Abstract
Most pediatric asthma is easily treated with low-dose inhaled corticosteroids, occasionally combined with a long-acting bronchodilator, provided the medications are administered regularly and correctly. If the child does not respond to treatment, rather than escalating treatment uncritically, a detailed, protocolized assessment is mandatory. This should include a review of the diagnosis and assessment of the presence or otherwise of any extrapulmonary comorbidities, such as obesity, exercise-induced laryngeal obstruction and lifestyle and social factors, such as adherence, perhaps the most important cause of “treatment resistant asthma,” and allergen and tobacco exposure; this enables successful management of 90% of referrals with apparent severe asthma. For the rest, bronchoscopic assessment of airway pathology is advisable, combined with a parenteral steroid trial, to deconstruct airway pathology by determining the presence and nature of any inflammation and whether there is fixed airflow obstruction. If inflammation is present, it is eosinophilic not neutrophilic but signature T-helper cell cytokines are difficult to detect, suggesting alternative pathways are important. There is no agreed upon pediatric definition of steroid responsiveness, and we advocate a multidomain approach. Other than for omalizumab, treatments for steroid-resistant asthma have no evidence base in children. The child with recurrent asthma attacks is particularly difficult to manage and is at high risk of further attacks and death from asthma. In summary, therapy-resistant asthma is rare but a really difficult problem when present. Most apparent therapy-resistant asthma can be successfully treated by optimizing basic management, especially ensuring adherence to standard therapy.
Keywords
asthma, exhaled nitric oxide, atopy, steroid responsiveness, fungal sensitization, bronchoscopy
Most children with asthma can be easily treated with low-dose inhaled corticosteroids (ICS) if these are regularly and correctly administered. Hence, refractory asthma probably accounts for less than 5% of all pediatric asthma. It may be becoming less common over time, possibly because of more effective modern treatments and likely also improved management. However, this group accounts for an enormous amount of morbidity and health care costs, and even mortality, and so although rare, it is important. Here, our practice approach to the child with apparent refractory asthma is described. Severe preschool wheeze is not discussed here.
Overarching Principles
The cardinal sin in asthma management is to continue to escalate asthma therapy in a child who is not responding, without asking, “Why is simple prescribed treatment not working?” We know that most children with asthma will respond very well to low-dose ICS, sometimes also requiring a second controller, such as long-acting beta-2 agonists (LABA), or a leukotriene receptor antagonist (LTRA). So, faced with the child with apparently refractory asthma, the pediatrician should not reach again for the prescription pad, but go through a rigorous protocol to determine what it is about this child and his or her asthma that means the anticipated response is not happening. The overall aim of the protocols discussed below is to determine whether the individual child is truly a candidate for “beyond guidelines” therapy or can, in fact, be managed with standard approaches.
Definitions
The conventional developed world definition of severe asthma is that the patient requires treatment with guideline-suggested medications for GINA (Global Initiative for Asthma) steps 4–5 asthma (high-dose ICS, conventionally 800 µg/day beclomethasone equivalent for 5- to12-year-olds; >1600 µg for children aged >12 years; and LABA or leukotriene modifier/theophylline) for the previous year; or systemic corticosteroids (CS) for ≥50% of the previous year to prevent it from becoming “uncontrolled”; or which remains “uncontrolled” despite this therapy; or controlled asthma that worsens on tapering of these high doses of ICS or systemic CS (or additional biologics). Uncontrolled asthma is currently defined as one or more or of:
- 1.
Poor symptom control: Asthma Control Questionnaire (ACQ) consistently >1.5, Asthma Control Test (ACT) <20 (or “not well controlled” by NAEPP [National Asthma Education and Prevention Program]/GINA guidelines).
- 2.
Frequent severe exacerbations: two or more bursts of systemic CS (>3 days each) in the previous year.
- 3.
Serious exacerbations: at least one hospitalization, intensive care unit (ICU) stay or mechanical ventilation in the previous year. However, objective evidence of the severity of the attack should be obtained. In theory, the treatment of an asthma attack is based on objective evidence of current severe airflow obstruction. In practice, especially in emergency situations dealt with by the inexperienced, the previous history may unduly influence practice. It is essential to determine what (if any) objective assessments were carried out before instituting treatment, and whether in fact the child was overtreated because of a “severe asthma” label. One child under our care was actually started on intravenous albuterol despite being fully saturated on room air! In fact she had dysfunctional breathing and vocal cord dysfunction.
- 4.
Airflow limitation: after withholding bronchodilators for 4 hours (short acting) or 12 hours (long acting) first second forced expired volume (FEV 1 ) <80% predicted (in the face of reduced FEV 1 /forced vital capacity (FVC) defined as less than the lower limit of normal); however, it should be noted that normal spirometry does not exclude severe asthma in children ; unlike in adults, spirometry is poorly discriminatory between different levels of asthma severity and is not a good end-point in pediatric asthma trials.
