Novel views on endotyping asthma, its remission, and COPD
Carpaij, Orestes
DOI:
10.33612/diss.136744640
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Publication date: 2020
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Carpaij, O. (2020). Novel views on endotyping asthma, its remission, and COPD. University of Groningen. https://doi.org/10.33612/diss.136744640
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Chapter 2
The pathophysiology of
asthma remission
Orestes A. Carpaij, Janette K. Burgess, Huib A. M. Kerstjens, Martijn C. Nawijn, Maarten van den Berge
Abstract
Asthma is a chronic respiratory condition, which is highly prevalent worldwide. Although no cure is currently available, it is well recognized that some asthma patients can spontaneously enter remission of the disease later in life. Asthma remission is characterized by absence of symptoms and lack of asthma-medication use. Subjects in asthma remission can be divided into two groups: those in clinical remission and those in complete remission. In clinical asthma remission, subjects still have a degree of lung functional impairment or bronchial hyperresponsiveness, while in complete asthma remission, these features are no longer present. Over longer periods, the latter group is less likely to relapse. This remission group is of great scientific interest due to the higher potential to find biomarkers or biological pathways that elicit or are associated with asthma remission.
Despite the fact that the definition of asthma remission varies between studies, some factors are reproducibly observed to be associated with remitted asthma. Among these are lower levels of inflammatory markers, which are lowest in complete remission. Additionally, in both groups some degree of airway remodeling is present. Still, the pathological disease state of asthma remission has been poorly investigated. Future research should focus on at least two aspects: further characterisation of the small airways and airway walls in order to determine histologically true remission, and more thorough biological pathway analyses to explore triggers that elicit this phenomenon. Ultimately, this will result in pharmacological targets that provide the potential to steer the course of asthma towards remission.
Introduction
Asthma is a usually chronic respiratory disease with an estimated 300 million individuals affected worldwide. It is characterized by variable airflow obstruction associated with symptoms of dyspnea, cough and bronchial hyperresponsiveness as outlined in the GINA guidelines [1]. Current treatments fail to cure the disease. Nevertheless, it has been reported that asthma can go into spontaneous remission [2,3], meaning that asthmatics at some point are no longer burdened by the disease, and do no longer require any asthma medication. These “ex-asthmatics” are labelled to be in clinical asthma remission, but might still have (asymptomatic) bronchial hyperresponsiveness or a low lung function [4]. In fewer cases, subjects go into complete asthma remission, additionally having no pulmonary function impairment or bronchial hyperresponsiveness [2,3]. To date, most discussion of asthma treatment goals revolves around disease control [1,5,6], whereas exploring the induction of asthma remission as a therapeutic goal has so far attracted little interest. In this review, we highlight the definition, prevalence and characteristics of asthma remission. Next, we describe factors associated with the induction of asthma remission, inflammatory markers, histological signs and genotypes linked to this phenomenon. Finally, we discuss current research on identifying biological pathways that could trigger asthma remission, which may be used for therapeutics in the future.
Definition of asthma remission
Defining asthma remission seems straightforward, but is not an easy task. Asthma is a usually chronic disease characterized by variable airflow obstruction, bronchial hyperresponsiveness and inflammation, and disease severity fluctuates over time. As such, episodes with little or no disease activity can alternate with periods of more disease symptoms and renewed dependence on medication use. Consequently, patients in remission of the disease have a certain risk of relapse [2,3,7,8]. This resembles “remission” of cancer [9], in which the disappearance of signs and symptoms does not ensure that the disease is cured. Yet, it is thought that remission of cancer is the closest to cure and has smaller chance of relapse, especially in “complete remission” of cancer, certainly for many non-operable lung cancers (National Cancer Institute, 2018). The risk of relapse also pertains to other inflammatory diseases, such as rheumatoid arthritis [6,10], inflammatory bowel disease [11], and multiple sclerosis [12]. In principle,
the relapse risk depends on how strict remission is defined and what features must be absent. Thus to apply similar reasoning to asthma where the label of remission needs to be associated with minimal occurrence of relapse, the definition of asthma remission should be strict including an absence of symptoms, its period, no medication use, as well as absence of lung function impairment and bronchial hyperresponsiveness. The complexities of and guidelines for defining asthma remission are discussed below. Symptom perception
The asthmatic’s perception of the severity of symptoms has a dominant important role in the effective management of asthma [13]. In line with this, individuals with asthma remission might also have poor perception of symptoms and feel no need for treatment. Yet, the mechanisms underlying poor perception are not well understood [14]. One concept explaining poor perception is that of temporal adaptation; the diminished perception of symptoms is caused by psychological modification due to chronic obstruction and dyspnea [14]. In other words, individuals with remitted asthma could experience symptoms differently than family and associates would judge them. Symptom-free period
According to most definitions, individuals in asthma remission should not have experienced any degree of asthma-related symptoms during a reasonable period of time. In the many studies carried out so far, a broad range of symptom-free periods is used to define asthma remission [6]. Table 1 shows that the duration of absence of symptoms was on average one year, with a range of 6 months to 5 years. Studies are limited in their accuracy to determine the symptom-free period for several reasons. First, in retrospective cohorts, asthma remission should not be defined as having “no medical records for current asthma” since these individuals could have been treated somewhere else. Second, questions such as “did you experience asthma symptoms in the previous year?” are dichotomous and do not allow for reporting subtle symptoms, resulting in an overestimation of remission prevalence in large survey studies. We think it is highly probable that standardized questioning with several lines (e.g. wheeze, dyspnea on exertion, several triggers) will identify more subjects who still have some symptoms. And last, determining the symptom-free period is affected by selection bias; asthma symptoms might be underestimated by the clinical researcher and the participant who wants to enroll, when investigating the relatively rare occurrence of
asthma remission [6]. Since individuals with remitted asthma are difficult to find, researchers might underrate wheezing in order to fill the cohort. In addition, it can be debated whether patients who re-experience symptoms during methacholine and adeno-‘5-monophosphate provocation tests should be labelled as symptom free [15], while healthy non-asthmatic individuals would not experience dyspnea [16]. In principle, true asthma remission should be defined as having no asthma symptoms (i.e. wheezing, asthma attacks, including dyspnea during provocation) for at least one year.
