

Most adult PAAPs recommend the increased use short acting beta agonists at the onset of acute symptoms (11). Most pediatric management plans suggest a titrated increased dose of beta-2 agonist using doses between 2 and 10 puffs of a salbutamol (pressure dose metered dose inhaler and spacer device) up to every 4 h (12). Safety net advice to seek medical advice and call an ambulance if not responding to treatment should be included. Judicial use of rescue oral steroids at home is sometimes included, although there is no consistent evidence of benefit for this practice (13).

A second approach in adults may be the use of a single combination inhaler for both preventer and relief [Maintenance and Reliever Therapy: (MART)] which patients may titrate in accordance to their symptoms (14). Preparations are not currently licensed or in formulations for younger adolescents or children in the UK.

A recent study in adults suggested a 4-fold increase in inhaled steroid dose used early during an attack resulted in fewer severe asthma exacerbations than a plan in which the dose was not increased and this would be a reasonable selfmanagement strategy in this situation (15). A similar pediatric paper suggesting a quintupled dose of ICS in children however showed no benefit (16). This may reflect a difference in causation of an attack, different responses by age or methodological differences between the studies.

Any patients with features of acute severe or life-threatening asthma should be referred to hospital immediately.

TABLE 1 | Comparison of symptoms and signs associated with levels of acute asthma severity in adults and children the BTS/SIGN (1) and GINA (4) asthma guidelines.

\**children 1–5 years;* \*\**children over 5 years.*

#### MEDICAL MANAGEMENT OF ACUTE ASTHMA IN HEALTHCARE FACILITIES

#### Oxygen

It is essential to monitor oxygen saturations when assessing an asthma attack. In adults there is evidence that hyperoxia may be detrimental plus there is also a possibility that the patient may have chronic obstruction so that the delivery of oxygen should be controlled to maintain an SpO2 level of 94–98% (17).

In children with saturations <92% in air after initial bronchodilator treatment it is advised that inpatient hospital treatment will be required as this reflects more severe asthma (18, 19). Oxygen should be administered to any child with acute asthma with SpO2 <94% via a tight fitting face mask or nasal cannula at sufficient flow rates to achieve normal saturations of 94–98%.

#### Short Acting Bronchodilators

The initial management of an acute asthma attack is usually given by the inhaled route. In adults it is recommended that in non-life threatening acute asthma, beta agonists can be given through repeated actuations of a pMDI via an appropriate large volume spacer. The recommendation is to give 4 puffs (400 mcg) as the initial dose and increase by 2 puffs every 2 min up to 10 puffs if needed. In life threatening asthma however wet nebulization of beta agonists with oxygen is preferable. Adult patients who do not respond to initial nebulization of beta agonist may be considered for repeated doses at 15–30 min intervals or continuous nebulization at 5–10 mg/h (2).

In Children, a pMDI and age-appropriate spacer device is the preferred option for delivering inhaled beta agonists with mild to moderate asthma as this is less likely to produce a tachycardia and hypoxia than using a nebulizer (20, 21). A facemask connected to the mouthpiece of a spacer is recommended in children <3 years old. In children drug dosing should be escalated as required from two puffs of salbutamol suitable for mild attacks up to 10 puffs for more severe attacks with 30–60 s between puffs. The inhalers should be activated into the spacer in in individual puffs and inhaled immediately by tidal breathing (for five breaths). In the hospital setting, with appropriate monitoring, doses can be repeated every 20 min over an hour if necessary. In children with severe or life-threatening asthma should receive nebulized bronchodilators driven by oxygen. These can be given in combination with ipratropium bromide which is recommended if there is a poor response to salbutamol alone (22). Repeated doses can be given every 20 min over a 1–2 h period. In contrast to adult recommendations continuous nebulized beta agonists are of no greater benefit than the use of frequent intermittent doses in the same hourly dosage (2, 23, 24).

After the first few hours salbutamol can be tapered down to one to two hourly and ipratropium tapered to four to six hourly or discontinued. In adults ipratropium bromide is recommended in acute severe or life-threatening asthma but is not necessary in milder asthma attacks or after stabilization.