- 5.
Fixed airflow limitation: FEV 1 <80% predicted (in the face of reduced FEV 1 /FVC defined as less than the lower limit of normal) despite a trial of systemic steroids and acute administration of short-acting beta-2 agonists (SABA).
- 6.
Disconnect symptoms: perhaps strictly the child presenting with a multitude of symptoms with no objective evidence of uncontrolled disease may belong in a separate disease category, and certainly is not placed conventionally in severe asthma guidelines, but the means of addressing this scenario are so very similar that this is pragmatically justified. The reverse scenario, the underreporting of symptoms, is also considered below.
Inherent in this definition is that basic management, including adherence, has been optimized, a process described in more detail below.
It can be argued that the level of ICS dose has been set too high. The Best Add-on Therapy Giving Effective Responses (BADGER) study shows that for most children, there is no benefit from increasing ICS above 100 µg bid (200 µg beclomethasone); a child not responding to this level of ICS plus one additional controller medication definitely merits a careful review.
Furthermore, the WHO has defined three types of severe asthma :
- 1.
Untreated: due to undiagnosed asthma or the unavailability of therapy (this being the most common worldwide)
- 2.
Difficult-to-treat: due to adherence issues, inappropriate or incorrect use of medicines, environmental triggers or comorbidity
- 3.
Treatment-resistant: this includes asthma for which control is not achieved despite the highest level of recommended treatment, or asthma that is controlled only with the highest level of recommended treatment.
Clearly, each of these categories merits a different response. The lack of availability of therapy needs to be tackled at a public health level, ensuring that each and every child with asthma has access to the basics; namely, inhaled beclomethasone and albuterol, prednisolone, and a plastic bottle spacer. Biologicals have no place in this setting. For those with treatment-resistant severe asthma, on the other hand, deploying novel therapeutics may be transforming.
An overlapping approach, which is also a useful conceptual framework, is to define risk by considering domains of asthma severity. Conventionally, these are:
- 1.
Level of prescribed treatment
- 2.
Level of baseline asthma control over the previous month
- 3.
Level of underlying airway eosinophilia (in adults, possibly children, also)
- 4.
Burden and nature of exacerbations over the last 6–12 months
- 5.
Risk of future complications, including the failure of normal airway growth (for which there is increasing evidence); the risk of either or both of future loss of control and exacerbations; the risk of medication side effects.
It could certainly be argued that the conventional definition fails to focus on domains that the patients and families find important, such as quality of life, the impact on school attendance, and the time away from work for the carers. Perhaps what we mean by “control” needs a broader perspective. Furthermore, the recent UK review of asthma deaths suggests that we need to refocus our definitions: around 60% of those who died from asthma were classified as “mild to moderate.” Since it is difficult to imagine a more severe outcome than dying, it is obvious that our definitions need to be reconsidered. These patients could be placed in the difficult to treat category, but patient factors ( Box 46.1 ) need to be added to the conventional definitions of risk.
- ▪
A single severe exacerbation
- ▪
Recent discharge from hospital after an acute asthma attack
- ▪
Use of hospital urgent care facilities in the previous year
- ▪
Utilization of more than six canisters of SABA/year
- ▪
Failure to attend follow-up appointments
SABA, Short-acting beta-2 agonists.
This underscores that difficult-to-treat asthma can be just as serious as treatment-resistant severe asthma, and merits a response that is just as focused if we are to impact deaths from asthma.
A New Approach: Airways Disease Deconstructed and Placed in Context
A new framework has been suggested for the assessment of airway disease. The problem is multicomponent, and is best considered under three headings: airway disease itself, extrapulmonary disease (comorbidities), and environmental/lifestyle factors. The initial assessment of problematic severe asthma focuses on the last two, because generally, the first is easily managed (above), and therefore the focus is on potential confounding factors. If the problem remains, the nature of the airway disease is ascertained invasively. The protocol used is discussed in more detail below.
Initial Evaluation: Problematic Severe Asthma
Problematic severe asthma is the umbrella term when a referral of a child meeting one or more of the above criteria is received in a specialist respiratory center ( Box 46.2 ). A full history and physical examination is the essential first step. The nature of the symptoms should be determined. The word “wheeze” is used very imprecisely, often being used to describe many nonspecific respiratory sounds, and even stridor ; until a physician has heard wheeze with a stethoscope, it should be considered as “possible.” Most children who have a cough as their sole symptom (particularly an isolated dry cough) do not have a disease.
- 1.
Not asthma at all: the diagnosis is wrong.
- 2.
Asthma plus: there are associated comorbidities that need to be addressed.
- 3.
