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The Proceedings of the American Thoracic Society 6:712-719 (2009)
© 2009 The American Thoracic Society
doi: 10.1513/pats.200906-046DP
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Phenotypic Differences between Pediatric and Adult Asthma

Andrew Bush1,2 and Andrew Menzies-Gow1,2

1 Department of Paediatric Respiratory Medicine, Imperial School of Medicine at National Heart and Lung Institute, London, United Kingdom; and 2 Department of Thoracic Medicine, Royal Brompton Hospital, London, United Kingdom

Correspondence and requests for reprints should be addressed to Andrew Bush, M.D., Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. E-mail: a.bush{at}rbh.nthames.nhs.uk

ABSTRACT

The goal of asthma phenotyping is to understand disease mechanisms or optimize management. Phenotypes show age-related variation. The phenotypes of wheezing in the first year of life are little studied; many remit in the second year of life, and the children who remit do not have later-onset wheeze, as far as is known. Preschool wheeze is optimally phenotyped by symptom pattern, defined as either episodic viral or multiple-trigger wheeze, which allows rational treatment planning. In school age and adult life, most patients with mild asthma can be managed adequately without phenotyping, but severe asthma clearly falls into several phenotypic groups. Children with severe asthma have no gender bias and are highly atopic with relatively well-preserved lung function, in contrast to the female-preponderant, non-atopic bias seen in adults. Phenotyping has been mainly by proximal luminal cellularity. However, this does not take account of any variation of cellularity over time, distal airway changes, or the relative contribution of mucosal and luminal inflammatory changes. There may be a separate exacerbating phenotype, characterized by airway eosinophilia. Particular adult phenotypes include late-onset asthma and a phenotype characterized by progressive loss of lung function, but critical review suggests that these phenotypes may also have childhood roots. Longitudinal data are needed to determine the stability of phenotypes and their prognoses. Retrospective recall of childhood events is of limited value. In conclusion, a full understanding the multifaceted phenotypes of asthma requires a thorough knowledge of early life events and their consequences over many decades.

Key Words: eosinophil • preschool wheeze • airway growth • persistent airflow limitation • exhaled nitric oxide

WHY PHENOTYPE ASTHMA?

A phenotype may be considered as a cluster of either or both clinical and pathological features that tend to be associated. Phenotypes may be constructed as a result of data collection and subjective analysis, and thus in a sense are forced on the data by the prejudices of the investigator. If the dataset is large enough, sophisticated methods of analysis (1–3) are preferable objectively to determine phenotypes. Both approaches require accurate and comprehensive descriptions of the problem, and are only as good as those descriptions. Phenotypes have to be useful in some way, such as in managing the child or understanding the mechanisms of disease (4). It should be noted that phenotypes may vary over time and are not fixed and immutable.

INFANT WHEEZE (AGE < 12 MONTHS)

Respiratory illness in the first year of life is poorly studied, first because the recognition of wheeze by parents is particularly poor, and many noises are mistaken for wheeze (5–8). Many infants who wheeze or make abnormal respiratory noises in the first 12 months of life are symptom-free from their second year. Even severe episodes of wheeze in the first year of life are not predictive of outcome at age 10 years (9). The basis of symptoms is not clear, but it is not eosinophilic inflammation (10). Possible tracheobronchomalacia, or even pharyngomalacia (11), may play a role, but this is conjectural, and more work is needed in this age group.

THE PRESCHOOL YEARS (AGE 1–6 YEARS)

It has long been known that there are different patterns of wheezing. Phenotyping by epidemiological pattern, the presence or absence of atopy, and symptom pattern have all been proposed.

Epidemiological Phenotypes
The classic epidemiological phenotypes were described from Tucson (Table 1) (12), based on the time of onset and persistence of symptoms. These have been amplified in the Avon Longitudinal Study of Parents and Children (13). This used latent class analysis to determine six phenotypes, namely never or infrequent wheeze, transient early wheeze, prolonged early wheeze, intermediate-onset wheeze, late-onset wheeze, and persistent wheeze. It is possible that some of these six are extremes of the Tucson phenotypes. Epidemiological phenotypes are extremely useful for understanding of mechanisms of wheeze and future disease in adults (below). Because they can only be applied retrospectively they are not useful for the clinical management of the child. A number of predictive indices have been proposed (9, 14, 15). These all have in common quite good negative predictive value, but a positive predictive value of little more than 50%. At the moment we have no disease-modifying strategies to prevent the development of persistent wheeze. Neither intermittent (16) nor prophylactic (17, 18) inhaled corticosteroids (ICS) prevent the progression from episodic (viral) to multiple-trigger wheeze. When novel therapeutic strategies do become available, we will certainly need biomarkers of which children are destined to progress to multiple-trigger wheeze for intervention studies.