Medication use
A key factor that should be assessed in order to ascertain asthma remission is absence of medication use. In contrast to fully controlled asthma, patients are usually considered to be in asthma remission when they did not take any asthma-related medication for at least one year. Thus in order to define true asthma remission, individuals should not take any symptom-relievers and anti-inflammatory agents, including immunosuppressant medication used for other diseases.
Lung function and bronchial hyperresponsiveness
In order to make the definition of asthma remission less dependent on symptom perception, Vonk et al. suggested dividing remission into clinical and complete asthma remission. Both definitions share the absence of wheeze, asthma attacks and use of asthma medication for more than one year. Yet in clinical asthma remission, individuals still have a positive bronchial hyperresponsiveness (BHR) test and/or lung function impairment, while in subjects with complete asthma remission, these features are absent [2]. Defining complete asthma remission results in fewer subjects who meet these criteria [2,3,17–19]. Despite the scarcity of subjects, studying complete asthma remission has two advantages. First, it is of scientific interest; this strict phenotype has higher potential to elucidate biological biomarkers and pathways that are associated with asthma remission [4,20]. Second, the risk of asthma relapse is lower in complete remission subjects: one quarter compared to two-third in clinical asthma remission subjects [3].
34 35
20
Excluded
Non-English: 103 studies Wrong topic: 492 studies
Title of interest 109 studies Excluded Reviews: 21 Only abstract: 3 Wrong topic: 42 Asthma diagnosis <6 years: 2
Included
Relevant studies: 41 Found in relevant studies: 3
(- 8 overlapping cohorts)
Relevant cohorts: 36
Figure 1: Pubmed search Last searched on 6-1-2019
(asthma[ti] AND (remission[tiab] OR outgrow[tiab] OR "free from symptoms"[tiab] OR remitted[tiab] OR "no symptoms"[tiab] OR "asymptomatic"[tiab] OR "absence of
symptoms"[tiab] OR "natural history"[tiab] OR "course of asthma"[tiab])) AND (prevalence[tiab] OR rate*[tiab] OR outcome[tiab] OR predictors[tiab] OR prognos*[tiab]
OR factors[tiab] OR characteriz*[tiab] OR determinants[tiab]) Results: 704 studies Ta bl e 1 : v ar io us d efi n it io n s, p re va le nc e r at es a nd f ac to rs a ss oc ia te d w it h a st h m a r em is si on St ud y 36 c oh or ts C oh or t d esi gn A st hm a d ia gn os is a nd q ua lit y o f t he s tu dy N A ge Enrollme nt D efi n it io n o f a st h m a rem is si on C la ssi fi ca ti on o f rem is si on Pr op or ti on A ss oc ia te d w it h r em is si on Th e C hi ld ho od A st hm a M an ag em en t P ro gr am (C A M P) , U SA [ 17 ,2 1] Pro sp ect iv e c oh or t w it h 15 -y ea r c li n ic al FU. Ast h m a: e n ro ll ed a st h m at ic c h il d re n i n C A M P t ri al , m il d-t o-m od er at e p er si st en t ast h m a w it h p os it iv e me th ac ho li ne te st . H ig h q ua li ty : l ar ge c oh or t, w el l-de fi n ed an d c li n ic al ly a ss es se d a st h m a a n d as th m a r em is si on d ia g n os is . 90 9 5-12 Y No si gn s o f: as th m a re p or te d s ym pt om s M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 1 y ea r R em is si on 6% ( 18 Y ) - N o p os it iv e S P T ’s - F ew er p os it iv e S P T ’s - L ess sen si ti ve to a ll er gen s - M il d s ym pt om s i n ch il d h oo d - H ig h er b as el in e F E V1 R em is si on -- N ot d efi n ed C li n ica l r em is si on , i .e . FE V1 /F V C r at io > 80 % 26 % ( 23 Y ) - F em al e s ex - L es s B H R a t b as el in e - H ig h er b as el in e F E V1 - H ig h er b as el in e F E V1 /F VC - L ow er b lo od I gE - L ow er b lo od e os in op h il s - W h eez es d u ri ng co ld s C om pl et e r em is si on , i.e . F E V1 /F VC ra ti o > 80 % , P C20 me th ac ho li ne > 25 m g/ ml 15% ( 23 Y ) - F em al e s ex - L es s B H R a t b as el in e - H ig h er b as el in e F E V1 - H ig h er b as el in e F E V1 /F VC - L ow er b lo od I gE - L ow er b lo od e os in op h il s - W h eez es d u ri ng co ld s O ut pa ti en t c oh or t o f Pe di at ri c c lin ic o f G ol es ta n U ni ve rs it y H os pi ta l I n Ah va z, I ra n [ 22 ] Pro sp ect iv e c oh or t w it h 5-ye ar c li n ic al FU. Ast h m a: r eg is te re d i n o ut pa ti en t p ed ia tr ic c li n ic w it h ≥2 a st h m a a tt ac ks in p as t. H ig h qu al it y: w el l-de fi n ed a n d c li n ic al ly asse sse d a st h m a a n d a st h m a r em iss io n d ia g n os is. 19 7 6-1 0Y No si gn s o f: as th m a sy mp to m s M ed ic at io n u se : n o I C S or S A B A Pe ri od : 1 y ea r R em is si on FE V1 /F V C > 80 % , ex er ci se ch al len ge te st < 15% d ec li n e a ft er 6 -8 min ut es o f r u n n in g 33 % ( 15 Y ) - N o f am il y h is to ry o f ast h m a - N o p as si ve s m ok in g - N o e cz em a