Difficult asthma: accounts for about 90% of those in whom the first two categories have been excluded. This comprises children who need to get the basic steps of asthma management correct; the percentage of difficult asthma compared with severe, therapy-resistant asthma has risen over the years as we have become more expert in assessing these children, in particular adherence issues.
- 4.
Severe, therapy-resistant asthma: these children appear to have ongoing problems with asthma despite the optimization of all basic steps of asthma management; such children are candidates for “beyond guidelines” therapy, and account for around 10% of referrals.
Physiological tests are mandatory at this point. It should be noted that spirometry is often normal in children with severe asthma, which is different from adults. Testing for airway hyperresponsiveness is not routine, and may be risky in these severe asthma patients. In any event, the relationship between PC 20 to methacholine and asthma severity is poor. The most common use of this test is in a child with normal spirometry who is reporting a multiplicity of symptoms; a normal methacholine challenge excludes asthma as a cause of these symptoms. Airflow obstruction, which changes over time or with treatment, must be documented and consideration given to determining whether the child is atopic and has airway eosinophilia. Nonatopic asthma does occur in childhood, but is uncommon, and if skin prick tests or specific immunoglobulin E (IgE) are negative, the diagnosis should be reevaluated. Blood eosinophilia may give a guide to airway eosinophilia, but an elevation may be due to other atopic disease, for example eczema. Fractional exhaled nitric oxide (FeNO) measured at a flow rate of 50 mL/s (FeNO 50 ) has been used as a diagnostic tool for asthma, but it should be noted that a low FeNO 50 does not exclude asthma, and elevation is seen in atopic children with no respiratory disease. An induced sputum cytospin will give more direct evidence of airway eosinophilia, but is not available in most centers. Although evidence of airway inflammation is not a mandatory diagnostic test for asthma, and a child already on treatment with ICS may be inflammation free, the absence of any evidence of airway inflammation in a child supposedly symptomatic with asthma should prompt a diagnostic review. Finally, the diagnostic process should not end at this stage; the possibility of a wrong diagnosis should be at the forefront throughout, and further testing should be considered in the presence of a surprising finding, such as airway neutrophilia (see later).
It may be thought inappropriate to be discussing basic asthma diagnosis in a chapter on severe asthma, but wrong diagnosis, often due to failure to perform objective tests, is an all-too-common reason why treatment fails.
The suggested flow chart for evaluating children with asthma who are not responsive to treatment is shown in Fig. 46.1 . The low level of ICS used to trigger evaluation may raise the specter of tertiary services being drowned in referrals, but this is not necessarily the case. Furthermore, this framework can be modified and adapted to all health care settings. Given (1) the plateau of the ICS dose response curve being low ; and (2) the generally poor response to LTRAs, time should not be wasted by increasing ICS doses ever higher, and adding in more and more different controllers. Rather, one should ask, “why is this child not responding to low-dose ICS and one controller?” Simple checks can easily be done in primary care. A diagnostic review is mandatory: are the symptoms in fact due to no more than repeated viral upper respiratory infections? Is the child using the medication delivery device correctly? Are there adverse environmental factors, such as tobacco smoke exposure (passive or active)? Nonadherence can easily be checked by examining prescription records. In one study, only one in six children was having enough prescriptions filled to take their prophylactic medication. Even patients referred to us with apparently severe asthma collect less than half of their prescriptions. Of course, picking up a prescription does not mean the medication has actually reached the lower airways (below)!
Referral may also be indicated even if the primary pediatrician is confident that the child has difficult asthma, but repeated interventions have failed to reduce the risk factors for asthma death. The possibility of diagnostic error still remains, and the use of a multifaceted intervention may be able to reduce risk.
Problematic Severe Asthma: Not Asthma at All
The differential diagnosis of problematic severe asthma is summarized in Table 46.1 . There is a wide differential diagnosis of asthma, the nature of which varies across the world. Important red flags, which should prompt investigation, include neonatal onset of symptoms, chronic productive cough for more than 8 weeks continuously (not recurrent acute cough with complete resolution between episodes), and evidence of systemic disease. The nonatopic child with apparently severe asthma should always be carefully reassessed, and alternative diagnoses sought. We do not routinely perform a chest high-resolution computed tomography (HRCT) in all children referred with problematic severe asthma, reserving this investigation for those with atypical features; there is no evidence in children to set against this selective approach. Specifically, HRCT cannot differentiate obliterative bronchiolitis from asthma, and severe asthma; HRCT phenotypes such as those known in adults have not been described in children. In general, testing should be focused to eliminate specific conditions, rather than taking a scattergun approach.
