Phenotypic Differences between Pediatric and Adult

Andrew Bush1,2 and Andrew Menzies-Gow1,2

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

The goal of asthma phenotyping is to understand disease mecha- poor, and many noises are mistaken for (5–8). Many nisms or optimize management. Phenotypes show age-related infants who wheeze or make abnormal respiratory noises in the variation. The phenotypes of wheezing in the first year of life are first 12 months of life are symptom-free from their second year. little studied; many remit in the second year of life, and the children Even severe episodes of wheeze in the first year of life are not who remit do not have later-onset wheeze, as far as is known. predictive of outcome at age 10 years (9). The basis of Preschool wheeze is optimally phenotyped by symptom pattern, symptoms is not clear, but it is not eosinophilic inflammation defined as either episodic viral or multiple-trigger wheeze, which (10). Possible tracheobronchomalacia, or even pharyngomalacia allows rational treatment planning. In school age and adult life, most (11), may play a role, but this is conjectural, and more work is patients with mild asthma can be managed adequately without needed in this age group. 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 con- THE PRESCHOOL YEARS (AGE 1–6 YEARS) trast to the female-preponderant, non-atopic bias seen in adults. It has long been known that there are different patterns of Phenotyping has been mainly by proximal luminal cellularity. How- wheezing. Phenotyping by epidemiological pattern, the presence ever, this does not take account of any variation of cellularity over or absence of atopy, and symptom pattern have all been proposed. time, distal airway changes, or the relative contribution of mucosal and luminal inflammatory changes. There may be a separate exac- Epidemiological Phenotypes erbating phenotype, characterized by airway eosinophilia. Particu- lar adult phenotypes include late-onset asthma and a phenotype The classic epidemiological phenotypes were described from characterized by progressive loss of lung function, but critical review Tucson (Table 1) (12), based on the time of onset and suggests that these phenotypes may also have childhood roots. persistence of symptoms. These have been amplified in the Longitudinal data are needed to determine the stability of pheno- Avon Longitudinal Study of Parents and Children (13). This types and their prognoses. Retrospective recall of childhood events used latent class analysis to determine six phenotypes, namely is of limited value. In conclusion, a full understanding the multifac- never or infrequent wheeze, transient early wheeze, prolonged eted phenotypes of asthma requires a thorough knowledge of early early wheeze, intermediate-onset wheeze, late-onset wheeze, life events and their consequences over many decades. and persistent wheeze. It is possible that some of these six are extremes of the Tucson phenotypes. Epidemiological pheno- Keywords: eosinophil; preschool wheeze; airway growth; persistent types are extremely useful for understanding of mechanisms of airflow limitation; exhaled nitric oxide wheeze and future disease in adults (below). Because they can only be applied retrospectively they are not useful for the WHY PHENOTYPE ASTHMA? clinical management of the child. A number of predictive indices have been proposed (9, 14, 15). These all have in A phenotype may be considered as a cluster of either or both common quite good negative predictive value, but a positive clinical and pathological features that tend to be associated. predictive value of little more than 50%. At the moment we Phenotypes may be constructed as a result of data collection and have no disease-modifying strategies to prevent the develop- subjective analysis, and thus in a sense are forced on the data by ment of persistent wheeze. Neither intermittent (16) nor pro- the prejudices of the investigator. If the dataset is large enough, phylactic (17, 18) inhaled (ICS) prevent the sophisticated methods of analysis (1–3) are preferable objectively progression from episodic (viral) to multiple-trigger wheeze. to determine phenotypes. Both approaches require accurate and When novel therapeutic strategies do become available, we will comprehensive descriptions of the problem, and are only as good certainly need biomarkers of which children are destined to as those descriptions. Phenotypes have to be useful in some way, progress to multiple-trigger wheeze for intervention studies. such as in managing the child or understanding