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  		TABLE 1. WHEEZING PHENOTYPES IN THE TUCSON STUDY

 
What the epidemiological phenotypes have done is focus us on mechanisms of disease. Patients with transient wheeze have impaired lung function at birth, focusing us on antenatal events. Maternal smoking has a direct effect on airway caliber, possibly via a reduction of alveolar tethering points seen in autopsy data in infants (19). Another mechanism, determined from primate studies, may be increased deposition of collagen (20). There are important gene–environment interactions; maternal and fetal glutathione metabolizing enzyme phenotypes both interact with environmental tobacco smoke. The fetal risk of exposure to maternal smoke is greater if the mother carries null polymorphisms, and the consequences are greater for the null child (21, 22). Maternal atopy has also been associated with impaired lung function in the newborn, although the precise mechanisms are not clear (23, 24). Maternal hypertension or preeclampsia is associated with an increased risk of transient early wheezing, persistent wheezing, and late-onset wheezing. Use of antibiotics for urinary tract infections was associated with transient early wheezing, and antibiotic administration at delivery was associated with both transient early wheezing and persistent wheezing (25). Children who had a mother with diabetes were more likely to have persistent wheezing (25). Amniocentesis or chorionic villus sampling was associated with the subsequent development of wheezing (25). There is increasing evidence that environmental pollution may adversely affect the fetus (26–28). Recently, and alarmingly, epigenetic mechanisms have been implicated in fetal lung development; grandparental smoking, even in the absence of maternal smoking, may affect the child's risk of asthma. There are emerging data about epigenetic mechanisms operating in childhood (29, 30). By contrast, children with persistent wheeze appear to have normal lung function at birth, but evidence of airway obstruction at age 4 to 6 years (31, 32), focusing on early life events. Early sensitization to aeroallergens has been shown to be predictive of persistent wheeze, bronchial responsiveness, and loss of lung function (32). These data show clearly how genetic events, probably operating antenatally, and postnatal environmental influences, can act together to produce disease. The natural experiment of immigration has shown that risk of asthma is of the country of birth if the child moves to a different risk country only after age 4 years (33). Excess weight gain in the first year of life has been shown to be associated with impaired development of airway function (34). The pathological correlates of the epidemiological data are that at 12 months the airway wall is structurally normal (10), but by 30 months, reticular basement membrane thickening and eosinophilic inflammation have started to appear (35).

Another great service that epidemiological phenotypes have performed is the focusing on early life events and their long-term implications. These include the tracking of lung function (36–38), the early origins of adult asthma, and the early origins of chronic obstructive pulmonary disease (COPD). So although the clinical usefulness of epidemiological phenotypes is not great, the insights generated are highly significant.

Phenotyping by Atopic Status
Atopy is a known risk factor for asthma, and phenotyping by the presence or absence of atopy has been proposed (39). However, in practice in the preschool years, this is of limited value. First, it is increasingly being realized that atopy is not an all or none phenomenon but may better be considered as a continuous variable (40). Second, atopy may take time to manifest (41). Third, just because a child who is atopic is wheezing, this does not prove that the two events are connected. Finally, a meta-analysis of studies of corticosteroid treatment for preschool wheeze showed that atopy could not be used to predict the response to therapy (42). The lack of usefulness of atopy as a phenotype-defining characteristic continues into adult life. In children, there is no difference in the airway histology of those with a clinical multiple-trigger wheeze phenotype, whether atopic or not (43). In adults, the airway histology of intrinsic and extrinsic asthma has also been shown to be similar (44).