#### Steroids

For adults and children it is important to give steroids early during an acute attack. Steroid tablets are as effective as injected steroids and should be given for at least 5 days in adults or until recovery. Evidence for the ideal duration of oral steroid treatment is still required (25). Once recovery is achieved, steroids can be stopped abruptly and do not need to be tapered unless the patient is on maintenance steroids or if they have received a prolonged course of three or more weeks (26). Inhaled steroid treatment should continue during prescription of oral steroids (2).

In children, oral prednisolone is the steroid of choice for asthma attacks and intravenous corticosteroids are only indicated for children who are vomiting or who have very severe symptoms which prevent swallowing (27). Some studies using dexamethasone have shown potential equivalence to prednisolone with the potential to reduce the number of doses and therefore potentially improving treatment adherence (28). The use of oral steroids is more controversial in preschool children (age 1–5). This may reflect the presence of common symptoms in asthma and lower respiratory tract infection in this age group. Additionally there may be more than one acute asthma phenotype, but one study considered this and found no difference in outcome between children with "viral induced wheeze" with and without atopy (29). Different prednisolone dose schedules have been recommended from 0.5–2 mg /kg (30) and others recommend an age related dose schedule (2). In children recommendations are usually for 3 days of treatment but may need to be extended from 5 to 10 days to bring about recovery. Tapering is not necessary unless the course exceeds 14 days.

There is no evidence to support the use of Inhaled steroids as an alternative to oral steroids during an asthma attack of this severity but it is good practice to continue the usual maintenance inhaled steroids during an attack (2).

#### Second Line Treatments Magnesium

There is some evidence that intravenous magnesium sulfate has bronchodilator effect during an acute asthma attack (31). In adults there is limited evidence that a single dose of iv magnesium may be some benefit in adults with a PEF <50%. This is felt to be safe and may improve lung function and reduce intubation rates in those with acute severe asthma. It may also reduce admission to hospital with asthma from ED in adults who have had little or no response to standard treatment. It should only be used following consultation with senior medical staff (2).

The use of IV magnesium has become more frequent in children with acute asthma. There is relatively little evidence compared to other intravenous therapies although there is one comparative study showing a more rapid improvement compared to IV salbutamol or aminophylline (32). It is generally safe with few side effects. It should be used if there is a poor response to first line therapies and is not recommended in mild to moderate asthma attacks.

The use of nebulized magnesium has been studied in one large UK based trial (33). Overall the benefits were small although did seem to offer some benefit when added to nebulized salbutamol and ipratropium in the first hour of hospital treatment in children presenting with a short duration of acute severe asthma symptoms presenting with an SpO2 <92% (34). At the time of writing, the role of nebulized magnesium in both adults and children is uncertain.

#### Aminophylline

In adults evidence suggests that the addition of intravenous aminophylline is unlikely to add any additional bronchodilation compared to standard care and side effects such as arrhythmias and vomiting are increased (35). However, patients with near fatal asthma with a poor response to initial therapy may gain additional benefit from IV aminophylline. It is advised that before its use consultation should take place with a senior member of medical staff as these patients are likely to be rare (2).

In children, aminophylline was previously considered the first line IV treatment following a poor response to initial management (bronchodilators and steroids) but now intravenous magnesium is recommended as first line due to reduced side effects and equal efficacy (2). There is some evidence of benefit in severe or life threatening asthma (36). The risk of side effects is high and ECG monitoring is recommended with the patient monitored in an HDU/PICU environment.

#### IV Salbutamol

There may be some benefit for the use of IV salbutamol in both adults and children who have not responded to first line treatments and IV magnesium (37).

In children an initial bolus dose (15 mcg/kg) may be given. In comparison with IV aminophylline (bolus and infusion) this has been shown to give equivalent results. Initially it was thought to cause fewer side effects compared to aminophylline but more recently nausea, tachycardia and lactic acidosis have been frequently recognized. There is very limited evidence for the use of a salbutamol infusion in children but is sometimes utilized in the PICU environment.