the mechanisms What the epidemiological phenotypes have done is focus us of disease (4). It should be noted that phenotypes may vary over on mechanisms of disease. Patients with transient wheeze have time and are not fixed and immutable. impaired lung function at birth, focusing us on antenatal events. Maternal smoking has a direct effect on airway caliber, possibly INFANT WHEEZE (AGE , 12 MONTHS) via a reduction of alveolar tethering points seen in autopsy data in infants (19). Another mechanism, determined from primate Respiratory illness in the first year of life is poorly studied, first studies, may be increased deposition of collagen (20). There are because the recognition of wheeze by parents is particularly important gene–environment interactions; maternal and fetal glutathione metabolizing enzyme phenotypes both interact with (Received in original form June 20, 2009; accepted in final form August 16, 2009) environmental tobacco smoke. The fetal risk of exposure to Supported by Asthma UK, the British Lung Foundation, and the TV James Trust. maternal smoke is greater if the mother carries null poly- Correspondence and requests for reprints should be addressed to Andrew Bush, morphisms, and the consequences are greater for the null child M.D., Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, (21, 22). Maternal atopy has also been associated with impaired Sydney Street, London SW3 6NP, UK. E-mail: [email protected] lung function in the newborn, although the precise mechanisms Proc Am Thorac Soc Vol 6. pp 712–719, 2009 DOI: 10.1513/pats.200906-046DP are not clear (23, 24). Maternal hypertension or preeclampsia is Internet address: www.atsjournals.org associated with an increased risk of transient early wheezing, Bush and Menzies-Gow: Age-related Asthma Phenotypes 713

TABLE 1. WHEEZING PHENOTYPES IN THE TUCSON STUDY In adults, the airway histology of intrinsic and extrinsic asthma has also been shown to be similar (44). Number Lung Function Wheeze Lung Function Wheeze (%) Shortly after Birth Age 3 Age 6 Age 6 Phenotyping by Symptom Pattern Normal 425 (51) Normal — Normal — subjects One easy pattern to determine is clinical manifestations. The Transient 164 (20) Obstructed 1 Some catch-up, — European Respiratory Society (ERS) Task Force proposed wheeze still obstructed phenotyping by symptom pattern, that is, either episodic (viral) Persistent 113 (14) Normal 1 Obstructed 1 wheeze or multiple-trigger wheeze (45). Episodic (viral) wheeze wheeze is defined as wheeze in discrete episodes, with the child being Late-onset 124 (15) Normal — Normal 1 well in between episodes. This is usually in association with viral wheeze 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 persistent wheezing, and late-onset wheezing. Use of antibiotics exacerbations. It has been sometimes assumed that episodic for urinary tract infections was associated with transient early (viral) and transient wheeze are synonymous, but this is not the wheezing, and antibiotic administration at delivery was associ- case—episodic (viral) may be more common in preschool ated with both transient early wheezing and persistent wheezing children (46) but is not unique to this age group (47, 48). This (25). Children who had a mother with diabetes were more likely classification has the merit of being able to be used at the time to have persistent wheezing (25). Amniocentesis or chorionic the child is seen, and may have relevance to treatment. There is villus sampling was associated with the subsequent development increasing evidence that episodic (viral) wheeze may be appro- of wheezing (25). There is increasing evidence that environ- priately treated with intermittent therapy, either montelukast (49, mental pollution may adversely affect the fetus (26–28). Re- 50) or high-dose ICS (50–52). ICS do not affect the progression to cently, and alarmingly, epigenetic mechanisms have been persistent wheeze (above), and there is no evidence that their implicated in fetal lung development; grandparental smoking, prophylactic use is valuable in episodic (viral) wheeze. It should even in the absence of maternal smoking, may affect the child’s be noted that these phenotypes are not fixed. Patients with risk of asthma. There are emerging data about epigenetic episodic (viral) wheeze frequently progress to a multiple-trigger mechanisms operating in childhood (29, 30). By contrast, phenotype, and inhaled corticosteroids may abolish all but viral children with persistent wheeze appear to have normal lung exacerbations in multiple-trigger wheeze, thereby apparently function at birth, but evidence of airway obstruction at age 4 to converting it to an episodic (viral) phenotype. Finally, there is 6 years (31, 32), focusing on early life events. Early sensitization emerging evidence that preschool lung function, in particular to aeroallergens has been shown to be predictive of persistent lung clearance index, and exhaled nitric oxide discriminate wheeze, bronchial responsiveness, and loss of lung function between these symptom-driven phenotypes, giving a physiological (32). These data show clearly how genetic events, probably and inflammatory readout to validate their use (53). 