| Class of Diagnosis | Examples |
|---|---|
| Defects of host defense | Cystic fibrosis, primary ciliary dyskinesia, persistent bacterial bronchitis The effects of high-dose inhaled steroids should be considered |
| Systemic immunodeficiency | Any, including B-cell and T-cell dysfunction |
| Intraluminal bronchial obstruction | Foreign body, carcinoid, other tumor |
| Intramural bronchial obstruction | Bronchomalacia, complete cartilage rings, intramural tumor In low- and middle-income countries, bronchiectasis due to severe infection in an otherwise healthy child is particularly important |
| Extraluminal bronchial obstruction | Vascular ring, pulmonary artery sling, congenital lung cyst, enlarged lymph nodes due to tumor or tuberculosis, other mediastinal masses In low- and middle-income countries, tuberculosis is a particularly important cause |
| Direct aspiration | Bulbar or pseudobulbar palsy; laryngeal cleft; laryngeal neuropathy or myopathy |
| Aspiration by direct contamination | H-type fistula, which may not present until adult life |
| Aspiration secondary to reflux | Any cause of gastro-esophageal reflux, including hiatus hernia and esophageal dysmotility (e.g., achalasia or after neonatal repair of tracheoesophageal fistula) |
| Complications of prematurity | Bronchomalacia, stricture secondary to intubation, vocal cord palsy secondary to surgery for patent arterial duct |
| Congenital heart disease | Bronchial compression from enlarged cardiac chambers or great vessels; pulmonary edema |
| Interstitial lung disease | Any not presenting with neonatal respiratory failure |
| Dysfunctional breathing | Vocal cord dysfunction, hyperventilation syndromes (usually a comorbidity in a known asthmatic, but may present in isolation) |
Airway Disease in Context: Asthma Plus (Extrapulmonary Comorbidities)
A so-called comorbidity may (1) worsen asthma; (2) be a coincidental fellow traveler; (3) obscure the assessment of asthma; or (4) be an example of Berkson fallacy. This last is a special example of selection bias. This occurs when, for example, the combination of exposure and disease under study increases the risk of hospital admission, thus leading to a higher exposure rate among the hospital cases than the hospital controls; and is a frequent cause of manuscripts being rejected! The clinical significance of the first three categories is obviously different: (1) and (3) are important as “treatable traits,” whereas (2) is not. Furthermore, it may be easy to identify a treatable trait, such as obesity, but in practice, treatment may be difficult. The ethics of escalating treatment with expensive and potentially hazardous drugs under these circumstances are debatable.
Obesity
The relationships between asthma and obesity are difficult to assess, and too many studies merely report associations that are difficult to disentangle. Obesity may cause breathlessness and “wheeze” especially on exercise without evidence of asthma, leading to inappropriate treatment. Obesity may be associated with a pauci-inflammatory form of asthma, at least in adults, although it is sometimes unclear whether this is true asthma ; asthma with raised sputum interleukin (IL)-5 and airway wall eosinophilia ; or steroid resistance. Obesity is a proinflammatory state, as is obstructive sleep apnea (see later). Asthma (via reduced exercise performance) and its treatment (prednisolone bursts or long-term therapy) may cause or contribute to obesity. Hence, particular care is necessary before escalating therapy for “asthma” in the obese child with respiratory symptoms; an exercise-induced asthma test may be enlightening. A normal methacholine challenge also may be useful to exclude asthma as a cause of symptoms. In asthmatic adults, bariatric surgery improved distal airway function (impulse oscillometry, systemic inflammation [serum high sensitivity C-reactive protein, adiponectin, and leptin] and airway inflammation [decrease in mast cell numbers]). In summary, obesity hits all three mechanisms of comorbidity: it may worsen asthma, obscure the assessment of asthma, and be a fellow traveler. Weight reduction is always beneficial in the obese child, but is often difficult to achieve, and its contribution to the clinical picture must be assessed on an individual basis.
Gastroesophageal Reflux
The relationship between respiratory disease and gastroesophageal reflux is also complex. Reflux can cause symptoms either by direct contamination of the lower airway, or indirectly by an esophago-bronchial reflex ; respiratory disease may lead to abnormal pleural pressure swings or altered configuration of the diaphragm—the latter reducing the efficiency of the lower esophageal sphincter; and reflux may be present but noncontributory. However, irrespective of any symptoms suggestive of reflux, therapy with, for example, a proton pump inhibitor does not improve severe asthma, which is certainly our experience. This does not exclude the possibility that nonacid reflux may be contributory, although there is also no positive evidence for this. So, reflux is a potentially treatable trait, and the symptoms of reflux may mimic or coexist with asthma, and thus complicate the assessment of asthma.