2
Ta bl e 1 : ( co nt in ued ) St ud y 36 c oh or ts C oh or t d esi gn A st hm a d ia gn os is a nd q ua lit y o f t he s tu dy N A ge Enrollme nt D efi n it io n o f a st h m a rem is si on C la ssi fi ca ti on o f rem is si on Pr op or ti on A ss oc ia te d w it h r em is si on O ut pa ti en t c oh or t o f H ac et te pe U ni ve rs it y Pe di at ri c A lle rg y a nd A st hm a U ni t, T ur ke y [2 3] Pro sp ect iv e c oh or t w it h 11 -y ea r c li n ic al FU. Ast h m a: r eg is te re d a t o ut pa ti en t c li n ic w it h ≥1 v is it e ve ry 2 y ea r f or 6 y ea rs , re ve rs ib le a ir w ay o bs tr uc ti on w it h spi rom et ry . H ig h qu al it y: w el l-de fi n ed a n d c li n ic al ly asse sse d a st h m a a n d a st h m a r em iss io n d ia g n os is. 115 5Y No si gn s o f: as th m a sy mp to m s M ed ic at io n u se : n o co nt rol le r m ed ic at io n Pe ri od : 1 y ea r R em is si on 53 % ( 17 Y ) - M al e s ex - N o b lo od e os in op h il ia C li n ic al r em is si on , i. e. % p re d. ≤8 0% , PC 20 me th ac ho li ne ≤8 m g/m l 26 % ( 17 Y ) - M al e s ex C om pl et e r em is si on , i.e . F E V1 % p re d. > 80 % , P C20 me th ac ho li ne > 8m g/ ml 27 % ( 17 Y ) - N ot d es cr ib ed Is le o f W ig ht B ir th C oh or t, U ni te d K in gd om [2 4-26 ] Pro sp ect iv e c oh or t w it h 18 -y ea r c li n ic al FU. Ast h m a: p h ys ic ia n d ia g n os ed < 10 y ea r, as th m a t re at m en t i n t h e l as t y ea r. H ig h qu al it y: r ea so n ab ly d efi n ed a st h m a d ia g n os is , w el l-de fi n ed a n d c li n ic al ly asse sse d a st h m a r em iss io n d ia g n os is . 181 1Y No si gn s o f: as th m a sy mp to m s M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 1 y ea r R em is si on 31 % ( 18 Y ) - M al e s ex - L es s B H R a t b as el in e - L es s a to py C li n ica l r em is si on , i.e . P C20 me th ac ho li ne <8 m g/ m l 11 % ( 18 Y ) C om pl et e r em is si on , i.e . P C20 me th ac ho li ne ≥8 m g/m l 10 % ( 18 Y ) O ut pa ti en t c oh or t o f M ar m ar a U ni ve rs it y Pe di at ri c A lle rg y a nd Im m un ol og y D ep ar tm en t, Tu rk ey [2 7] R et ro sp ect iv e co hor t w it h 10 -y ea r cl in ic al F U. A st h m a: d ia g n os is b as ed o n G IN A a n d A RI A g ui de li n es . H ig h qu al it y: r ea so n ab ly d efi n ed a st h m a d ia g n os is , w el l-de fi n ed a n d c li n ic al ly asse sse d a st h m a r em iss io n d ia g n os is . 62 2-8Y No si gn s o f: as th m a sy mp to m s M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 1 y ea r R em is si on 50 % ( 16 Y ) - N eg at iv e f am il y h is to ry - L es s B H R a t b as el in e - A bs en ce o f r h in it is - H ig h er c h il d h oo d F E V1 - H ig h er c h il d h oo d FE F25-7 5% C li n ica l r em is si on , i.e . P C20 me th ac ho li ne <8 m g/ m l, n eg at iv e SP T 16 % (16 Y ) - N ot d es cr ib ed C om pl et e r em is si on , i.e . P C20 me th ac ho li ne ≥8 m g/ m l, n eg at iv e SP T 34 % ( 16 Y ) - N ot d es cr ib ed Ta bl e 1 : ( co nt in ued ) St ud y 36 c oh or ts C oh or t d esi gn A st hm a d ia gn os is a nd q ua lit y o f t he s tu dy N A ge Enrollme nt D efi n it io n o f a st h m a rem is si on C la ssi fi ca ti on o f rem is si on Pr op or ti on A ss oc ia te d w it h r em is si on O bs tr uc ti ve L un g D is ea se in N or th er n S w ed en St ud ie s ( O LI N ), S w ed en [2 8-2 9] Pro sp ect iv e c oh or t w it h 12 - y ea r c li n ic al FU. Ast h m a: p h ys ic ia n d ia g n os ed b y p ed ia tr ic ia n s. H ig h qu al it y: r ea so n ab ly d efi n ed a st h m a d ia g n os is , w el l-de fi n ed a n d c li n ic al ly asse sse d a st h m a r em iss io n d ia g n os is . 248 7-8Y No si gn s o f: w h eez e M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 3 y ea rs R em is si on , m ea n F E V1 % p re d. 9 0% , m ed ia n PC 20 me th ac ho li ne : 3. 4m g/m l 21 % ( 19 Y ) - M al e s ex - N o S P T p os it iv it y t o an im als O ut pa ti en t c oh or t of P ed ia tr ic A lle rg y O ut pa ti en t U ni t a t t he Ce nt ra l H os pi ta l o f Sk öv de , S w ed en [ 30 ] Pro sp ect iv e c oh or t w it h 21 -y ea r c li n ic al FU. Ast h m a: r eg is te re d a t o ut pa ti en t c li n ic , ≥3 e pis od es o f w h eez in g. H ig h qu al it y: r ea so n ab ly d efi n ed a st h m a d ia g n os is , w el l-de fi n ed a n d c li n ic al ly asse sse d a st h m a r em iss io n d ia g n os is . 