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 SCHOOL AGE CHILDREN (AGE . 6 YEARS) birth if the child moves to a different risk country only after age AND ADULTS 4 years (33). Excess weight gain in the first year of life has been shown to be associated with impaired development of airway General Principles function (34). The pathological correlates of the epidemiological Phenotyping is in general not a useful exercise at least for data are that at 12 months the airway wall is structurally normal planning treatment in most patients with mild to moderate asthma (10), but by 30 months, reticular basement membrane thickening controlled on low-dose ICS. Whether this is because mild disease and eosinophilic inflammation have started to appear (35). is a uniform category or because ICS have multiple actions is Another great service that epidemiological phenotypes have unclear. Thus using a strategy based on normalizing sputum performed is the focusing on early life events and their long- eosinophil counts was effective in severe asthma, but made no term implications. These include the tracking of lung function differences to patients with mild asthma (54). There may be some (36–38), the early origins of adult asthma, and the early origins exceptions; for example, exercise-induced asthma may be related of chronic obstructive pulmonary disease (COPD). So although to cysteinyl leukotriene production and respond better to leuko- the clinical usefulness of epidemiological phenotypes is not triene receptor antagonists than ICS (55), but in the main, great, the insights generated are highly significant. phenotyping is best reserved for patients with severe asthma. If this is agreed, then the different manifestations of severity Phenotyping by Atopic Status must be dissected. Patterns of severe asthma include: (1) Atopy is a known risk factor for asthma, and phenotyping by the Persistent chronic symptoms most days for at least 3 months presence or absence of atopy has been proposed (39). However, with the necessity for short-acting b2 agonists for symptomatic in practice in the preschool years, this is of limited value. First, it relief at least three times per week despite high-dose ICS and is increasingly being realized that atopy is not an all or none trials of long-acting b2 agonist, leukotriene receptor antagonist, phenomenon but may better be considered as a continuous and low-dose oral theophylline. High-dose ICS is defined in variable (40). Second, atopy may take time to manifest (41). children as beclomethasone equivalent 800 mg/d, and in adults Third, just because a child who is atopic is wheezing, this does not as beclomethasone equivalent 1,000 mg/d. (2) Recurrent severe prove that the two events are connected. Finally, a meta-analysis asthma exacerbations despite attempts with medication includ- of studies of treatment for preschool wheeze ing trials of allergen avoidance, low-dose daily ICS (56), showed that atopy could not be used to predict the response to intermittent high-dose inhaled corticosteroids (50, 52), and therapy (42). The lack of usefulness of atopy as a phenotype- intermittent leukotriene receptor antagonists (49, 50) to reduce defining characteristic continues into adult life. In children, there the frequency of exacerbations. Exacerbations must be of is no difference in the airway histology of those with a clinical sufficient severity to warrant either at least one admission to multiple-trigger wheeze phenotype, whether atopic or not (43). an intensive care unit, or at least two hospital admissions 714 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 6 2009 requiring intravenous medication, or two or more courses of tive diagnoses, although it was not possible to determine how oral steroids during the preceding year, despite the therapy. (3) much they contributed to the morbidity. Twenty-four percent Persistent airflow obstruction: post oral steroid, postbronchodi- reported one or more food