Phenotyping by Symptom Pattern
One easy pattern to determine is clinical manifestations. The European Respiratory Society (ERS) Task Force proposed phenotyping by symptom pattern, that is, either episodic (viral) wheeze or multiple-trigger wheeze (45). Episodic (viral) wheeze is defined as wheeze in discrete episodes, with the child being well in between episodes. This is usually in association with viral infections, although in clinical practice, viral studies are often not performed. Multiple-trigger wheeze is characterized by wheeze in response to other triggers, as well as episodic exacerbations. It has been sometimes assumed that episodic (viral) and transient wheeze are synonymous, but this is not the case—episodic (viral) may be more common in preschool children (46) but is not unique to this age group (47, 48). This classification has the merit of being able to be used at the time the child is seen, and may have relevance to treatment. There is increasing evidence that episodic (viral) wheeze may be appropriately treated with intermittent therapy, either montelukast (49, 50) or high-dose ICS (50–52). ICS do not affect the progression to persistent wheeze (above), and there is no evidence that their prophylactic use is valuable in episodic (viral) wheeze. It should be noted that these phenotypes are not fixed. Patients with episodic (viral) wheeze frequently progress to a multiple-trigger phenotype, and inhaled corticosteroids may abolish all but viral exacerbations in multiple-trigger wheeze, thereby apparently converting it to an episodic (viral) phenotype. Finally, there is emerging evidence that preschool lung function, in particular lung clearance index, and exhaled nitric oxide discriminate between these symptom-driven phenotypes, giving a physiological and inflammatory readout to validate their use (53).

SCHOOL AGE CHILDREN (AGE > 6 YEARS) AND ADULTS

General Principles
Phenotyping is in general not a useful exercise at least for planning treatment in most patients with mild to moderate asthma controlled on low-dose ICS. Whether this is because mild disease is a uniform category or because ICS have multiple actions is unclear. Thus using a strategy based on normalizing sputum eosinophil counts was effective in severe asthma, but made no differences to patients with mild asthma (54). There may be some exceptions; for example, exercise-induced asthma may be related to cysteinyl leukotriene production and respond better to leukotriene receptor antagonists than ICS (55), but in the main, phenotyping is best reserved for patients with severe asthma.

If this is agreed, then the different manifestations of severity must be dissected. Patterns of severe asthma include: (1) Persistent chronic symptoms most days for at least 3 months with the necessity for short-acting β2 agonists for symptomatic relief at least three times per week despite high-dose ICS and trials of long-acting β2 agonist, leukotriene receptor antagonist, and low-dose oral theophylline. High-dose ICS is defined in children as beclomethasone equivalent 800 µg/d, and in adults as beclomethasone equivalent 1,000 µg/d. (2) Recurrent severe asthma exacerbations despite attempts with medication including trials of allergen avoidance, low-dose daily ICS (56), intermittent high-dose inhaled corticosteroids (50, 52), and intermittent leukotriene receptor antagonists (49, 50) to reduce the frequency of exacerbations. Exacerbations must be of sufficient severity to warrant either at least one admission to an intensive care unit, or at least two hospital admissions requiring intravenous medication, or two or more courses of oral steroids during the preceding year, despite the therapy. (3) Persistent airflow obstruction: post oral steroid, postbronchodilator z score less than –1.96 for FEV1, with normative data from appropriate reference populations (57) despite the therapy. (4) The necessity of prescription of alternate-day or daily oral steroids to achieve control of asthma. (5) Brittle asthma (58), either type 1 (persistent wild swings in peak flow) or type 2 (sudden acute deteriorations out of a pattern of apparent excellent control). Key is to understand that exacerbations and baseline control are not the same thing (59); in the extreme phenotype of episodic (viral) wheeze, exacerbations may be severe, but between exacerbations no medications are required, and indeed, prophylactic ICS have no effect on exacerbations.

Before phenotyping any patient, it is important to determine if the diagnosis of asthma is correct, if there are comorbidities, and if the patient is adherent to the prescribed therapy. The concept of problematic, severe asthma is an umbrella term, used to describe the patient with putative severe asthma on referral for specialist care, before detailed assessment (60). This catch-all term will turn out to include wrong diagnosis (not asthma), significant comorbidity (asthma plus), difficult asthma (the basics are not right [61]—for example, poor adherence, bad environmental circumstances; these patients would not be candidates for sophisticated approaches until the basics are right), and patients with severe, therapy-resistant asthma, who would be candidates for phenotyping.