#### Antibiotics

In adults an infection precipitating an attack is most likely to be viral and therefore routine prescription of antibiotics is not indicated. Objective measures such as serum procalcitonin where available should be used to guide decisions on using antibiotics (2).

TABLE 2 | Summary of similarities and differences in the diagnoses, assessment and treatment of acute asthma in adults and children.

In children the role of bacterial infection is also less common than a viral trigger. Antibiotics are not recommended. Procalcitonin is not routinely used at present in children. CRP is more frequently used but less specific.

#### Critical Care

In both adults and children with acute asthma and a poor response to standard therapy it is important to involve clinicians with the appropriate skills in airway management and critical care support early. There is little good quality evidence to guide treatment at this stage and a national audit of treatment for acute asthma in adults in the UK found a wide variation in clinical practice (38).

In adults admission to critical care is recommended in those requiring ventilator support and acute severe life-threatening asthma indicated by: deteriorating PEF, persisting or worsening hypoxia, hypercapnia, arterial blood gas analysis showing fall in pH or rising hydrogen concentration, exhaustion, feeble respiration, drowsiness, confusion, altered conscious state or respiratory arrest (2).

In children admitted to hospital with status asthmaticus two small studies have reported the use of non-invasive ventilation suggesting that it is safe and feasible but there was insufficient evidence of its effectiveness. In adults there has also been suggestions that the use of NIV can be safe and effective however the evidence is limited and inconclusive. One trial of NIV in a small number of patients showed improvement in hospitalization rates, discharge from emergency departments and lung function. Other trials have shown safety and feasibility of using NIV in treating acute exacerbations of asthma but little evidence of benefit in comparison with standard care. It is recommended that NIV should only be considered in adults in a critical care or equivalent setting (2).

Invasive ventilation strategies are beyond the scope of this article.

The BTS asthma guidelines are able to recommend the following advice for therapies at this stage. In both adults and children Ketamine may be considered as a potential bronchodilator although further prospective trials are required before conclusions about effectiveness can be drawn (39, 40).

In children the anesthetic gas Sevoflurane is potentially an option for correcting high levels of PaCO2 in mechanically ventilated children however its use would be limited to areas where appropriate scavenging facilities to extract gas are available (41).

There is an increasing trend in the use of Recombinant DNase in pediatric intensive care in children with acute asthma due to airway plugging. There is little or no published evidence to support this practice. A study in non-intubated adults with severe asthma showed no improvement in FEV1 (42).

### Extracorporeal Membrane Oxygenation (ECMO)

ECMO is a form of cardiopulmonary life-support, where blood is drained from the vascular system, circulated outside the body by a mechanical pump, and then reinfused into the circulation. While outside the body, hemoglobin becomes fully saturated with oxygen and CO2 is removed. Oxygenation is determined by flow rate, and CO2 elimination can be controlled by adjusting the rate of countercurrent gas flow through the oxygenator. It is a highly specialized form of treatment and available in only a few centers in the UK. It has been shown to be useful and an option in severe asthma refractory to mechanical ventilation in both children and adults by providing adequate gas exchange and preventing lung injury. However, careful management is required to avoid complications (43).

### Discharge and Follow Up

In adults it is recommended discharge can be considered when clinical signs are compatible with home management i.e., medical therapy can continue safely at home. Patients with PEF <75% best or predicted and diurnal variability of PEF >25% are at greater risk of early relapse and readmission therefore this should be borne in mind when deciding on timing of discharge. This is also true in children (2).

In both adults and children it is important to assess and attend to correct risk factors that may have lead to a loss of control of asthma leading to admission e.g., smoking or exposure to smoke in the household in children. Education prior to discharge is important including advice on inhaler technique, a review of the personal asthma plan and, if used, PEF record keeping. Tools such as the BTS asthma discharge bundle are available to provide help with this process (44).

All patients both adult and children should have an appointment arranged with their primary care team within 48 h of hospital discharge. Secondary care review should be arranged within a few weeks.