allergies. Forty-seven (46%) patients lator z score less than 21.96 for FEV1, with normative data had high-resolution computed tomography (HRCT) performed; from appropriate reference populations (57) despite the ther- three patients (6%) had . Positive bronchoalveo- apy. (4) The necessity of prescription of alternate-day or daily lar lavage (BAL) cultures were seen in 19/76 (25%), of which oral steroids to achieve control of asthma. (5) Brittle asthma neutrophilia was present in 10/15 (67%). BAL eosinophilia was (58), either type 1 (persistent wild swings in peak flow) or type 2 present in 25/68 (37%) and neutrophilia in 30/68 (44%), in- (sudden acute deteriorations out of a pattern of apparent cluding 11/68 (16%) with mixed cellularity. Endobronchial excellent control). Key is to understand that exacerbations biopsy could be analyzed in 68 patients. Mucosal eosinophilia and baseline control are not the same thing (59); in the extreme was present in 53% and neutrophilia in 53%, including 17/36 phenotype of episodic (viral) wheeze, exacerbations may be (47%) with mixed cellularity. Increased RBM thickening was severe, but between exacerbations no medications are required, present in 73%. A pH study was completed in 55/102 (54%) of and indeed, prophylactic ICS have no effect on exacerbations. children, 75% of whom showed evidence of gastroesophageal Before phenotyping any patient, it is important to determine if reflux; in most cases, treatment of reflux did not appear to affect the diagnosis of asthma is correct, if there are comorbidities, and if asthma control. Corticosteroid responsiveness, either to 40 mg the patient is adherent to the prescribed therapy. The concept of prednisolone orally for 2 weeks or a single intramuscular problematic, severe asthma is an umbrella term, used to describe injection of triamcinolone, was assessed by symptom score, the patient with putative severe asthma on referral for specialist spirometry including bronchodilator responsiveness, and care, before detailed assessment (60). This catch-all term will turn inflammometry. The tests performed were FENO and sputum out to include wrong diagnosis (not asthma), significant comorbid- cytology, but not all children could perform these tests. Only ity (asthma plus), difficult asthma (the basics are not right [61]—for 11% normalized all these parameters after a steroid trial; partial example, poor adherence, bad environmental circumstances; these responsiveness was common. We could not convincingly predict patients would not be candidates for sophisticated approaches until steroid responsiveness from baseline data. From these results, it the basics are right), and patients with severe, therapy-resistant is clear that children with severe asthma are predominantly asthma, who would be candidates for phenotyping. highly atopic, there may be a male preponderance, and com- Early attempts at phenotyping have been based on patterns of plete steroid responsiveness is unusual. This is in marked sputum cellular inflammation: eosinophilic, neutrophilic, mixed, contrast to adult studies. The European Network for Under- and paucicellular (62). This has the merit of leading to differences standing Mechanisms of Severe Asthma study reported that in treatment approaches: in the eosinophilic phenotype, normal- severe asthma was dominated by women with less atopy and izing sputum eosinophils as a goal of treatment, and in neutro- more neutrophilic inflammation (75). The Severe Asthma Re- philic, the use of macrolides. However, using this classification, search Program group also reported that there was less skin prick phenotype switching is very common in children (63) and the level test positivity in patients with severe asthma (76). Analysis of the of sputum eosinophilia varies significantly over time in adults (64). Furthermore, this classification focuses on luminal inflam- mation and does not assess either mucosal inflammation, which TABLE 2. DEMOGRAPHIC AND CLINICAL BASELINE may be very different (65), or distal inflammation (66). Mathe- CHARACTERISTICS OF PEDIATRIC PATIENTS WITH SEVERE ASTHMA matical partitioning of fractional exhaled nitric oxide (FENO) into airway (JNO) and alveolar components (CALV) (67, 68) gives Whole Group a noninvasive potential handle on distal airway inflammation. (n 5 102)(%) CALV was elevated in poorly controlled asthma (69, 70) and in Atopy 88/102 (86) another study was reduced by the use of fine-particle ICS (71), Sex, male:female 60:42 suggesting this approach may be useful in distal inflammation. Age, yr; mean (SD) (range) 