Early attempts at phenotyping have been based on patterns of sputum cellular inflammation: eosinophilic, neutrophilic, mixed, and paucicellular (62). This has the merit of leading to differences in treatment approaches: in the eosinophilic phenotype, normalizing sputum eosinophils as a goal of treatment, and in neutrophilic, the use of macrolides. However, using this classification, phenotype switching is very common in children (63) and the level of sputum eosinophilia varies significantly over time in adults (64). Furthermore, this classification focuses on luminal inflammation and does not assess either mucosal inflammation, which may be very different (65), or distal inflammation (66). Mathematical partitioning of fractional exhaled nitric oxide (FENO) into airway (JNO) and alveolar components (CALV) (67, 68) gives a noninvasive potential handle on distal airway inflammation. CALV was elevated in poorly controlled asthma (69, 70) and in another study was reduced by the use of fine-particle ICS (71), suggesting this approach may be useful in distal inflammation.

Phenotyping by sputum cell type has been illuminating, but modern biology has given us more powerful tools. Recently gene expression in bronchial epithelial brushings has been used to define high and low Th2 gene expression phenotypes (72, 73). The high-expressing phenotype had greater eosinophilia, bronchial responsiveness, reticular basement membrane thickness, and mucin gene expression; importantly, patients had a better response to ICS, which reduced the signature gene expression.

An important new concept is that of phenotypes that are concordant (symptoms and inflammation mirror each other) and discordant (symptoms and inflammation disproportionate to each other); it is this latter group that may benefit from the monitoring of inflammatory markers (3), justifying the use of sophisticated "inflammometry" techniques.

Age-Related Phenotype of Severe Asthma
The Brompton series of children (74) with severe asthma included baseline data on 102 children, mean age 11.6 (SD: 2.8) years with difficult asthma (DA) in a cross-sectional study, and assessment of corticosteroid responsiveness in 89 children. Full details of the patients are given in Table 2. Eighty-six percent were atopic, 59% were male, and 23% had persistent airflow limitation. Fifty-one percent had additional or alternative diagnoses, although it was not possible to determine how much they contributed to the morbidity. Twenty-four percent reported one or more food allergies. Forty-seven (46%) patients had high-resolution computed tomography (HRCT) performed; three patients (6%) had bronchiectasis. Positive bronchoalveolar lavage (BAL) cultures were seen in 19/76 (25%), of which neutrophilia was present in 10/15 (67%). BAL eosinophilia was present in 25/68 (37%) and neutrophilia in 30/68 (44%), including 11/68 (16%) with mixed cellularity. Endobronchial biopsy could be analyzed in 68 patients. Mucosal eosinophilia was present in 53% and neutrophilia in 53%, including 17/36 (47%) with mixed cellularity. Increased RBM thickening was present in 73%. A pH study was completed in 55/102 (54%) of children, 75% of whom showed evidence of gastroesophageal reflux; in most cases, treatment of reflux did not appear to affect asthma control. Corticosteroid responsiveness, either to 40 mg prednisolone orally for 2 weeks or a single intramuscular injection of triamcinolone, was assessed by symptom score, spirometry including bronchodilator responsiveness, and inflammometry. The tests performed were FENO and sputum cytology, but not all children could perform these tests. Only 11% normalized all these parameters after a steroid trial; partial responsiveness was common. We could not convincingly predict steroid responsiveness from baseline data. From these results, it is clear that children with severe asthma are predominantly highly atopic, there may be a male preponderance, and complete steroid responsiveness is unusual. This is in marked contrast to adult studies. The European Network for Understanding Mechanisms of Severe Asthma study reported that severe asthma was dominated by women with less atopy and more neutrophilic inflammation (75). The Severe Asthma Research Program group also reported that there was less skin prick test positivity in patients with severe asthma (76). Analysis of the Brompton cohort of adults with severe asthma also demonstrated a female preponderance (75%) with 70% demonstrating evidence of atopy (77). Sixty-nine percent of this cohort reported that their asthma first manifested before they were 20 years old. The relationship between childhood and adult phenotypes is unclear; recall bias is such that without longitudinal studies, it is impossible to know what sort of problems the adult with severe asthma had as a child (78). However, our data suggest that many children continue with a severe phenotype (79), and the Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study also reported that over a 2-year period, few patients with severe asthma achieve control of their disease (80). There is much still to learn about adult and pediatric asthma phenotypes and their interrelationships.