Food Allergy
Atopy is almost inevitable in severe pediatric asthma, and indeed “non-atopic asthma” merits the most careful diagnostic review. However, food allergy is reported more commonly than expected in severe asthma. Whether food allergy is causative of the problem or a marker is unclear; certainly anaphylaxis enters the differential diagnosis of acute, severe asthma, and should always be considered because it is treatable. Exercise-induced anaphylaxis must be differentiated from other causes of breathlessness on exercise (see later) by a careful history. Food allergy should always be documented with a double-blind challenge unless there is overwhelming evidence for the diagnosis if exclusion diets are proposed; however, blind dietary exclusions are frequently tried and inevitably useless in our experience.
Rhinosinusitis
Upper airway disease worsens the quality of life, and should be treated on its own merits in any context. There is increasing evidence that treating rhinosinusitis may be beneficial at least in mild-to-moderate asthma. The mechanisms of any benefit remain conjectural. Upper airway symptoms may complicate the assessment of asthma; for example, causing night waking, which may be mistaken for uncontrolled asthma. In our series, significant rhinosinusitis is unusual in severe asthma, but in the U-BIOPRED ( U nbiased BIO markers for the PRED iction of respiratory disease outcomes) cohort, two-thirds had a diagnosis of allergic rhinitis. An assessment of the respiratory tract is incomplete without consideration of the nose.
Sleep Disordered Breathing
There is an increasing amount of literature on asthma and obstructive sleep apnea (OSA). Although the literature reports associations in at least mild-to-moderate asthma, in our patients, OSA is very rare in severe asthma, except in the presence of concomitant obesity. We do not routinely perform polysomnography on children with severe asthma who are not obese. OSA has been reported to cause sputum neutrophilia rather than eosinophilia in one study ; this inflammatory pattern rarely, if ever, occurs in true severe, therapy-resistant asthma, and if seen, it should prompt a diagnostic reevaluation. As with rhinosinusitis, disturbed sleep due to OSA may be misdiagnosed as uncontrolled asthma.
Syndromes of Vocal Cord Dysfunction and Other Functional Breathing Issues
Dysfunctional breathing is common in some, but not all, asthma cohorts. The symptoms are easily confused with uncontrolled asthma, leading to inappropriate treatment escalation. There is much less work in children than in adults. Of the children investigated in our protocol, 15% had evidence of dysfunctional breathing, including hyperventilation and vocal cord dysfunction. Clues include the absence of symptoms at night, and often stridor rather than expiratory noises. Spirometry is frequently not reproducible, and there may be attenuation of the inspiratory curve during attacks.
Breathlessness on exercise may be challenging to evaluate, with a wide differential diagnosis ( Box 46.3 ). Exercise induced laryngeal dysfunction (EILO) may be particularly challenging to diagnose. There are important points on the history; exercise-induced bronchoconstriction is common in asthma, and is characterized by symptoms usually more than 5 minutes after exercise, a feeling of difficulty breathing out, and a good response to pretreatment with SABA. By contrast, EILO (which often complicates asthma) is characterized by symptoms during exercise in which breathing in, not out, is difficult, and is accompanied by an inspiratory noise, which are not helped by asthma medications. A video during an attack of exercise-induced breathlessness may be very informative; in older children, direct laryngoscopy during an exercise test enables direct demonstration of the problem.
- ▪
Exercise-induced bronchoconstriction
- ▪
VCDEILO
- ▪
Deconditioning (which may have resulted from asthma)
- ▪
Obesity (which may also be the consequence of asthma and its treatment)
- ▪
Exercise-induced anaphylaxis (a detailed history of food intake prior to exercise is essential)
- ▪
Pulmonary hypertension (consider especially in children who “faint” during exercise)
EILO, Exercise-induced laryngeal obstruction; VCD, vocal cord dysfunction.
A large community-based questionnaire study in 3838 adolescents reported a prevalence of exercise-induced bronchoconstriction of 19.2%, with 5.7% reporting EILO. A sub-sample ( n = 99 with exercise dyspnea; n = 47 without) underwent standard treadmill exercise-induced asthma and EILO (direct laryngoscopy) tests. A total of 39.8% had exercise-induced bronchoconstriction, 6% EILO, and 4.8% had both on objective testing. Thus, nearly 50% had neither condition, but many were being prescribed treatment for asthma. The cause of breathlessness in this group could not be determined, but they were not the obese. This important manuscript underscores the importance of objective assessment of breathlessness on exercise.
If dysfunctional breathing is suspected, an experienced respiratory physiotherapist should be asked to assess the breathing pattern. Treatment with breathing exercises may be helpful, although currently there is no randomized, controlled trial evidence of benefit. The services of a sports psychologist may also be useful.