11.58 (2.8) (6–19) Phenotyping by sputum cell type has been illuminating, but Median height percentile (range) 50 (2–99) modern biology has given us more powerful tools. Recently Median age at first symptoms, yr (range) 1.25 (0.2–10) gene expression in bronchial epithelial brushings has been Smokers at home 37/100 (37) Previous intubation (for asthma) 14/101 (14) used to define high and low Th2 gene expression phenotypes Rhinoconjunctivitis (on treatment) 32/101 (31) (72, 73). The high-expressing phenotype had greater eosinophilia, Positive SPTs/RASTs to grasses/pollen 61/87 (70) bronchial responsiveness, reticular basement membrane thick- Positive SPTs/RASTs to HDM present 67/95 (70) ness, and mucin gene expression; importantly, patients had a better Median IgE (range) IU/ml 584 (2–11,355) response to ICS, which reduced the signature gene expression. Pets in household 41/102 (40) An important new concept is that of phenotypes that are Positive specific IgE/SPTs to pet (if pet present) 21/34 (62) Medications, median ICS dose (range) mg/d 2 (0.4–4) concordant (symptoms and inflammation mirror each other) Long-acting b2 agonist 92/102 (90) and discordant (symptoms and inflammation disproportionate Leukotriene receptor antagonist 50/102 (49) to each other); it is this latter group that may benefit from the Maintenance oral prednisolone 36/102 (35) monitoring of inflammatory markers (3), justifying the use of Maintenance triamcinolone 1/102 (1) sophisticated ‘‘inflammometry’’ techniques. Oral theophylline 14/102 (14) Mean % predicted FEV1 (SD) 67.1 (19.2) Age-Related Phenotype of Severe Asthma Mean % predicted FEV1 postbronchodilator (SD) 79.4 (18.3) BDR median, % predicted (range) 18 (0–130) The Brompton series of children (74) with severe asthma Number with BDR present (> 12%) 56/81 (69) included baseline data on 102 children, mean age 11.6 (SD: Number with raised FENO 35/81 (43) 2.8) years with difficult asthma (DA) in a cross-sectional study, and assessment of corticosteroid responsiveness in 89 children. Definition of abbreviations: BDR 5 % bronchodilator reversibility; FENO 5 fractional exhaled nitric oxide; HDM 5 house dust mite; RAST 5 radioallergo- Full details of the patients are given in Table 2. Eighty-six sorbent assay; SPT 5 skin prick testing. percent were atopic, 59% were male, and 23% had persistent FEV1 is expressed as % predicted for height. Reprinted by permission from airflow limitation. Fifty-one percent had additional or alterna- Reference 73. Bush and Menzies-Gow: Age-related Asthma Phenotypes 715

Brompton cohort of adults with severe asthma also demonstrated respiratory symptoms and disability. Adults who as children a female preponderance (75%) with 70% demonstrating evi- suffered from what was then called wheezy , but would dence of atopy (77). Sixty-nine percent of this cohort reported now be called episodic (viral) wheeze, have an accelerated that their asthma first manifested before they were 20 years old. decline in lung function, even in the absence of asthma (94). The relationship between childhood and adult phenotypes is These children would likely have had early impairment of airway unclear; recall bias is such that without longitudinal studies, it is function (above) most likely but not certainly of antenatal origin. impossible to know what sort of problems the adult with severe Overlapping cohort studies have demonstrated tracking of early asthma had as a child (78). However, our data suggest that many lung function deficits into late middle age. There are genetic links children continue with a severe phenotype (79), and the Epide- between early life events and adult lung function; polymorphisms miology and Natural History of Asthma: Outcomes and Treat- in ADAM33, a gene that is important in antenatal lung de- ment Regimens study also reported that over a 2-year period, few velopment (95), are important in early life lung function (96) and patients with severe asthma achieve control of their disease (80). rate of decline of lung function (97). Another important group There is much still to learn about adult and pediatric asthma that may be at risk of accelerated decline in lung function is the phenotypes and their interrelationships. survivors of premature birth, who are known to have impaired lung function in childhood (98, 99), irrespective of whether it is The Exacerbating Phenotype worsened by the consequences of treatment. The CAMP study revealed that there is an ill-understood group of patients with The difference between exacerbations and loss of control has childhood asthma (around 