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  		TABLE 2. DEMOGRAPHIC AND CLINICAL BASELINE CHARACTERISTICS OF PEDIATRIC PATIENTS WITH SEVERE ASTHMA

 
The Exacerbating Phenotype
The difference between exacerbations and loss of control has been discussed above and described elsewhere (60). It is important to distinguish factors that affect numbers of exacerbations and those that lead to increased severity. In the Childhood Asthma Management Program (CAMP) study, 30% of children (admittedly, these were patients with relatively mild asthma) never exacerbated, also suggesting that there is a true nonexacerbating phenotype (81). The eosinophilic phenotype has been suggested to be the hallmark of exacerbations (82–85). This has also been proposed as a discordant phenotype (73), with often few symptoms between exacerbations, in which an eosinophil-reducing treatment strategy has been proposed to be effective. The recent positive trials with anti–IL-5 therapy targeting patients with frequent exacerbations with an eosinophilic phenotype (84, 85) provides evidence that logical targeting can produce clinical benefit. There may be genotype differences in the exacerbating phenotype, including CD14 and CD16 (86, 87). Factors increasing severity of exacerbations may include food allergy (88), denial and other psychosocial factors, and previous severe exacerbations (89, 90). In adults, the factors underlying the exacerbation-prone phenotype have recently been reviewed (91). They are not fully understood but include extrinsic factors, such as cigarette smoking, sensitization to fungal allergens, medication noncompliance, psychosocial factors, and comorbidities such as gastroesophageal reflux disease, rhinosinusitis, obesity, and intolerance to nonsteroidal antiinflammatory medications; and intrinsic factors, such as deficient epithelial cell production of the antiviral type I interferon β (92) and the type 111 interferon {lambda} (93). Blood group antigens have also been implicated (J. Fahy, personal communication, 2009). Many of these factors are probably common to children and adults, but there are far fewer data in the former. There is a real need for biomarkers of the exacerbating phenotype and also an impending exacerbation.

Impaired Airway Development and Progressive Loss of Lung Function
There is considerable interest in adult asthma in the subgroup with accelerated loss of lung function, but this is very likely overlapping with, or related to, early life events. The patterns of change in spirometry over the age range have been well described. There is a growth phase until the age of about age 25 years, and then a decline sets in. However, there is clearly a group who fail to increase their lung function adequately (below) and fall off their lung function centiles. It is likely, but unproved, that they will also be rapid losers of lung function after age 25 years. Failure to attain the normal plateau of spirometry or an accelerated rate of decline brings forward the time of respiratory symptoms and disability. Adults who as children suffered from what was then called wheezy bronchitis, but would now be called episodic (viral) wheeze, have an accelerated decline in lung function, even in the absence of asthma (94). These children would likely have had early impairment of airway function (above) most likely but not certainly of antenatal origin. Overlapping cohort studies have demonstrated tracking of early lung function deficits into late middle age. There are genetic links between early life events and adult lung function; polymorphisms in ADAM33, a gene that is important in antenatal lung development (95), are important in early life lung function (96) and rate of decline of lung function (97). Another important group that may be at risk of accelerated decline in lung function is the survivors of premature birth, who are known to have impaired lung function in childhood (98, 99), irrespective of whether it is worsened by the consequences of treatment. The CAMP study revealed that there is an ill-understood group of patients with childhood asthma (around 25%) who do not have the expected growth in spirometry, irrespective of the treatment arm (ICS, nedocromil, placebo) (100). Little is known of the defining characteristics of this group. In children with persistent airflow limitation, in whom there were no measurements of rate of decline of lung function, only an increase in surface area of airway smooth muscle and the density of the vascular network were increased compared with patients with asthma without persistent obstruction (101). In adults, asthma is of itself a cause of accelerated decline in lung function. It is suggested that there is a phenotype of even greater decline in lung function. Important factors may be intrinsic rather than extrinsic asthma, smoking, asthma exacerbations, cockroach antigen exposure (102), Chlamydia infections (103), and latent viral infection (104). Inflammatory markers of this phenotype are elevated FeNO (105) and bronchial mucosal CD8+ lymphocyte counts (106). The end result of this phenotype is persistent airflow limitation, which can also be the result of an early step reduction in spirometry due to adenovirus infection or other cause of obliterative bronchiolitis. We hypothesize that this apparently adult phenotype of rapid loss of lung function may in fact have its origins in childhood. Currently we have little knowledge of the pathobiology of abnormal growth or accelerated decline in lung function or fixed airflow obstruction, and no therapeutic strategies to modulate it.

