Accepted Manuscript

Prognosis of new-onset asthma diagnosed at adult age

Dr Leena E. Tuomisto, MD, PhD, Pinja Ilmarinen, Hannu Kankaanranta

PII: S0954-6111(15)00155-9
DOI: 10.1016/j.rmed.2015.05.001
Reference: YRMED 4707

To appear in: Respiratory Medicine

Received Date: 19 December 2014

Revised Date: 24 April 2015
Accepted Date: 5 May 2015

Please cite this article as: Tuomisto LE, Ilmarinen P, Kankaanranta H, Prognosis of new-onset asthma
diagnosed at adult age, Respiratory Medicine (2015), doi: 10.1016/j.rmed.2015.05.001.

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 ACCEPTED MANUSCRIPT
Abstract

Background: Asthma is a common chronic disease, which can affect patients at any age. Recently,

cluster analyses have suggested that patients with asthma can be divided into different phenotypes

and that the age at the onset of the disease is a critical defining factor. The prognosis of allergic

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childhood-onset asthma is relatively well known, whereas the prognosis of adult-onset asthma

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remains unclear.

Methods: We undertook a systematic review to identify studies that evaluated the long-term

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prognosis of new-onset asthma diagnosed at adult age. Criteria used (set 1) were: 1. adult-onset

asthma, 2. physician diagnosed asthma (including objective lung-functions) < 1 year before the first

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visit, 3. follow-up time of at least 5 years, 4. objective lung function measurements used at follow-
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up and 5. not a comparative trial. Another set of studies (set 2) with less strict criteria were
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gathered.

Results: The main result of this systematic review is that the amount of evidence on the prognosis
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of new-onset asthma diagnosed at adult age is very limited. Only one study (n=250) fulfilled the
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criteria (set 1) and it suggests that the five-year prognosis of new-onset asthma diagnosed at adult

age may not be favorable, the proportion of patients being in remission was less than 5 %.
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Furthermore, six additional follow-up studies (n=964) were identified including mainly patients

with adult-onset asthma (set 2). These studies had variable endpoints and the results could not be
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combined.

Conclusion: Further follow-up studies that recruit patients with new-onset adult asthma are needed

to understand the prognostic factors in adult-onset asthma.

 ACCEPTED MANUSCRIPT
1 PROGNOSIS OF NEW-ONSET ASTHMA DIAGNOSED AT ADULT AGE

3 A Systematic review

5 Leena E. Tuomisto1, Pinja Ilmarinen1 and Hannu Kankaanranta1,2

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6

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7 Department of Respiratory Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland
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8 Department of Respiratory Medicine, University of Tampere, Tampere, Finland

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9

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11 Corresponding author:
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Dr. Leena E. Tuomisto, MD, PhD
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12 Seinäjoki Central Hospital
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13 Department of Respiratory Medicine

14 60220 Seinäjoki
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15 FINLAND
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16 Tel: +358 6 415 5375

17 Fax: +358 6 415 4989

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18 e-mail:leena.tuomisto@epshp.fi

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20 Take home message: The long-term prognosis of new-onset asthma diagnosed at adult age and

21 based on lung-function measurements remains unknown.

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23 Key-words: Asthma, phenotypes, adult-onset, remission, control, prognosis

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25

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26 Abstract

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28 Asthma is a common chronic disease, which can affect patients at any age. Recently, cluster

29 analyses have suggested that patients with asthma can be divided into different phenotypes and that

30 the age at the onset of the disease is a critical defining factor. The prognosis of allergic childhood-

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31 onset asthma is relatively well known, whereas the prognosis of adult-onset asthma remains

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32 unclear.

33 We undertook a systematic review to identify studies that evaluated the long-term prognosis of

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34 new-onset asthma diagnosed at adult age. Criteria used (set 1) were: 1. adult-onset asthma, 2.

35 physician diagnosed asthma (including objective lung-functions) < 1 year before the first visit, 3.