EILO also may be related to laryngomalacia in the newborn period. A total of 20/23 (87%) of infants hospitalized for laryngomalacia (half with an unconfirmed clinical diagnosis) were followed up at a mean age of 11 years and compared to a group of matched controls. A respiratory symptom questionnaire, and spirometry and laryngoscopy at rest and during exercise were performed, and the exercise laryngoscopy findings scored blind. EILO was found on exercise in 14/20 (compared with 2/20 controls) and at rest in 9 (none in controls). Thus a neonatal history is an important part of the evaluation of suspected EILO, and laryngomalacia in infancy may be a less benign condition than previously thought.
A further problem is that the perception of dyspnea has been little studied in severe pediatric asthma, but in adults, severe asthmatics do not become as dyspneic as mild during bronchoconstriction. The possibility of poor symptom perception as a cause of an apparent sudden catastrophic deterioration should be borne in mind.
Airway Disease in Context: Environmental/Lifestyle (Difficult Asthma)
When, as far as possible, a correct diagnosis has been ensured, and comorbidities dealt with, a detailed nurse-led assessment is performed ( Table 46.2 ). We evaluate allergic sensitization by both skin prick tests (SPTs) and sIgE tests, because there is imperfect concordance (76%–83%) between them. Because it is so labor intensive, we are increasingly using electronic monitoring to screen out the nonadherent before going on to a detailed work-up, which is led by the specialist asthma nurse and often involves the clinical psychologist and respiratory physiotherapist. This includes both a hospital outpatient visit and a community assessment, which includes a home visit and at least a telephone call to the school by the nurse specialist.
| Issue to Be Addressed | Tests Performed |
|---|---|
| Symptom pattern |
|
| Psychosocial factors |
|
| Lung function |
|
|
|
| Airway inflammation |
|
| Tobacco exposure |
|
| Medication adherence |
|
| Home visit |
|
| School visit or contact by telephone |
|
The nurse-led home visit is a pivotal key part of the work-up of problematic, severe asthma ; doctors sitting in the clinic know little or nothing of what is really happening at home. Five areas are explored: adherence, tobacco smoke, allergens, psychosocial issues, and asthma education. If the patient has been referred from a distant center, the home visit may be performed by a local specialist nurse after discussion with our own team. This approach may not be feasible everywhere, but in our hands, it allows the identification of significant and potentially reversible factors in more than half of those referred with problematic severe asthma. It is absolutely clear that relying purely on a hospital-based assessment by a pediatrician will lead to many mistakes.
Adherence
Physician estimates of adherence are notoriously inaccurate, adherence is often poor, and parents overestimate how much medication is being administered. In our hands, questionnaires that rely on self-report, such as medication adherence rating scale (MARS) are not useful. There are multiple reasons for poor adherence. The Practicalities and Perceptions Approach (PAPA) helpfully divides these into intentional (e.g., doubts about need for medications, their efficacy, and side effects) and unintentional (e.g., regime impractical because too complex) reasons; clearly different strategies are needed to deal with these. The biggest adherence studies are in children in the community and adult severe asthmatics, rather than severely asthmatic children. Medication issues are the commonest cause of failure of response to treatment in our severe asthma clinic.
Prescription Records
We found that less than half the patients had picked up more than 80% of the required prescriptions, and nearly one-third had picked up less than 50% (24), similar to other work. Although those who have not collected prescriptions by definition cannot be using them, electronic monitoring (see later) has shown no relationship in prescription uptake and medication use even in those who do collect prescriptions. We also determine the number of refills forSABA, which have been represcribed; collecting ≥6/year is associated with a poor outcome.
The Home Visit
Medications were commonly found to be past the expiration date, and 25% could not produce a complete set of in-date medications during the visit. Other issues identified were total inaccessibility of any medications, and medications unopened in their original wrapping, both suggesting nonadherence.
Parental Supervision
In one study, even young children (20% of 7-year-olds, 50% of 11-year-olds) were left to take asthma medications unsupervised. Often parents think they are supervising treatment, but in fact are actually not directly witnessing the therapy being taken by the child; they are merely calling reminders when the child is upstairs. This situation requires sensitive exploration. When parental supervision is not working, we have used directly observed therapy (DOT) at school, on the basis that 5 days’ treatment is better than none. However, this founders if the child does not attend school. Even if the child goes to school, school staff often fail to appreciate that DOT means closely watching the child take the medication with their full attention, not carrying on with other tasks while the child “takes” the medication standing behind their back.
Use of Inhaler Devices
These are often wrongly used. Regular teaching sessions may lead to improvements, but do not guarantee good technique in the long term. However, all the children in our series had had repeated instruction in specialized centers, and yet still had a poor technique. A common adolescent issue is using pressurized metered-dose inhalers without spacers, because spacers are thought to be babyish; however, without a spacer, drug deposition in the lower airway will be minimal.