#### CONCLUSION/SUMMARY

There are similarities and differences in the diagnoses, assessment and treatment of acute asthma in adults and children, and these are summarized in **Table 2**. The mainstay of management is to ensure early assessment of severity with appropriate use of bronchodilators with corticosteroids. There are some differences in the recommendations of how these medications

#### REFERENCES

are given and their associated doses but because the pathological processes are essentially the same the general principles of treatment are also the same. The more cautious use of oral corticosteroids in children may reflect concern over longer term side effects as well as questionable response in preschool children. The use of variable dose regimes of inhaled steroids may reflect the availability of suitable drug preparations and the difference between an individual feeling their own innate symptoms and a parent recognizing their child's symptoms.

#### AUTHOR CONTRIBUTIONS

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2019 Chavasse and Scott. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Two Sides of the Same Coin?—Treatment of Chronic Asthma in Children and Adults

Li Ping Chung1 \* and James Y. Paton2

*1 Department of Respiratory Medicine, Fiona Stanley Hospital, Perth, WA, Australia, 2 School of Medicine, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, United Kingdom*

Globally, asthma is one of the most common chronic conditions that affect individuals of all ages. When poorly controlled, it negatively impacts patient's ability to enjoy life and work. At the population level, effective use of recommended strategies in children and adults can reduce symptom burden, improve quality of life and significantly reduce the risk of exacerbation, decline of lung function and asthma-related death. Inhaled corticosteroid as the initial maintenance therapy, ideally started within 2 years of symptom onset, is highly effective in both children and adults and across various degrees of asthma severity. If asthma is not controlled, the choice of subsequent add-on therapies differs between children and adults. Evidence supporting pharmacological approach to asthma management, especially for those with more severe disease, is more robust in adults compared to children. This is, in part, due to various challenges in the diagnosis of asthma, in the recruitment into clinical trials and in the lack of objective outcomes in children, especially those in the preschool age group. Nevertheless, where evidence is emerging for younger children, it seems to mirror the observations in adults. Clinicians need to develop strategies to implement guideline-based recommendations while taking into consideration individual variations in asthma clinical phenotypes, pathophysiology and treatment responses at different ages.

Keywords: chronic asthma, pharmacotherapy, treatment, adult, children, guidelines

## INTRODUCTION

### Asthma Burden

Asthma is a chronic inflammatory disease of the airways with typical symptoms of wheezing, breathlessness and cough and variable airflow obstruction. The WHO estimates that some 235 million people currently suffer from asthma (1) and it is the commonest chronic disease of children worldwide. Asthma causes long term effects: it affects patient's quality of life, daily activities, their work and school attendance; it causes anxiety—to the patients themselves, and to their families and caregivers; it imposes a substantial economic burden on families and societies; and it causes death. Yet, with appropriate management most people with asthma can enjoy excellent symptom control and a good quality of life (1).

Control of asthma symptoms, reduction of future risk in terms of asthma attacks, and prevention of decline in lung function are recognized as the key goals of asthma management (**Figure 1**). These goals are relevant to all patients with asthma irrespective of age. Pharmacological therapies are the main tools for controlling asthma but non-pharmacological interventions such as allergen or

#### Edited by:

*Steve Turner, University of Aberdeen, United Kingdom*

#### Reviewed by:

*Kelvin D. MacDonald, Oregon Health & Science University, United States Marco H.-K. Ho, The University of Hong Kong, Hong Kong*

#### \*Correspondence:

*Li Ping Chung<EMAIL_ADDRESS>
#### Specialty section:

*This article was submitted to Pediatric Pulmonology, a section of the journal Frontiers in Pediatrics*

Received: *08 November 2018* Accepted: *18 February 2019* Published: *11 March 2019*

#### Citation:

*Chung LP and Paton JY (2019) Two Sides of the Same Coin?—Treatment of Chronic Asthma in Children and Adults. Front. Pediatr. 7:62. doi: 10.3389/fped.2019.00062*

**34**

irritant (especially tobacco smoke) avoidance, and education about the disease, inhaler device use and self-management strategies are also important.