55 5-14 Y No si gn s o f: as th m a sy mp to m s M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 1 y ea r R em is si on 16 % ( 30 Y ) - M al e s ex O ut pa ti en t c oh or t o f Pe di at ri c p ul m on ol og y de pa rt m en t o f t he U ni ve rs it y M ed ic al Ce nt er G ro ni ng en , T he N et he rl an ds [ 2] Pro sp ect iv e c oh or t w it h 30 -y ea r c li n ic al FU. Ast h m a: r eg is te re d a t o ut pa ti en t c li n ic , ph ys ic ia n d ia g n os ed , p os it iv e h is ta m in e te st . H ig h qu al it y: w el l-de fi n ed a n d c li n ic al ly asse sse d a st h m a a n d a st h m a r em iss io n d ia g n os is. 119 5-14 Y No si gn s o f: w h ee ze o r as th m a a tt ac ks M ed ic at io n u se : n o IC S Pe ri od : 1 y ea r R em is si on 52 % ( 32 -4 2Y ) - H ig h er b as el in e F E V1 - H ig h er i n cr ea se i n F E V1 - L es s p ac k y ea rs i n ad u lt h oo d C li n ica l r em is si on , i.e . P C20 me th ac ho li ne ≤1 6m g/ m l o r F E V1 % pr ed . ≤ 90% 30 % ( 32 -4 2Y ) - N ot d es cr ib ed C om pl et e r em is si on , i.e . P C20 me th ac ho li ne an d > 16 m g/ m l, F E V1 % pr ed . > 90 % 22 % ( 32 -4 2Y ) - N ot d es cr ib ed
2
Ta bl e 1 : ( co nt in ued ) St ud y 36 c oh or ts C oh or t d esi gn A st hm a d ia gn os is a nd q ua lit y o f t he s tu dy N A ge Enrollme nt D efi n it io n o f a st h m a rem is si on C la ssi fi ca ti on o f rem is si on Pr op or ti on A ss oc ia te d w it h r em is si on O ut pa ti en t c oh or t o f Pe di at ri c p ul m on ol og y de pa rt m en t o f t he U ni ve rs it y M ed ic al Ce nt er G ro ni ng en , T he N eth er la nd s [3 1] Pro sp ect iv e c oh or t w it h 39 -y ea r c li n ic al FU. Ast h m a: r eg is te re d a t o ut pa ti en t c li n ic , ph ys ic ia n d ia g n os ed , p os it iv e h is ta m in e te st . H ig h qu al it y: w el l-de fi n ed a n d c li n ic al ly asse sse d a st h m a a n d a st h m a r em iss io n d ia g n os is. 63 7-1 2Y No si gn s o f: as th m a sy mp to m s M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 1 y ea r R em is si on 18 % (2 5Y ) - N ot w h ee zi ng d u ri ng c ol d - N o p n eu m on ia i n ch il d h oo d - D us ty h ou se i n c h il d h oo d - L eu ke m ia i n f am il y h is tor y - N o F E V1 < 80 % i n ch il d h oo d 40 % ( 49 Y ) - H av in g p et s i n c h il d h oo d C li n ica l r em is si on , i.e . F E V1 % p re d. ≤9 0% or P C20 me th ac ho li ne ≤9 .8 m g/m l 11 % (2 5Y ) - N ot d es cr ib ed 30 % ( 49 Y ) - N ot d es cr ib ed C om pl et e r em is si on , i.e . F E V1 % p re d. > 90 % an d P C20 me th ac ho li ne > 9. 8m g/m l 7% (2 5Y ) - N ot w h ee zi ng d u ri ng c ol d - N o m at er n al a to py - L eu ke m ia i n f am il y h is tor y - H av in g a h ig h er F E V1 /F VC - S P T p os it iv it y t o m ou ld 10 % ( 49 Y ) - N ot f ou n d Ad ul t-O ns et A st hm a an d I nfl am m at or y Su bp he no ty pe s ( A D O N IS ), Th e N et he rl an ds [ 32 ] Pro sp ect iv e c oh or t w it h 5-ye ar c li n ic al FU. Ast h m a: p h ys ic ia n d ia g n os ed , re ve rs ib il it y ≥1 2% o r p os it iv e m et h ac h ol in e t es t, e xc lu de d i f a st h m a i n ch il d h oo d. H ig h q ua li ty : w el l-de fi n ed a n d c li n ic al ly asse sse d a st h m a a n d a st h m a r em iss io n d ia g n os is , y et w id e a ge -r an ge o f en rol lm ent . 19 4 18 -7 5Y No si gn s o f: as th m a sy mp to m s M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 1 y ea r R em is si on 16 % ( + 5Y ) - L ow er I C S d os ag e a t o n se t - L es s B H R a t b as el in e - N o n as al p ol yp s - L es s b lo od n eu tr op h il s C li n ica l r em is si on , i.e . P C20 me th ac ho li ne < 4m g/m l 6% ( + 5Y ) - N ot d es cr ib ed C om pl et e r em is si on , i.e . F E V1 % p re d. > 80 % a n d P C20 me th ac ho li ne > 4m g/ ml 10 % ( + 5Y ) - N ot d es cr ib ed Ta bl e 1 : ( co nt in ued ) St ud y 36 c oh or ts C oh or t d esi gn A st hm a d ia gn os is a nd q ua lit y o f t he s tu dy N A ge Enrollme nt D efi n it io n o f a st h m a rem is si on C la ssi fi ca ti on o f rem is si on Pr op or ti on A ss oc ia te d w it h r em is si on O ut pa ti en t c oh or t of D ep ar tm en t o f Ch es t D is ea se s, A nk ar a U ni ve rs it y S ch oo l o f M ed ic in e, T ur ke y [ 33 ] R et ro sp ec ti ve co ho rt w it h 7-ye ar c li n ic al FU. Ast h m a: r eg is te re d a t o ut pa ti en t c li n ic , d ia g n os ed a cc or d in g t o t h e G IN A g u ide li ne s. H ig h q ua li ty : r ea so n ab ly d efi n ed a st h m a d ia g n os is , w el l-de fi n ed a n d c li n ic al ly asse sse d a st h m a a n d a st h m a r em iss io n d ia g n os is. 20 0 < 47 Y No si gn s o f: as th m a sy mp to m s M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 2 y ea rs R em is si on 11 % ( 53 Y ) - Y ou ng er a ge o f o n se t C li n ic al r em is si on , i .e . p os it iv e me th ac ho li ne te st 4% ( 53 Y ) - N ot d es cr ib ed C om pl et e r em is si on , i. e. n eg at iv e me th ac ho li ne te st 2% ( 53 Y ) - N ot d es cr ib ed D un ed in M ul ti -di sc ip lin ar y H ea lt h a nd D ev el op m en t S tu dy (D M H D S) , N ew Z ea la nd [19] Pro sp ect iv e c oh or t w it h 26 -y ea r c li n ic al FU. Ast h m a: q ues ti on n ai re -b as ed , w h eez in g re p or te d. M od er at e q ua lit y: d eb at ab le d efi n it io n of a st h m a d ia g n os is , c li n ic al ly a ss es se d as th m a r em is si on d ia g n os is , y et n o m ed ic at io n u se d es cr ib ed . 