Electronic Monitoring: Towards a Definitive Test
We increasingly use electronic monitoring inhalers to assess adherence. We always tell the families that they are being monitored in this way. Our current technology records the time and number of actuations, but not whether the child actually inhaled; this last is a weakness, which means that adherence may still be overestimated. The first lesson we have learned is that all the above methods are inadequate to determine adherence; they can, of course, determine a definitely nonadherent group. Electronic monitoring allows us to divide children who are apparently not responding to treatment into one of three groups requiring different management strategies:
- 1.
The child starts with poorly controlled asthma, often with a reduced FEV 1 and FeNO 50 ), and is adherent during monitoring. During this time, and despite no change in treatment, asthma control improves, FEV 1 rises, and FeNO 50 falls ( Fig. 46.2 ). This group was clearly previously nonadherent, and when they took the medication they responded well. The treatment is left unchanged, and the findings and ways to maintain adherence are discussed with the child and family.
Fig. 46.2
Electronic monitoring. The adherence is good, and despite no change in treatment, first second forced expired volume (FEV 1 ) has risen, and fractional exhaled nitric oxide (FeNO) has fallen, both becoming normal. The child was clearly nonadherent prior to monitoring.
(Courtesy Dr A Jochmann.)
- 2.
The child remains poorly controlled, and does not take the medication during monitoring. There is no point in escalating treatment, and the reasons for nonadherence are explored.
- 3.
The child adheres to treatment well, but the condition remains poorly controlled. The possible explanations include activation of the inhaler without inhalation; environmental factors (below) driving asthmatic inflammation to override the effects of treatment; and true steroid resistance. These different factors are teased out on an individual basis.
On the basis of our experience, we believe that access to electronic monitoring is essential for the proper management of many children presenting with problematic severe asthma.
Environmental Factors
Allergen Exposure
Denial of the importance of allergen exposure is common. At a level insufficient to cause acute deterioration, allergen exposure leads to increased airway inflammation, bronchial responsiveness, and steroid resistance via IL-2 and IL-4 dependent mechanisms in adults. Allergen exposure in the home, combined with evidence of sensitization, synergizes with viral infection to cause asthma attacks. The relationships between allergen exposure, allergen sensitization, and symptoms, are complex, and may vary from antigen to antigen. Indeed, an allergen may lead to symptoms even without evidence of specific IgE-mediated sensitization. Nonetheless, in a child with significant symptoms of asthma, and in particular with severe asthma attacks, it seems reasonable to try to reduce environmental allergen exposure, since neither sensitization nor viral infection can be modulated.
Home Exposure.
The aeroallergens likely most susceptible to intervention are pets, cockroaches, molds, and house dust mites (HDM)—with the latter being a controversial area. Ideally, we would use environmental dust sampling to determine exposures and any response to avoidance measures. Exposure is common in asthmatics of all severites. Pet and cockroach sensitization may be a marker for high morbidity ; although whether the latter can be separated from the effects of low socioeconomic status is arguable. Passive smoking may increase the likelihood of pet sensitization. The use of synthetic bedding may be associated with severe wheeze. In our study, 17 of 30 children who owned furry pets were sensitized to that pet on SPT, and only two had any allergen avoidance precautions in place. A total of 31 children were clinically thought to have significant HDM exposure; 5 were using comprehensive allergen avoidance measures, 15 partial, and 11 none. Reduction of mold exposure may be particularly important if severe asthma with fungal sensitization (SAFS) is suspected. This is discussed in more detail below.
School Exposure.
Allergen exposure in school may also be important, but difficult to change. Exposure to cat allergen on the clothes of classmates at school is sufficient to cause deterioration of asthma with a pattern similar to occupational exposure; namely, worsening during the week and improving at weekends, assuming there is no cat in the home.
Passive and Active Smoking.
Active smoking by adult asthmatics causes steroid resistance, and passive smoke exposure likely has the same effect. This is common in asthmatic children, being 25% in our series ; the prevalence of active smoking as well as other risk-taking behaviors is also likely to be high in children and young people. The mechanisms of tobacco smoke-induced steroid resistance have been researched mainly in adults ; the phenotype is neutrophilic. In a pediatric study, we found that parental smoking reduced histone deacetylase protein expression and activity, and reduced the in vitro inhibitory effects of dexamethasone on tumor necrosis factor-α-induced IL-8 release from alveolar macrophages in severe, therapy-resistant asthma. Bronchoalveolar lavage (BAL) had higher IL-8 concentrations and neutrophil counts and the children had lower ACT scores compared with nonpassive smoke-exposed children, which are findings supported by adult data. Additionally, it is likely that symptoms are exacerbated by a direct irritant effect of smoke. Other environmental irritants sometimes encountered include incense or joss sticks, and the extensive use of air fresheners and other aerosol sprays. Environmental pollution is also important, but difficult to modulate except at the level of public health.