25%) who do not have the expected been discussed above and described elsewhere (60). It is growth in spirometry, irrespective of the treatment arm (ICS, important to distinguish factors that affect numbers of exac- nedocromil, placebo) (100). Little is known of the defining erbations and those that lead to increased severity. In the characteristics of this group. In children with persistent airflow Childhood Asthma Management Program (CAMP) study, limitation, in whom there were no measurements of rate of 30% of children (admittedly, these were patients with rela- decline of lung function, only an increase in surface area of tively mild asthma) never exacerbated, also suggesting that airway smooth muscle and the density of the vascular network there is a true nonexacerbating phenotype (81). The eosino- were increased compared with patients with asthma without philic phenotype has been suggested to be the hallmark of persistent obstruction (101). In adults, asthma is of itself a cause exacerbations (82–85). This has also been proposed as a dis- of accelerated decline in lung function. It is suggested that there cordant phenotype (73), with often few symptoms between is a phenotype of even greater decline in lung function. Important exacerbations, in which an eosinophil-reducing treatment factors may be intrinsic rather than extrinsic asthma, smoking, strategy has been proposed to be effective. The recent positive asthma exacerbations, cockroach antigen exposure (102), Chla- trials with anti–IL-5 therapy targeting patients with frequent mydia infections (103), and latent viral infection (104). Inflam- exacerbations with an eosinophilic phenotype (84, 85) pro- matory markers of this phenotype are elevated FeNO (105) and vides evidence that logical targeting can produce clinical bronchial mucosal CD81 lymphocyte counts (106). The end re- benefit. There may be genotype differences in the exacerbat- sult of this phenotype is persistent airflow limitation, which can ing phenotype, including CD14 and CD16 (86, 87). Factors also be the result of an early step reduction in spirometry due to increasing severity of exacerbations may include food allergy adenovirus infection or other cause of obliterative . (88), denial and other psychosocial factors, and previous We hypothesize that this apparently adult phenotype of rapid loss severe exacerbations (89, 90). In adults, the factors underlying of lung function may in fact have its origins in childhood. Cur- the exacerbation-prone phenotype have recently been rently we have little knowledge of the pathobiology of abnormal reviewed (91). They are not fully understood but include growth or accelerated decline in lung function or fixed airflow extrinsic factors, such as cigarette smoking, sensitization to obstruction, and no therapeutic strategies to modulate it. fungal allergens, medication noncompliance, psychosocial fac- tors, and comorbidities such as gastroesophageal reflux dis- Adult Studies: Noneosinophilic Phenotype ease, rhinosinusitis, obesity, and intolerance to nonsteroidal This phenotype is believed to be particularly steroid resistant antiinflammatory medications; and intrinsic factors, such as (107). One etiological factor may be active or passive smoke deficient epithelial cell production of the antiviral type I exposure (108–110). In a series of careful studies in patients interferon b (92) and the type 111 interferon l (93). Blood with asthma who smoke, carefully defined to avoid including group antigens have also been implicated (J. Fahy, personal patients with COPD, active smoking was associated with communication, 2009). Many of these factors are probably resistance to the clinical effects of inhaled and oral cortico- common to children and adults, but there are far fewer data in steroids. Other groups in which noneosinophilic phenotype the former. There is a real need for biomarkers of the asthma may be seen include the obese, some types of exacerbating phenotype and also an impending exacerbation. occupational asthma, elite athletes, and menopausal women (111). The etiology of steroid resistance varies between groups Impaired Airway Development and Progressive Loss of (112); for example, smoking induces steroid resistance Lung Function by reduction of histone deacetylase–2 activation (113), and There is considerable interest in adult asthma in the subgroup obesity via a decreased mitogen activated protein kinase-specific with accelerated loss of lung function, but this is very likely phosphatase–1 response to steroids (114). Steroid resistance is overlapping with, or