613 3Y No si gn s o f: w h eez e M ed ic at io n u se : n ot de fi ne d Pe ri od : 2 y ea rs R em is si on 15 % ( 26 Y ) - N ot d es cr ib ed C li n ica l r em is si on , i.e . P C20 me th ac ho li ne ≤8 m g/ m l o r re ve rs ib il it y ≥1 0% a t an y a sse ss m en t f ro m 9-21 Y 10 % ( 26 Y ) - N ot d es cr ib ed C om pl et e r em is si on , i.e . P C20 me th ac ho li ne > 8m g/ m l a n d re ve rs ib il it y < 10 % a t an y a sse ss m en t f ro m 9-21 Y 5% ( 26 Y ) - N ot d es cr ib ed Ch ild ho od A st hm a S tu dy (C A S) , U SA [3 4] Pro sp ect iv e c oh or t w it h 11 -y ea r c li n ic al FU. Ast h m a: p h ys ic ia n d ia g n os ed a n d tr ea te d f or ≥1 y ea r. M od er at e q ua lit y: r ea so n ab ly d efi n ed as th m a d ia g n os is , w el l-de fi n ed a n d cl in ic al ly a sse sse d a st h m a r em iss io n d ia g n os is , i m m u n ot h er ap y u se i n as th m a r em is si on g ro up . 85 5-12 Y No si gn s o f: as th m a sy mp to m s M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 1 y ea r R em is si on * FE V1 % p re d. > 80 % , FE V1 /F V C r at io > 80 % , m ea n P C20 m et h ac h ol in e: 0 .2 mg / ml *46% u se d a ct iv e imm un ot he rap y 15 % ( 23 Y ) - L ow er b lo od I gE - F ew er p os it iv e S P T ’s
2
Ta bl e 1 : ( co nt in ued ) St ud y 36 c oh or ts C oh or t d esi gn A st hm a d ia gn os is a nd q ua lit y o f t he s tu dy N A ge Enrollme nt D efi n it io n o f a st h m a rem is si on C la ssi fi ca ti on o f rem is si on Pr op or ti on A ss oc ia te d w it h r em is si on M el bo ur ne A st hm a S tu dy (M A S) , A us tr al ia [3 5-38 ] Pro sp ect iv e c oh or t w it h 42 -y ea r c li n ic al FU. Ast h m a: r ep or ts o f w h ee zi ng b y s el f-re p or t b y t h e p ar en t a t r ec ru it m en t. Se ve re a st h m a: ≥1 0 a tt ac ks i n 2 y ea rs be fo re a ge o r p er si st en t s ym pt om s a t a ge 10 , a cc or d in g t o G IN A g u id el in es . M od er at e q ua lit y: deb at ea bl e a st h m a de fi n it io n , w el l-de fi n ed a n d c li n ic al ly asse sse d a st h m a r em iss io n d ia g n os is , m u lt ipl e f ol lo w -u p v is it s. 26 9 7-1 0Y No si gn s o f: w h eez e M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 3 y ea rs R em is si on 20 % ( 14 Y ) 33 % ( 21 Y ) 40 % ( 42 Y ) 52 % ( 50 Y ) - M al e s ex - M il d s ym pt om s i n ch il d h oo d - N o c h il d h oo d h ay fe ve r - N o c h il d h oo d e cz em a - N o S P T p os it iv it y O ut pa ti en t c oh or t A st hm a cl in ic a t B ea tr ix -o or d ho sp it al H ar en , T he N eth er la nd s [1 8] Pro sp ect iv e c oh or t w it h 25 -y ea r c li n ic al FU. Ast h m a: r eg is te re d a t o ut pa ti en t c li n ic , ph ys ic ia n d ia g n os ed , p os it iv e h is ta m in e te st . M od er at e q ua li ty : w el l-de fi n ed a st h m a d ia g n os is , c li n ic al ly a ss es se d a st h m a re m is si on , y et p u lm on ar y m ed ic at io n w as u se d w it h in t h e r em is si on -g ro up . 181 13 -4 4Y No si gn s o f: co ug h , sp ut u m , d ys pn ea , w h ee ze an d a st h m a a tt ac ks M ed ic at io n u se : n ot de fi ne d Pe ri od : 3 y ea rs R em is si on * 40 % ( 48 Y ) - M al e s ex - Y ou ng er a ge o f o n se t - H ig h er b as el in e F E V1 - L es s B H R a t b as el in e C li n ica l r em is si on , i.e . P C20 h ist am ine ≤4 m g/ m l o r F E V1 % pr ed . ≤ 90% 25% ( 48 Y ) - N ot d es cr ib ed C om pl et e r em is si on , i.e . P C20 h ist am ine >4 m g/ m l a n d F E V1 % pr ed . > 90 % *5 % u se d p ul m on ar y me di ca ti on 11 % ( 48 Y ) - N ot d es cr ib ed M ili ta ry s er vi ce m en i n 19 87 –1 99 0 r ef er re d t o t he Ce nt ra l M ili ta ry H os pi ta l, Fi nl an d [ 39 ] Pro sp ect iv e c oh or t w it h 20 -y ea r c li n ic al FU. Ast h m a: b as ed o n m ed ic al r ec or ds ; as th m a s ym pt om s, m ed ic at io n u se , l u ng fu n ct io n a n d a ll er g y t es ts . M od er at e q ua li ty : r ea so n ab ly d efi n ed as th m a d ia g n os is , w el l-de fi n ed a n d cl in ic al ly a sse sse d a st h m a r em iss io n d ia g n os is , y et p re do m in an tl y m en . 