36
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follow-up time of at least 5 years, 4. objective lung function measurements used at follow-up and 5.
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37 not a comparative trial. Another set of studies (set 2) with less strict criteria were gathered.
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38 The main result of this systematic review is that the amount of evidence on the prognosis of new-

39 onset asthma diagnosed at adult age is very limited. Only one study (n=250) fulfilled the criteria
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40 (set 1) and it suggests that the five-year prognosis of new-onset asthma diagnosed at adult age may
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41 not be favorable, the proportion of patients being in remission was less than 5 %. Furthermore, six

42 additional follow-up studies (n=964) were identified including mainly patients with adult-onset
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43 asthma (set 2). These studies had variable endpoints and the results could not be combined. Further

44 follow-up studies that recruit patients with new-onset adult asthma are needed to understand the
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45 prognostic factors in adult-onset asthma.

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47 250 words

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49

50

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51 INTRODUCTION

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53 Asthma is a common chronic disease that can affect patients at any age with varying severities.

54 Until the last decade, asthma has been considered mainly as a single allergic, eosinophilic, TH2-

55 mediated and glucocorticoid-responsive disease [1, 2]. However, more recently, it has become

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56 apparent that a vast amount of heterogeneity exists among asthma patients. Cluster analyses have

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57 suggested that patients with asthma can be divided into different phenotypes [3-5]. In all of these

58 studies, the age at disease onset was found as a key differentiating factor between phenotypes.

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59 Atopy and allergy are generally associated with early- or childhood-onset disease with varying

60 severities. In contrast, later- or adult-onset disease is generally less associated with allergy and

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phenotypes such as late-onset eosinophilic (often severe), exercise-induced, obesity-related,
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62 neutrophilic and smooth-muscle-mediated (paucigranulocytic) asthma have been proposed [6, 7]. In
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63 addition, comorbidities and confounders such as smoking, hormonal influences, infection and

64 occupational exposures can influence the underlying immunoinflammatory processes [6, 8-10].
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65 While many of these are not short-term and momentary incidents but rather cumulative exposures
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66 after many years, one may hypothesize that their contribution is larger in late-onset asthma and

67 could thus also contribute to the outcome of the disease.

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68 There is no uniform definition for the age that separates adult- or late-onset asthma from child- or

69 early-onset asthma; it varies between 12-20 years and in some studies late-onset asthma refers to
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70 asthma diagnosed at age of 65 or above [9]. A cut-point of 18-19 years has often been used in

71 epidemiological studies evaluating the incidence of adult-onset asthma [11].

72 As asthma has been considered mainly as a single allergic disease, a vast majority of asthma studies

73 have focused on allergic asthma usually starting in childhood [6, 9, 12]. The prognosis of allergic

74 childhood-onset asthma is relatively well known [13-16], and may be better than the prognosis of

75 adult-onset asthma. The symptoms in the first 3 years of life and at school age are often transient
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76 and approximately 3 of 4 asthmatic patients will outgrow their asthma by mid-adulthood [15].

77 Remission was 3.7 times as likely with childhood-onset (onset < 10 years) asthma and >1.3 times as

78 likely with adolescent-onset (onset 10-20 years) asthma compared with adult-onset asthma (onset >

79 20 years) [16]. Severity of symptoms and sensitization seems to be inversely associated with

80 remission i.e. increase risk of persistence [15]. Patients with severe asthma beginning at adult age

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81 had a three-fold greater risk of persistent airflow limitation when compared to patients with severe

asthma beginning before 18th birthday [17]. Also subjects with late-onset asthma (onset > 12 years)

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82

83 have lower lung function despite shorter duration of the disease than those with early-onset severe

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84 disease [18].

85 Variability of the disease phenotypes complicates generalizability of the disease outcomes from

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childhood asthma studies to the adult-onset phenotypes. For example, the response of allergic
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87 childhood asthma to inhaled glucocorticoids is generally very good [19], whereas in adults different
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88 add-on therapies are often needed [20, 21] and the therapeutic response still remains insufficient,

89 especially in some phenotypes [22, 23].