related to, early life events. The patterns of not confined to the non-eosinophilic phenotype; prolonged change in spirometry over the age range have been well allergen exposure in sensitized patients leads to reduced steroid described. There is a growth phase until the age of about age binding to the glucocorticoid receptor via an IL-2 and IL-4– 25 years, and then a decline sets in. However, there is clearly mediated mechanism (115, 116). The treatment of these steroid- a group who fail to increase their lung function adequately resistant phenotypes is difficult; low-dose theophylline may (below) and fall off their lung function centiles. It is likely, but reverse the histone deacetylase–2 resistant phenotypes, and unproved, that they will also be rapid losers of lung function after macrolides have been used to treat particularly neutrophilic age 25 years. Failure to attain the normal plateau of spirometry phenotypes (112). Whether and to what extent these pheno- or an accelerated rate of decline brings forward the time of types are consistent over time needs further study. 716 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 6 2009

Adult Studies: Late-Onset Phenotype the exclusion of cystic fibrosis. The true prevalence of aspirin The so-called adult-onset phenotype characteristically has a fe- sensitivity in adults with asthma is unclear, with estimates male preponderance, worse lung function despite apparently ranging from 2 to 23% (126). It is more commonly found in shorter duration of disease, and less atopy compared with early- non-atopic, middle-aged patients with asthma with chronic onset disease (117). Airway eosinophilia is a marker of more rhinosinusitis. The exact pathogenesis of aspirin-sensitive severe disease. This is the classic phenotype that shows the asthma is not fully understood, but involves chronic eosinophilic importance of pediatric-adult collaboration and the understand- inflammatory changes with evidence of increased mast cell ing of early life events. The Tucson study showed that patients activation. Interference with arachidonic acid metabolism in with late-onset, physician-diagnosed incident asthma were pre- the lungs plays an important part; inhibition of cyclooxygenase dominantly women (35 of 49), but strong predictors of this is accompanied by overproduction of cysteinyl leukotrienes. phenotype were late onset and persistent wheezing at age 6 years This overproduction, in combination with decreased availability (presumably long forgotten about by the family) and low airway of the bronchodilator prostaglandin E2, may precipitate asth- function and cold air bronchial responsiveness all at age 6 years matic symptoms. Aspirin-sensitive asthma is associated with (118). That early life events were forgotten should come as no more severe asthma, increased corticosteroid burden, more surprise; major illnesses such as pertussis and are also emergency care, and the risk of life-threatening reactions after notoriously poorly recalled after the passage of years (78). There nonsteroidal antiinflammatory drug ingestion (127). The triad of is a lot more to be learned about this phenotype, but clearly it will asthma, aspirin sensitivity, and nasal polyps (Samter triad) is not happen if the significance of the Tucson findings is ignored. 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 Adult Studies: Brittle Asthma with a marked eosinophilia of the blood, airways, and nasal There is very little work on this phenotype in children (119). mucosa. Patients with aspirin-sensitive asthma frequently re- Anecdotally, many have seen individual cases of children quire intensive asthma therapy, and given the possible over- who develop a sudden acute severe attack of asthma out of production of leukotrienes it is logical to include a leukotriene a background of apparent good control. Often it is unclear receptor antagonist in their treatment regimen (129). Given the whether in fact previous control had been poor and there was eosinophilic nature of this phenotype, they may well gain an issue with perception of symptoms. Most work is extrapolated significant benefit from targeted therapies such as anti–IL-5. 