#### Asthma Phenotypes

There is increasing recognition of different clinical and pathophysiological patterns of asthma ('phenotypes') in both children and adults.

The most striking asthma phenotype is found in young children who present with wheezing attacks associated with viral infection, particularly rhinovirus infection, often with no symptoms between attacks. For many of these children, the wheezing attacks stop in later childhood (2). In older children, a more classic asthma pattern of attacks with chronic interval symptoms usually with an atopic background emerges (3). However, these patterns overlap and are unstable, at least in early childhood, and may change from one to another over times scales as short as a year (4, 5). Lung function testing in young children is generally not possible and making a diagnosis of asthma without objective testing has been criticized (6). The implications for the choice of treatments of the different phenotypes is complex and has resulted in a wide variety of approaches often compounded by a lack of evidence (7).

In adults, the pattern of airway inflammation is more diverse and the clinical presentation is often clouded by co-existing comorbidities especially in those with severe asthma (8, 9). Currently an emerging concept, but an important focus of asthma management in adults is the identification and management of pulmonary, extrapulmonary and behavioral "treatable traits". The hope is that treatment of these modifiable elements (e.g., bronchodilator reversibility, eosinophilic airway inflammation, depression) even in the absence of a deeper understanding of the mechanisms of airway inflammation will improve patient outcomes (10). Although the concept of treatable traits has been developed in relation to adults it is also likely to be useful in children with asthma.

There are some patients, both adult and children, with "discordant" disease who suffer substantial symptom burden with little evidence of eosinophilic inflammation or those with high level of inflammation but few symptoms (11). However, the majority of patients will have asthma symptoms that parallel the degree of inflammation in which step-wise guideline recommended approach is likely to be effective.

This review summarizes evidence about differences in the approaches to asthma treatments in adults and children as currently recommended in commonly used asthma guidelines (12, 13) (**Table 1**).

## GUIDELINE RECOMMENDED APPROACH FOR CHRONIC ASTHMA

### Step 1: As Needed SABA

For patients of all ages, as needed short acting beta2 agonist (SABA) reliever therapy is highly effective for rapid relief of asthma symptoms. SABA as the sole treatment is now only recommended for those with the mild and intermittent symptoms (<2 per week and no nocturnal awakenings), no history of asthma attacks in the previous year and normal lung function.

Historically, there has been a perception that patients with intermittent symptoms are not at risk of asthma attacks, a view increasingly challenged. Evidence from adult studies showed that airways inflammation occurs at a very early stage of the disease even in patients with intermittent asthma, albeit at a lower level than in those with persistent asthma (14, 15). Furthermore, early introduction of once daily inhaled corticosteroid (ICS) in adults and children > 5years with mild asthma symptoms

TABLE 1 | Comparison of recommended treatments for chronic asthma in adults and children from widely used international guidelines (12, 13).

*ICS, inhaled corticosteroid; LABA, long acting beta2 agonist; LTRA, leukotriene receptor antagonist; SABA, short acting beta2 agonist.*

reduced the risk of severe asthma exacerbation by almost half, with better asthma control although it did not affect lung function (16, 17).

This has led widely used international guidelines (12, 13) to update their recommendation for the consideration of ICS use as Step 1 treatment in all adults, adolescents and children over 6 years with mild asthma, even those with infrequent symptoms, to reduce the risk of severe, potentially life-threatening exacerbations (18–20).

### Step 2: Regular Low Dose ICS Plus as Needed SABA

#### Adults and Children (Age >5years)

Regular low dose ICS significantly improves lung function, quality of life and reduces asthma exacerbations in both adults and children with mild persistent asthma (13, 18). O'Byrne et al showed that introduction of low dose budesonide reduced the risk of asthma exacerbation by 60% and improved asthma control days by half (19). Selected studies in adults also showed less rescue SABA use (18). It was suggested that duration of therapy of at least 4 weeks may be an important determinant of overall treatment response (18).