119 19 -2 1Y No si gn s o f: as th m a sy mp to m s M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 3 y ea rs R em is si on 12 % ( 41 Y ) - N ot d es cr ib ed Ta bl e 1 : ( co nt in ued ) St ud y 36 c oh or ts C oh or t d esi gn A st hm a d ia gn os is a nd q ua lit y o f t he s tu dy N A ge Enrollme nt D efi n it io n o f a st h m a rem is si on C la ssi fi ca ti on o f rem is si on Pr op or ti on A ss oc ia te d w it h r em is si on Eu ro pe an C om m un it y R es pi ra to ry H ea lt h S ur ve y II ( EC R H SI I), E ur op e, N or th A m er ic a, O ce an ia [4 0] Pro sp ect iv e c oh or t w it h 9-ye ar o f c li n ic al FU. Ast h m a: p h ys ic ia n d ia g n os ed , a st h m a-li ke s ym pt om s a n d/ or m ed ic at io n i n t h e la st y ea r. M od er at e q ua lit y: d eb at ab le d efi n it io n of a st h m a, c li n ic al ly a ss es se d a st h m a re m is si on d ia g n os is , y et I C S u se i n su bs et o f a st h m a r em is si on s ub je ct s. 856 20 -4 4Y No si gn s o f: as th m a-l ik e sy m pt om s o r a st h m a at tac ks M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 1 y ea r R em is si on * *1 6% u se d I CS i n t he l as t 12 m on th s 12 % ( 35 Y ) - H ig h er b as el in e F E V1 - L ow es t i n cr ea se o f B M I R is k Fa ct or s f or A st hm a in A du lt s S tu dy ( R AV ), D en m ar k [ 41 ] Pro sp ect iv e c oh or t w it h 9-ye ar c li n ic al FU. Ast h m a: q ue st io n n ai re b as ed , ‘ h av e yo u e ve r h ad a st h m a? ’, c om bi n ed w it h a st h m a-li ke s ym pt om s, u se o f m ed ic at io n i n t h e l as t y ea r o r a ir fl ow ob st ruc ti on . M od er at e q ua lit y: q ue st io n n ai re b as ed as th m a d ia g n os is , w el l-de fi n ed a n d cl in ic al ly a sse sse d a st h m a r em iss io n d ia g n os is. 23 9 20 -4 4Y No si gn s o f: as th m a sy mp to m s M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 1 y ea r R em is si on 28 % ( + 9Y ) N ot d es cr ib ed Se in äj ok i A du lt-on se t A st hm a S tu dy ( SA A S) , Fi nl an d [ 42 ] Pro sp ect iv e c oh or t w it h 12 -y ea r c li n ic al FU. Ast h m a: p h ys ic ia n d ia g n os ed , o bj ec ti ve lu ng f u n ct io n m ea su re m en ts s h ow in g re ve rs ib le o bs tr uc ti on , s ym pt om s o f ast h m a. H ig h qu al it y: r ea so n ab ly d efi n ed a st h m a d ia g n os is , a st h m a r em is si on d efi n it io n 6 m on th s a n d s ti ll c ou ld h av e a d eg re e o f sy mp to m s. 203 46Y No si gn s o f: as th m a sy m pt om s, A st h m a C on tr ol T es t s co re o f 2 5 M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 6 m on th s R em is si on 6% ( 58 Y ) - H ig h er b as el in e F E V1 /F VC - L ow er b lo od I gE C li n ic al ly a ss ess ed , i.e . FE V1 % p re d. > 80 % , FE V1 /F V C > 70 % , re ve rs ib il it y < 12 % , Fe NO ≤ 20 pp b 3% ( 58 Y ) - N ot d es cr ib ed
2
Ta bl e 1 : ( co nt in ued ) St ud y 36 c oh or ts C oh or t d esi gn A st hm a d ia gn os is a nd q ua lit y o f t he s tu dy N A ge Enrollme nt D efi n it io n o f a st h m a rem is si on C la ssi fi ca ti on o f rem is si on Pr op or ti on A ss oc ia te d w it h r em is si on Lu ng D is ea se i n N or th er n Sw ed en s tu dy ( O LI N ), Sw ed en [ 43 ] Pro sp ect iv e c oh or t w it h 10 -y ea r c li n ic al FU. Ast h m a: ≥2 a st h m a a tt ac ks d u ri ng la st y ea r, r ev er si bi li ty > 15% o r P C20 me th ac ho li ne < 4m g/ m l, inc lu d in g ≥3 f ol lo w in g: 1. R ec u rr en t w h ee ze , 2 . A tt ac ks o f s h or tn es s o f b re at h , 3 . ≥ 2 as th m a p ro vo ki ng f ac to rs , 4 . N or m al br ea th in g b et w ee n a st h m a a tt ac ks o r p er io ds o f a st h m a. M od er at e q ua li ty : d eb at ab le d efi n it io n o f as th m a, w el l-de fi n ed a st h m a r em is si on , ye t i n cl ud in g s ub je ct s w it h p er si st en t w he ez e a nd me d ic ine u se. 26 7 35-66 Y No si gn s o f: re cu rre n t w h ee ze o r a tt ac ks o f sh or tn es s of br ea th M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 1 y ea r R em is si on * 6% ( +1 0Y ) - Y ou ng er a ge o f o n se t - M il d a st h m a i n a du lt h oo d - C es sa ti on o f s m ok in g C li n ic al ly a ss es se d, i.e . FE V1 % p re d. ≥8 0%* *I nc lu di ng f ew s ub je ct s w it h p er si st en t w he ez e an d m ed ic in e u se 4% ( +1 0Y ) En vi ron me nt a nd Ch ild ho od A st hm a ( EC A) St ud y i n O sl o, N or w ay [4 4] Pro sp ect iv e co hor t w it h 10 -y ea r qu es ti on n ai re F U. A st h m a: 2 o f 3 c ri te ri a: 1. S ym pt om s 0 -1 0 ye ar s, 2 . D oc to r’ s d ia g n os is , 3 . U se o f as th m a m ed ic at io n 0 -1 0 y ea rs . Lo we r q ua li ty : d eb at ab le d efi n it io n o f as th m a, a st h m a r em is si on d efi n ed b y n o c u rr en t r ec or d o f a st h m a, i n cl ud in g ch il d re n w it h d oc to r’ s d ia g n os is < 6 ye ar s. 61 6 0Y No si gn s o f: dy sp n ea , che st t ig h tne ss a nd /o r w h ee zi ng ( n o r ec or d o f cu rr en t a st h m a) M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 1 y ea r R em is si on * *i nc lu di ng c hi ld re n w it h