Psychosocial Morbidity
The relationships between asthma and the brain are complex. Acute and chronic stress may trigger asthma exacerbations. Stress has been shown to amplify the airway eosinophilic response to allergen challenge. Functional magnetic resonance imaging scanning has identified asthma neurophenotypes in circuits that process emotional information, with greater anterior insular activation with asthma-related psychological stimuli, and associated more profound airway inflammatory response and increased disease severity, although which was cause and which was consequence could not be established. We, and others, have shown that psychosocial issues are common, especially anxiety and depression. Most issues only emerged during discussions between the nurse and the family in the home. Altogether, about half the families were referred to clinical psychology for a more detailed assessment. It is not productive to try to determine whether anxiety and depression are the cause or result of severe asthma; both are treated on their individual merits.
Asthma Education
Some adherence issues relate to basic misunderstandings of asthma and the purpose of treatment, and this is also addressed. If the child does not have a detailed asthma plan, this is put in place and communicated to the school. It is hoped that this will have been done previously, but the asthma plan is always reassessed in detail.
Safeguarding Issues: Symptom Reporting
We have safeguarding concerns in around 10% of children with “severe” asthma. Much relates to symptom overreporting; parents not reporting asthma severity accurately may be the underlying problem, and this is extremely difficult to detect. This is separate from the effect of understandable parental anxiety leading to exaggeration of symptoms. Motivation may include access to financial and other benefits as a result of having a “sick” child, right up to deliberate fabrication of symptoms, or Munchausen by proxy. Unfortunately, diagnosis is often long delayed because a basic tenet of pediatrics is to believe the mother. In such circumstances, contact with the school can be illuminating. Teachers are an important resource; they are experienced in assessing children, and spend many hours each day with them. One child allegedly suffering from severe asthma was, in fact, the captain of sports and was nicknamed “the Greyhound.” The school did not know that the child had a diagnosis of asthma, and had no short-acting β-2 agonist in case of emergency. The lesson here is that early discussion with the safeguarding team is essential if there are any concerns, and that no pediatric referral center for severe asthma can function without access to a really good safeguarding service.
Increasingly Important in the Assessment Process: A Hospital Admission
We find that an admission to hospital for assessment over 2 weeks is valuable when symptoms are thought to be overreported. A detailed plan is worked out in advance ( Box 46.4 ), including regular measurement of lung function and FeNO 50 ; there is a regular program of exercise; all medications are supervised; and no short-acting β-2 agonist is given unless the child has first been assessed. The usual outcome is that the child is well and active without additional rescue medication; their lung function improves; and importantly, the FeNO 50 falls. This last point cannot be attributed to lack of exercise in hospital. On occasion, the admission serves to rehabilitate the child and demonstrates that exercise is not prevented by asthma; and restored confidence is maintained after discharge. Often, it is clear that the problem is either nonadherence to medication or an adverse home environment, or both, which needs addressing rather than escalating prescribed treatment.
The purpose of this admission is to allow a period (usually 2 weeks) of observation and assessment in a controlled and safe environment. As far as possible, normal activities, including attending the hospital school and participating in physical activity, should continue. This is intended as an opportunity to adjust and hopefully reduce some asthma medications.
Admission plan
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To remain resident on the ward during the period of the admission and only leave the ward for short periods with the permission of ward staff or longer trip supervised by a nurse
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Attend school on school days. Our school staff will liaise with the child’s school to ensure that appropriate work and, if necessary, assessments are undertaken
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Review by the physiotherapists at the beginning of the admission and a program of physical activity agreed
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Psychology review early on in the admission and further input as decided following the initial consultation
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All medications (including inhalers) are to be kept by the nursing staff and directly observed as per ward policy
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If albuterol is requested, to be assessed by a doctor first and peak flow readings recorded before and after albuterol (and documented in the case notes)
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Morning and evening peak flows every day
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Ward spirometry with bronchodilator reversibility on admission and thereafter on Tuesdays and Fridays
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Exhaled nitric oxide measurements on admission and thereafter on Tuesdays and Fridays
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ACT to be completed at the beginning of the admission
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Paediatric Asthma Quality of Life Assessment to be completed at the beginning and the end of admission
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Regular review by one of the Respiratory Clinical Nurse Specialists. The Difficult Asthma Team will liaise closely with the attending medical team throughout the admission
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Urine cotinine on admission
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Prednisolone level and random cortisol on the day of admission for all children prescribed prednisolone. If not on prednisolone, blood tests including total IgE, specific IgEs, FBC, and other clinically indicated tests can be performed during the first few days of the admission
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Other tests, including histamine challenge, cardiopulmonary exercise test, induced sputum and cardiorespiratory polygraphy, as indicated by the clinical team
ACT, Asthma control test; FBC, full blood count; IgE, immunoglobulin E.
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