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90 The characterization of phenotypes or endotypes of asthma is still far from finished [24, 25]
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91 However, a critical factor defining phenotypes has been characterized, i.e. the age at the onset of the

92 disease. As the studies in which these novel phenotypes were characterized are published relatively
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93 recently (i.e. since 2008), there has not been enough time for long-term follow-up studies to be

94 conducted. In view of the clinical relevance and scarcity of data on these phenotypes, we conducted
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95 a systematic literature review to identify studies that evaluated the prognosis of adult-onset asthma,

96 a common feature to the other phenotypes except the allergic childhood-onset asthma.

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98 MATERIALS AND METHODS

99 Search strategy

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100 We carried out a systematic electronic literature search in Pubmed (1950-May 2013) according to

101 the PRISMA statement [26]. The following keywords were used: (("asthma"[MeSH Terms] OR

102 "asthma"[All Fields]) AND ("adult"[MeSH Terms] OR "adult"[All Fields]) AND onset[All Fields])

103 AND ("prognosis"[MeSH Terms] OR "prognosis"[All Fields]) OR follow-up[All Fields]) in May

104 20th, 2013. In addition to this search we surveyed other relevant studies fulfilling these criteria.

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105 Only papers in English language were evaluated. The titles, abstracts and full articles, when

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106 necessary, were reviewed separately by two reviewers (LET and HK). All identified papers were

107 assessed independently by these two reviewers and disagreements about their eligibility were

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108 resolved by consensus among all authors. Data on the inclusion criteria and characteristics of the

109 patients in the beginning of study and the results of the follow-up were extracted from the studies.

110
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111 Inclusion criteria
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112 For this systematic review, the following inclusion criteria (set 1) of studies were used 1) the study

113 population consisted only of patients with adult-onset asthma (onset ≥ 18 years) 2) physician-
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114 diagnosed asthma (including objective lung function measurement) less than one year before the
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115 first visit 3) follow-up time of at least five years 4) objective lung function measurements used at

116 follow-up and 5) not a comparative clinical trial.

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117 To obtain a larger view on the prognosis of adult asthma, another set of studies was tabulated with

118 less strict inclusion criteria. The inclusion criteria for these studies (set 2) were as follows: 1)
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119 patients with adult-onset asthma included in the study population 2) physician-diagnosed asthma

120 (including objective lung function measurement) 3) follow-up time of at least five years 4) objective

121 lung function measurements used at follow-up.

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123 Outcome measures

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124 Assessment of prognosis of asthma may be based on measurements on asthma remission, severity

125 or lung function. Definition of asthma remission varies [13, 27, 28]. Most often, remission is

126 defined as a period of at least one year without symptoms of asthma and without any usage of

127 asthma medication. Additionally changes in lung function and questionnaires of health-related

128 quality of life have also commonly been used as outcome variables in long-term studies. The level

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129 of airway inflammation has been determined by measuring bronchial hyperreactivity (BHR) and/or

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130 exhaled nitric-oxide (NO) and absence or low level of either or both has been suggested to indicate

131 true remission of asthma [29]. In long-term follow-up studies, changes in disease severity or asthma

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132 control based on Global Initiative for Asthma (GINA) reports [30, 31] have been commonly used.

133 As the outcomes for prognosis vary, we included studies with all kinds of endpoints as long as they

134
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provided also objective lung function data and the follow-up time was at least five years. For sets 1
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135 and 2 the primary outcome variable was the percentage of asthmatic patients being in remission.
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136 Other possible outcomes such as mortality, severity or control of asthma and annual decline of

137 forced expiratory volume in one second (FEV1) were collected. No meta-analysis was planned as it
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138 was expected that the studies have different follow-up times (sets 1 & 2) and the percentage of
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139 patients with adult-onset asthma differs between studies (set 2) and the data could not be combined.

140 Thus, studies and data included in the set 2 should be considered as an explorative analysis rather
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141 than a definite result.