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 Occupational Asthma: A Pure Late-Onset Phenotype? days, despite being prescribed at least 1.5 mg/day beclometha- Space precludes reviewing occupational asthma in detail. How- sone equivalent. Some of the attacks are of rapid onset, typically ever, it cannot be assumed to have no roots in childhood. Active over 3 hours. Type 2 patients are asymptomatic between attacks, smoke cigarette exposure clearly is pivotal in the causation of but have sudden-onset exacerbations as defined above. Type 1 COPD, but there are risk factors for COPD that are established patients are often highly atopic and exposed to high-dose antenatally and in early childhood (130). There is no reason that aeroallergen, have psychosocial morbidity (although distinguish- the same could not be true for occupational asthma. ing 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 terbuta- PHENOTYPES IN CHILDREN AND line. This treatment is supported by a single adult trial without ADULTS: CONCLUSIONS a placebo arm (120) and a pediatric case series (121), also not placebo controlled. We therefore admit the patients to hospital This review has given a developmental perspective on the and perform a double-blind trial to exclude a placebo effect, as far similarities and differences in asthma phenotypes. The key factor as possible. Not infrequently, we find that on admission, the missing from the equation is longitudinal studies from childhood patient gets better independent of treatment, attributable to to adult life of patients with severe asthma in particular. A reduced allergen exposure and/or proper administration of number of different initiatives are attempting to further the standard therapy. Much less is known about type 1 patients; understanding of severe asthma phenotypes; these include the management of those with severe, rapid-onset attacks might Global Initiative Against Asthma, the National Asthma Educa- include the provision of preloaded adrenaline syringes (Epipen), tion and Prevention Program, and within Europe, GA2LEN and but there is no good-quality evidence for this recommendation. It the Innovative Medicines Initiative Project Unbiased Biomarkers is likely that a percentage of type I patients are in fact suffering for the Prediction of outcomes. These and from anaphylaxis and potential triggers should be carefully others in the future will hopefully increase collaboration across considered at the time of evaluation. It is possible, but unproved, age ranges, and understanding of how childhood disease interacts that for patients with severe brittle asthma, with marked bron- with later environmental risk factors to produce adult disease. chial responsiveness but little inflammation, TNF-a blockade It has already been shown that so-called late-onset asthma has might be useful, because this improved symptoms and airway at least some causes operative in early life. It has been shown that reactivity while having no effect on airway inflammation in one recall of even severe illnesses such as pertussis and pneumonia is study (122). However, this was not confirmed in a much larger very unreliable, and so only prospective studies can determine recent study (123). Larger studies have also demonstrated an whether adult phenotypes originate in childhood. Gender differ- increased risk of malignancy (124) and a risk of reactivating ences may be a fruitful research avenue; boys seem to remit, but tuberculosis (125). This therapy is unlikely to be introduced into girls get late-onset recrudescence of disease, for reasons that are clinical practice for severe asthma. 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 Adult Studies: Aspirin-sensitive Asthma asthma to adequately prove that there were no childhood origins This group is rarely if ever seen in children, for reasons that are of the problem. Retrospective recall is not an adequate way of not clear. Nasal polyps in an ‘‘asthmatic’’ child should prompt doing this. Bush and Menzies-Gow: Age-related Asthma Phenotypes 717

Conflict of Interest Statement: A.B. does not have a financial relationship with 22. Gilliland FD, Li YF, Dubeau L, Berhane K, Avol E, McConnell R, a commercial entity that has an interest in the subject of this manuscript. A.M.G. Gauderman WJ, Peters JM. Effects of glutathione S-transferase M1, has received reimbursement for serving on advisory boards with GlaxoSmithKline maternal smoking during pregnancy, and environmental tobacco ($1,001–$5,000), and Novartis ($1,001–$5,000). He has received honoraria for smoke on asthma and wheezing in children. Am J Respir Crit Care 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 Med 2002;166:457–463. Novartis ($50,001–$100,000). 23. Stick SM, Burton PR, Gurrin L, Sly PD, LeSouef PN. Effects of maternal smoking during pregnancy and a family history of asthma on respiratory function in newborn infants. Lancet 1996;348:1060–1064. 24. 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