The greatest benefits of ICS in adults and children older than 5 years old have been achieved when ICS therapy was started within 2 years of symptom onset (21, 22); this effectively halved the overall risk of severe or life-threatening exacerbations (16, 17). After this time, higher ICS doses are required for adults and there is a negative correlation between duration of symptoms and maximal increases in lung function (22–24). Low dose ICS appears protective against potential long-term decline in lung function following severe exacerbations. Interestingly, this effect is only seen in adults and children but not adolescents (25). It is unclear if this is due to the relatively small number of adolescents studied or relates to the improvements in asthma that have been noted during adolescence (26). Early initiation of ICS also improves asthma control and diminished subsequent needs for additional maintenance therapy (24).

One important difference in children compared with adults is a persistent concern about the impact of regular ICS in children on linear growth. As an example, in the START study Pauwels et al. reported that children aged 5–15years treated with budesonide showed reduced growth especially in the first year of treatment (16). However, other studies found that children attain normal projected adult height while on prolonged inhaled budesonide (21, 22).

The evidence on linear growth in children treated with ICS has recently been updated to take account of newer inhaled steroid molecules. The regular use of ICS at low or medium daily doses was found to be associated with statistically significant growth suppression during a 1-year treatment period in children with mild to moderate persistent asthma. The mean growth reduction was 0.48 cm/year in linear growth velocity and 0.61 cm change from baseline height during a one year treatment period. ICSinduced growth suppression appears to be maximal during the first year of treatment and less pronounced in subsequent years and appears to be more strongly associated with ICS molecule than with the device or dose in the low to medium dose range (27). A second review looking at dose response effects found a small but statistically significant group difference in growth velocity between low doses and low to medium doses, favoring the use of low-dose ICS (28). Thus the evidence confirms the relative safety of ICS in relation to growth effects but supports the use of the lowest effective dose of ICS, with regular monitoring of linear growth. It is surprising how many gaps still exist in the current evidence base about ICS and growth (29).

#### Preschool Children (Age <5years)

There is also strong and consistent evidence to support the use of daily ICS for preventing exacerbations in preschool children with recurrent wheeze, especially in those with persistent asthma symptoms (30). The effect of ICS appears to be stronger in those with a diagnosis of asthma compared with recurrent wheezing and is independent of age (pre-schoolers vs. infants), atopic condition, type of ICS, and mode of delivery (spacer vs. nebulizer) (31).

The evidence about growth suppression in pre-school children is limited. Nevertheless, because of concerns about side effects, an important question is whether ICS therapy can be targeted to those children most likely to respond? One recent study in children requiring step 2 treatment showed that while individual treatment responses were phenotypically diverse, children with aeroallergen sensitization and increased blood eosinophil counts responded best to a daily ICS as opposed to a leukotriene receptor antagonist (LTRA) or as needed-ICS. Daily ICS was associated with more asthma control days and fewer exacerbation (32). However, a very recent real-world study of large matched cohort analysis of anonymized UK medical record data found no evidence that stepping up therapy by adding ICS or monteleukast, compared with as-needed use of SABA, reduced wheezing/asthma attacks in a diverse population of preschool children with at least two documented prior wheezing episodes (33). In the absence of better tools to help target treatments, and in light of improved outcomes over time in preschool children a "wait-and-see approach" may be a clinically prudent approach for many with infrequent, intermittent attacks.

#### Alternative Options

#### Low Dose Combination ICS/Long Acting Beta2 Agonist (LABA)

For steroid-naïve adults and adolescents with mild persistent asthma, ICS/LABA works faster in achieving GINA-defined good asthma control compared to ICS alone. However, there is little difference in exacerbation rate between the two therapies. In practice, the additional cost for ICS/LABA compared to low dose ICS may be an important consideration for the individual patient (34). Data as to whether there would be similar benefits in children is not available.

#### Intermittent ICS Regimes

Regular use of ICS raises concerns from patients and clinicians about adherence and steroid side effects. Poor adherence to ICS potentially results in patients relying on SABAs to control symptoms, possibly resulting in overuse.