Adult Studies: Noneosinophilic Phenotype
This phenotype is believed to be particularly steroid resistant (107). One etiological factor may be active or passive smoke exposure (108–110). In a series of careful studies in patients with asthma who smoke, carefully defined to avoid including patients with COPD, active smoking was associated with resistance to the clinical effects of inhaled and oral corticosteroids. Other groups in which noneosinophilic phenotype asthma may be seen include the obese, some types of occupational asthma, elite athletes, and menopausal women (111). The etiology of steroid resistance varies between groups (112); for example, smoking induces steroid resistance by reduction of histone deacetylase–2 activation (113), and obesity via a decreased mitogen activated protein kinase-specific phosphatase–1 response to steroids (114). Steroid resistance is not confined to the non-eosinophilic phenotype; prolonged allergen exposure in sensitized patients leads to reduced steroid binding to the glucocorticoid receptor via an IL-2 and IL-4–mediated mechanism (115, 116). The treatment of these steroid-resistant phenotypes is difficult; low-dose theophylline may reverse the histone deacetylase–2 resistant phenotypes, and macrolides have been used to treat particularly neutrophilic phenotypes (112). Whether and to what extent these phenotypes are consistent over time needs further study.

Adult Studies: Late-Onset Phenotype
The so-called adult-onset phenotype characteristically has a female preponderance, worse lung function despite apparently shorter duration of disease, and less atopy compared with early-onset disease (117). Airway eosinophilia is a marker of more severe disease. This is the classic phenotype that shows the importance of pediatric-adult collaboration and the understanding of early life events. The Tucson study showed that patients with late-onset, physician-diagnosed incident asthma were predominantly women (35 of 49), but strong predictors of this phenotype were late onset and persistent wheezing at age 6 years (presumably long forgotten about by the family) and low airway function and cold air bronchial responsiveness all at age 6 years (118). That early life events were forgotten should come as no surprise; major illnesses such as pertussis and pneumonia are also notoriously poorly recalled after the passage of years (78). There is a lot more to be learned about this phenotype, but clearly it will not happen if the significance of the Tucson findings is ignored.

Adult Studies: Brittle Asthma
There is very little work on this phenotype in children (119). Anecdotally, many have seen individual cases of children who develop a sudden acute severe attack of asthma out of a background of apparent good control. Often it is unclear whether in fact previous control had been poor and there was an issue with perception of symptoms. Most work is extrapolated from adults. Type 1 is defined as showing a peak flow variability of greater than 40% for more than 50% of the time over at least 150 days, despite being prescribed at least 1.5 mg/day beclomethasone equivalent. Some of the attacks are of rapid onset, typically over 3 hours. Type 2 patients are asymptomatic between attacks, but have sudden-onset exacerbations as defined above. Type 1 patients are often highly atopic and exposed to high-dose aeroallergen, have psychosocial morbidity (although distinguishing cause from effect may be very difficult), and reported food allergy and intolerance. Management is with allergen avoidance, and, in some cases, continuous infusions of subcutaneous terbutaline. This treatment is supported by a single adult trial without a placebo arm (120) and a pediatric case series (121), also not placebo controlled. We therefore admit the patients to hospital and perform a double-blind trial to exclude a placebo effect, as far as possible. Not infrequently, we find that on admission, the patient gets better independent of treatment, attributable to reduced allergen exposure and/or proper administration of standard therapy. Much less is known about type 1 patients; management of those with severe, rapid-onset attacks might include the provision of preloaded adrenaline syringes (Epipen), but there is no good-quality evidence for this recommendation. It is likely that a percentage of type I patients are in fact suffering from anaphylaxis and potential triggers should be carefully considered at the time of evaluation. It is possible, but unproved, that for patients with severe brittle asthma, with marked bronchial responsiveness but little inflammation, TNF-{alpha} blockade might be useful, because this improved symptoms and airway reactivity while having no effect on airway inflammation in one study (122). However, this was not confirmed in a much larger recent study (123). Larger studies have also demonstrated an increased risk of malignancy (124) and a risk of reactivating tuberculosis (125). This therapy is unlikely to be introduced into clinical practice for severe asthma.