do ct or ’s d ia gn os is < 6 ye ar s. 55 % ( 10 Y ) - F em al e s ex Tu cs on C hi ld re n’ s R es pi ra to ry S tu dy , U SA [45 ] Pro sp ect iv e c oh or t w it h 16 -y ea r c li n ic al FU. Ast h m a: r ep or ti ng p re se n ce o f w h ee zi ng >3 e pi so de s i n p re vi ou s y ea r i n a t l ea st o n su rv ey o r p h ys ic ia n d ia g n os ed . Lo we r q ua li ty : d eb at ab le d efi n it io n o f as th m a, u n de fi n ed m ed ic at io n u se i n as th m a r em is sio n. 16 6 2Y No si gn s o f: w h eez e M ed ic at io n u se : n ot de fi ne d Pe ri od : 1 y ea r R em is si on 42 % (1 3-1 6Y ) - N o o be si ty - N o e ar ly o n se t o f p ub er ty - N o c h il d h oo d s in us it is - N o p os it iv e S P T Ta bl e 1 : ( co nt in ued ) St ud y 36 c oh or ts C oh or t d esi gn A st hm a d ia gn os is a nd q ua lit y o f t he s tu dy N A ge Enrollme nt D efi n it io n o f a st h m a rem is si on C la ssi fi ca ti on o f rem is si on Pr op or ti on A ss oc ia te d w it h r em is si on Co m pr eh en si ve m ed ic al re co rd d at ab as e o f t he O lm st ed M ed ic al C en te r, US A [4 6] R et ro sp ec ti ve co ho rt w it h 10 -y ea r o f d at aba se F U . A st h m a: e xt en si ve c ri te ri a l is t i n pu bl ic at io n. Lo we r q ua li ty : r ea so n ab ly d efi n ed as th m a d ia g n os is u si ng a d at ab as e, de ba ta bl e d efi n it io n o f a st h m a re m is sio n. 117 8Y No si gn s o f: n o m ed ic al re co rd s i n d ic at in g a st h m a sy m pt om s, v is it s o r ad m is sio n s M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 3 y ea rs R em is si on 24 % ( 18 Y ) - C au ca si an e th n ic it y Po pu la ti on-ba se d s am pl e of 1 1. 04 8 n eo na te s, G re ec e [4 7] Pro sp ect iv e c oh or t w it h 18 -y ea r qu es ti on n ai re F U. A st h m a: p h ys ic ia n d ia g n os ed a n d tr ea te d a t s om e p oi n t i n l if e. Lo we r q ua li ty : d eb at ab le d efi n it io n o f as th m a, a st h m a r em is si on d efi n ed b y n o c u rr en t r ec or d o f a st h m a, i n cl ud in g ch il d re n w it h d oc to r’ s d ia g n os is < 6 ye ar s. 56 2 0Y No si gn s o f: as th m a sy m pt om s ( n o r ec or d o f cu rr en t a st h m a M ed ic at io n u se : n ot de fi ne d Pe ri od : 1 y ea r R em is si on * *i nc lu di ng c hi ld re n w it h do ct or ’s d ia gn os is < 6 ye ar s. 69 % ( 18 Y ) - F em al e s ex - N o f am il y h is to ry o f a to py - S m ok in g c es sa ti on - N o m at er n al s m ok in g du ri ng p re g n an cy . D un ed in M ul ti -di sc ip lin ar y H ea lt h a nd D ev el op m en t S tu dy (D M H D S) , N ew Z ea la nd [5] Pro sp ect iv e c oh or t w it h 23 - y ea r c li n ic al FU. Ast h m a: q ue st io n n ai re -b as ed : ‘ do y ou h av e a st h m a?’ Lo we r q ua li ty : q ues ti on n ai re -b as ed de fi n it io n o f a st h m a d ia g n os is , u n de fi n ed m ed ic at io n u se i n a st h m a rem iss io n . 176 3Y No si gn s o f: w h eez e M ed ic at io n u se : n ot de fi ne d Pe ri od : 1 y ea r R em is si on 39 % ( 18 Y ) - O ld er a ge o f o n se t - H ig h er b as el in e F E V1 - H ig h er b as el in e F E V1 /F VC - L es s B H R a t b as el in e - L es s r ev er si bi li ty 25% ( 26 Y ) - N ot d es cr ib ed
2
Ta bl e 1 : ( co nt in ued ) St ud y 36 c oh or ts C oh or t d esi gn A st hm a d ia gn os is a nd q ua lit y o f t he s tu dy N A ge Enrollme nt D efi n it io n o f a st h m a rem is si on C la ssi fi ca ti on o f rem is si on Pr op or ti on A ss oc ia te d w it h r em is si on Co m pr eh en si ve m ed ic al ev al ua ti on f or e lig ib ili ty fo r n at io na l s er vi ce be tw ee n 1 99 9 a nd 2 00 8, Isr ae l [4 8] C ro ss -s ec ti on al c oh or t w it h 3-ye ar o f d at aba se F U . A st h m a: m ed ic al r ec or ds i n d ic at in g as th m a s ym pt om s, r eq u ir in g me d ic at io n, F E V1 < 80 % a n d/ or p os it iv e ex er ci se ch al len ge te st . Lo we r q ua li ty : c ro ss -s ect io n al d es ig n , d at ab as e r ec or d d efi n ed a st h m a a n d as th m a r em is si on d ia g n os is . 26 .4 00 17Y No si gn s o f: as th m a sy mp to m s M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 3 y ea rs C om pl et e r em is si on , i.e . F E V1 a n d F E V1 / FV C > 80 % , n o d ec li n e of < 10 % i n F E V1 ex er ci se ch al len ge te st , me th ac ho li ne ch al len ge P C20 > 8m g/ ml 22 % ( 17 Y ) - N ot d es cr ib ed R an do m s tr at ifi ed c lu st er sa m pl e o f n on-M ex ic an w hi te Am er ic an ho us eh ol ds in T uc so n, U SA [7] Pro sp ect iv e c oh or t w it h 9-ye ar o f c li n ic al FU. Ast h m a: q ue st io n n ai re -b as ed ‘ h av e y ou ev er h ad a st h m a? ’, ‘ h ow m an y a st h m a at ta ck s h av e y ou h ad i n t h e p as t y ea r? ’, ‘h ow o ft en a re y ou b ot h er ed b y a tt ac ks o f sh or tn es s o f b re at h a n d w h ee zi ng ?’ Lo we r q ua li ty : q ue st io n n ai re b as ed as th m a d ia g n os is , w id e a ge -r an ge a t en ro ll m en t, d eb at ab le a st h m a r em is si on de fi n it io n , l im it ed a ss es sm en t o f a st h m a re m is si on a t f ol lo w -u p. 13 6 6-80Y No si gn s o f: as th m a at ta ck s, < 2 a tt ac ks o f sh or tn es s o f b re at h w it h w h eez in g M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 1 y ea r R em is si on 22 % (o ve ra ll ) 35% ( < 10 Y ) 65% ( 10 -1 9Y ) 28 % ( 20 -2 9Y ) 15% ( 30 -3 9Y ) 6% ( 40 -4 9Y ) 18 % ( 50 -5 9Y ) 27 % ( 60 -6 9Y ) 25% ( 70 -7 9Y ) - M il d a st h m a i n a du lt h oo d - Y ou ng er a ge o f o n se t - H ig h er b as el in e F E V1 - C o-ex is ti ng em ph ysem a O ut pa ti en t c oh or t o f P ri nc e of W al es ’s G en er al H os pi ta l D ep ar tm en t o f P ed ia tr ic s an d A lle rg y, L on do n [ 49 ] R et ro sp ec ti ve co ho rt w it h 20 -y ea r qu es ti on n ai re F U. A st h m a: r ec u rr en t ≥ 3 a tt ac ks o f pa ro xy sm al d ys pn ea w it h w h ee zi ng . Lo we r q ua li ty : d eb at ea bl e d efi n it io n o f as th m a, u n de fi n ed m ed ic at io n u se i n as th m a r em is sio n. 26 7 < 12Y No si gn s o f: as th m a sy mp to m s M ed ic at io n u se : n ot de fi ne d Pe ri od : 2 y ea rs R em is si on 28 % ( <3 2Y ) - N ot d es cr ib ed Ta bl e 1 : ( co nt in ued ) St ud y 36 c oh or ts C oh or t d esi gn A st hm a d ia gn os is a nd q ua lit y o f t he s tu dy N A ge Enrollme nt D efi n it io n o f a st h m a rem is si on C la ssi fi ca ti on o f rem is si on Pr op or ti on A ss oc ia te d w it h r em is si on Eu ro pe an C om m un it y R es pi ra to ry H ea lt h S ur ve y I ( EC R H SI ), E ur op e, N or th Am er ic a, O ce an ia [ 50 ] C ro ss -s ec ti on al c oh or t, s u rv ey -b as ed . A st h m a: qu es ti on n ai re -b as ed : ‘ h av e y ou ev er h ad a st h m a ?’ a n d ‘ h ow o ld w er e y ou w h en y ou h ad y ou r fi rs t a st h m a a tt ac k? ’ Lo we r q ua li ty : c ro ss -s ect io n al d es ig n , qu es ti on n ai re b as ed a st h m a d ia g n os is , as th m a r em is si on d efi n ed b y n o c u rr en t re co rd o f a st h m a. 1.5 58 0-4 4Y No si gn s o f: as th m a at ta ck s ( n o r ec or d o f cu rr en t a st h m a) M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 2 y ea rs R em is si on 43 % ( < 10 Y ) 34 % ( 10 -2 0Y ) 16 % ( 20 -4 4Y ) - Y ou ng er a ge o f o n se t - N eg at iv e f am il y h is to ry - L es s a cu te r es p. in fect io n s - C on ta ct w it h o ld er ch il d ren - P et s i n c h il d h oo d ho us eho ld Ta sma nia n Lon gi tu di na l H ea lt h S tu dy ( TA H S, Au st ra lia [5 1] Pro sp ect iv e c oh or t w it h 36 -y ea r qu es ti on n ai re F U. A st h m a: qu es ti on n ai re -b as ed , ‘ h av e y ou ev er h ad a st h m a? Lo we r q ua li ty : q ue st io n n ai re b as ed as th m a- a n d a st h m a r em is si on d ia g n os is. 1. 62 0 7-13Y No si gn s o f: as th m a at ta ck s ( n o r ec or d o f cu rr en t a st h m a) M ed ic at io n u se : n o ast h m a-me d ic at io n Pe ri od : 2 y ea rs R em is si on 65 % ( 46 Y ) - M al e s ex - Y ou ng er a ge o f o n se t - N o m at er n al a st h m a - N o p n eu m on ia i n ch il d h oo d Al um na e a dd re ss d at ab as e of t he B ro w n U ni ve rs it y Sc ho ol o f M ed ic in e, U SA [5 2] Pro sp ect iv e c oh or t w it h 23 -y ea r qu es ti on n ai re F U. A st h m a: p h ys ic ia n d ia g n os ed , h is to ry of ≥3 c li n ic al ly r ec u rr en t, r ev er si bl e ep is od es o f w h ee zi ng a n d d ys pn ea . Lo we r q ua li ty : d eb at ab le d efi n it io n o f as th m a, u n de fi n ed m ed ic at io n u se i n as th m a r em is sio n. 84 16 -20 Y No si gn s o f: as th m a sy mp to m s M ed ic at io n u se : n ot de fi ne d Pe ri od : 5 y ea rs R em is si on 40 % ( 40 Y ) - Y ou ng er a ge o f o n se t Th re e p op ul at io n-ba se d m ul ti ce nt re s tu di es: EC R H S-It al y, I SA YA an d G EI R D p er fo rm ed i n It al y [ 53 ] C ro ss -s ec ti on al c oh or t, s u rv ey -b as ed . A st h m a: qu es ti on n ai re b as ed , ‘ h av e yo u e ve r h ad a st h m a? ’, ‘ h ow o ld w er e yo u w h en y ou h av e y ou r fi rs t a tt ac k o f as th m a?’ Lo we r q ua li ty : c ro ss -s ect io n al d es ig n , qu es ti on n ai re b as ed a st h m a d ia g n os is , as th m a r em is si on d efi n ed b y n o c u rr en t re co rd o f a st h m a, w id e a ge -r an ge o f en rol lm ent . 3. 08 7 20 -8 4Y No si gn s o f: as th m a at ta ck s ( n o r ec or d o f cu rr en t a st h m a) M ed ic at io n u se : i n h al er s, ae ros ol s o r t ab le ts Pe ri od : 2 y ea rs R em is si on 65 % ( 0-14Y ) 36 % ( 15 -2 9Y ) 21 % ( >3 0Y ) - M al e s ex - Y ou ng er a ge o f o n se t