Recently, it was shown that adults and adolescents with mild asthma using as-needed combination ICS and fast acting LABA had better asthma symptom control measured by an electronic diary compared to as-needed SABA (35). However, the magnitude of effect was inferior to regular low dose ICS therapy. A second trial in a similar cohort reported no difference in exacerbation rate when comparing ICS/formoterol as needed vs. regular ICS (36).

There isless evidence about the use of as needed ICS treatment in children. One study in children from 5 years upwards with mild well-controlled asthma stepping down from daily ICS found ICS and SABAs as needed more effective at reducing attacks than SABA use alone (37). Liner growth was 1.1 cm a year less when ICS was used regularly but not when used on an as needed basis.

In children under 5 years, the most common asthma phenotype is intermittent viral triggered wheezing attacks with no interval symptoms. In this group, intermittent ICS, usually as high-dose ICS at the first sign of an URTI for 7 to 10 days led to a 35% reduction in severe attacks (30). Intermittent ICS were associated with greater linear growth of 0.41 cm per year (i.e., less growth suppression) compared with daily treatment (38).

#### Oral Leukotriene Receptor Antagonist (LTRA) in Preschool Children

Because of concerns about ICS side effects and difficulties using inhaled therapies in young children, oral montelukast has been widely prescribed as an alternative to regular ICS. While early studies showed it to be effective, the most recent review found no evidence of benefit from the use of montelukast, continuously or intermittently on the number of wheezing episodes, unscheduled medical attendance, or oral corticosteroid use in preschool children with recurrent wheeze (39). There is also little evidence of benefit for other secondary outcomes (7).

### Step 3: One or two Maintenance Treatments Plus as Needed Reliever Therapy

For adults and adolescents with suboptimal symptom control or more than 1 exacerbation in the previous year despite treatment with low dose ICS, guidelines recommend low dose ICS/LABA as maintenance therapy plus SABA or ICS/formoterol as single inhaler therapy (12, 13). In children, at present, moderate dose ICS plus as needed SABA is the preferred treatment for children.

#### ICS/LABA Maintenance Plus SABA as Required

Historically, there were concerns that LABA may mask airway inflammation leading to potential adverse events including asthma exacerbations. To the contrary, the addition of LABA to ICS significantly increases the odds of achieving good overall asthma control as defined by guidelines (34). Combination low dose ICS/LABA therapy was highly effective at reducing the risk of exacerbations needing oral corticosteroid (19, 40, 41) and hospitalizations (40, 42, 43) in symptomatic adults and adolescents with mild to moderate asthma compared to ICS alone. The addition of LABA also leads to improvement in lung function (especially in those with lower baseline FEV1), proportion of symptom-free days (19, 44) and a slight reduction in rescue SABA use compared to same or higher dose of ICS (41, 43).

The advantages of adding a LABA have been less clear in children. In children with persistent asthma, the addition of LABA to ICS was not associated with a significant reduction in the rate of exacerbations requiring systemic steroids, but it was superior for improving lung function compared with the same or higher doses of ICS. There were no differences in adverse effects, with the exception of significantly lower linear growth over a year in the children treated with a higher ICS dose, with a mean difference of 1.21cm/yr. A trend toward an increased risk of hospital admission with LABA, irrespective of the dose of ICS, was noted as a matter for concern (45).

#### ICS/Formoterol as Single Maintenance and Reliever Therapy

Combination of ICS with formoterol as fast acting bronchodilator allows patients to use their regular maintenance inhaler also for rapid relief of symptoms. Single inhaler therapy is more effective at reducing mild to moderate exacerbations while providing similar levels of asthma control compared with medium dose ICS monotherapy or fixed dose of ICS/LABA and as required SABA (46–50). It has been suggested that using single inhaler for both maintenance and reliever therapy may improve adherence but definitive data is lacking.

The role of single maintenance and reliever therapy in children age 12 years and below is unclear at present and requires further study. It is not currently licensed for use in this way in this age group.

#### Alternative Treatment Options