Adult Studies: Aspirin-sensitive Asthma
This group is rarely if ever seen in children, for reasons that are not clear. Nasal polyps in an "asthmatic" child should prompt the exclusion of cystic fibrosis. The true prevalence of aspirin sensitivity in adults with asthma is unclear, with estimates ranging from 2 to 23% (126). It is more commonly found in non-atopic, middle-aged patients with asthma with chronic rhinosinusitis. The exact pathogenesis of aspirin-sensitive asthma is not fully understood, but involves chronic eosinophilic inflammatory changes with evidence of increased mast cell activation. Interference with arachidonic acid metabolism in the lungs plays an important part; inhibition of cyclooxygenase is accompanied by overproduction of cysteinyl leukotrienes. This overproduction, in combination with decreased availability of the bronchodilator prostaglandin E2, may precipitate asthmatic symptoms. Aspirin-sensitive asthma is associated with more severe asthma, increased corticosteroid burden, more emergency care, and the risk of life-threatening reactions after nonsteroidal antiinflammatory drug ingestion (127). The triad of asthma, aspirin sensitivity, and nasal polyps (Samter triad) is well recognized in adult severe asthma populations and often leads to a more rapid decline in FEV1 and increased need for oral corticosteroids (128). This condition is usually associated with a marked eosinophilia of the blood, airways, and nasal mucosa. Patients with aspirin-sensitive asthma frequently require intensive asthma therapy, and given the possible overproduction of leukotrienes it is logical to include a leukotriene receptor antagonist in their treatment regimen (129). Given the eosinophilic nature of this phenotype, they may well gain significant benefit from targeted therapies such as anti–IL-5.

Occupational Asthma: A Pure Late-Onset Phenotype?
Space precludes reviewing occupational asthma in detail. However, it cannot be assumed to have no roots in childhood. Active smoke cigarette exposure clearly is pivotal in the causation of COPD, but there are risk factors for COPD that are established antenatally and in early childhood (130). There is no reason that the same could not be true for occupational asthma.

PHENOTYPES IN CHILDREN AND ADULTS: CONCLUSIONS

This review has given a developmental perspective on the similarities and differences in asthma phenotypes. The key factor missing from the equation is longitudinal studies from childhood to adult life of patients with severe asthma in particular. A number of different initiatives are attempting to further the understanding of severe asthma phenotypes; these include the Global Initiative Against Asthma, the National Asthma Education and Prevention Program, and within Europe, GA2LEN and the Innovative Medicines Initiative Project Unbiased Biomarkers for the Prediction of Respiratory Disease outcomes. These and others in the future will hopefully increase collaboration across age ranges, and understanding of how childhood disease interacts with later environmental risk factors to produce adult disease.

It has already been shown that so-called late-onset asthma has at least some causes operative in early life. It has been shown that recall of even severe illnesses such as pertussis and pneumonia is very unreliable, and so only prospective studies can determine whether adult phenotypes originate in childhood. Gender differences may be a fruitful research avenue; boys seem to remit, but girls get late-onset recrudescence of disease, for reasons that are unclear. Continued dialogue on phenotyping between adult and pediatric respiratory physicians may be enlightening for both groups, but the onus is on those who believe in true adult-onset asthma to adequately prove that there were no childhood origins of the problem. Retrospective recall is not an adequate way of doing this.

FOOTNOTES

Supported by Asthma UK, the British Lung Foundation, and the TV James Trust.

Conflict of Interest Statement: A.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.M.G. has received reimbursement for serving on advisory boards with GlaxoSmithKline ($1,001–$5,000), and Novartis ($1,001–$5,000). He has received honoraria for lectures with AstraZeneca ($1,001–$5,000), GlaxoSmithKline ($1,001–$5,000), and Novartis ($1,001–$5,000). He has also received funding for research with Novartis ($50,001–$100,000).

(Received in original form June 20, 2009; accepted in final form August 16, 2009)

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