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142
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143 RESULTS

144 Study selection

145 The flow of studies found by the search strategy according to the PRISMA statement [26] is shown

146 in Figure 1. A total of six studies were included for the review; one study with a total of 250

147 patients followed fulfilled the inclusion criteria for set 1 [32] and 6 studies with a total 964 of

148 patients followed fulfilled the inclusion criteria for set 2 [28,33-37].
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149

150
Records identified through PubMed database Records identified through searching
151screening using MeSH-terms “adult-onset” or publications, reference lists and other sources
“adult”, “asthma”, “prognosis” or “follow-
152 Figure 1 up”
N = 490 N = 472

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Records screened after Not relevant studies excluded
based on study title and/or

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duplicates were removed
abstract
N=863 N = 840

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Not relevant articles excluded

Review, not original study N=3

U Not mainly adult-onset asthma N=1

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Full text articles screened
N = 23 Not a follow-up study N=3

Follow-up time < 5 years N=1

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No objective lung function

measurements available N=6
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Other reasons N=3

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Studies included in the

review N = 16
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N=7
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Set 1 Set 2
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Not comparative clinical trial Not comparative or comparative clinical trial

Only adult-onset asthma, Follow-up time Adult-onset asthma included, Follow-up time ≥
≥ 5 years, Physician diagnosed asthma, 5 years, Physician diagnosed asthma, Asthma
Asthma diagnosed ≤ 1 year, Objective diagnosed < or > 1 year, Objective lung
lung function measurements available function measurements available

N=1 N=6

7 Figure 1. PRISMA flow diagram.

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153 Studies evaluating the long-term (≥ 5 years) prognosis of new-onset asthma at adult age (set 1)

154 One prospective study on the outcome of adult-onset asthma fulfilled all the search criteria for set 1

155 [32]. All patients (n=473) had contacted health care due to respiratory symptoms during 1995-1999.

156 Eighty nine percent (n=419) were invited to clinical examinations including a structured interview,

157 lung-function tests, metacholine test and skin prick test. Diagnosis was based on symptoms and

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158 physiologically verified by bronchial variability demonstrated either by metacholine test,

159 spirometry or peak expiratory flow follow-up. All patients included had asthma with onset of

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160 symptoms during previous 12 months before the diagnosis. Chronic obstructive pulmonary disease

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161 (COPD), but not smoking, was an exclusion criterion and 22 % of the patients were smokers at visit

162 2. Basic details of the final study population (n=309) are shown in Table 1A.

163
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Response rate at visit 2 was 81% (n=250). Mean follow-up time of the patients was 5,8 years. Main
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164 outcomes of the study were remission of asthma and changes in severity (Table 1B). Remission was

165 defined as no wheeze, no asthma attacks and no asthma medication usage during the last year. More
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166 strict definition for remission included also FEV1 > 80% and no BHR (PC20 > 8 mg / ml) as
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167 additional criteria. Grading of severity followed the GINA 2000 classification [30].
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168
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169 Table 1A Details of the study populations at visit 1 in studies evaluating the prognosis of new-onset asthma diagnosed at adult age.

Study Patients Age at asthma Child-onset Age Duration of asthma Inclusion criteria at visit 1 Exclusion
(n) onset (< 18 years) (range) before first visit (objective basis of criteria

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(range) asthma (%) physician diagnosed
asthma)
≥ 1 positive test for

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Rönmark 2007 bronchial variability
309 19-60 years 0 20-60 years ≤ 1 years COPD#
[32] (metacholine challenge,

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PEF follow-up, spirometry)
#
170 Exact definition of COPD not reported, PEF = peak expiratory flow

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171

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172 Table 1B Result of the follow-up in studies evaluating the prognosis of new-onset asthma diagnosed at adult age.

Study Average Patients Current Outcome variables Factors related to outcome

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follow- (response smokers
up time rate) at visit

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(SD) 2
Remission# Strict Severity grading* Predictors of Predictors of

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definition of remission severe asthma
remission¶
mild intermittent 9% → 21% Higher mean FEV1% Low FEV1 at
Rönmark 70
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250 mild persistent 16% → 30% at visit 1, absence of visit 1 and
2007 months 22% 4.8% 3.0%
(81%) moderate persistent or severe rhinitis, non-smoker, weight gain at
[32] (17)
75% →49% negative SPT visit 2
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#
173 No wheeze, asthma attacks and asthma medication usage during the last year ¶No wheeze, asthma attacks and asthma medication usage during the last year and FEV1 > 80%
174 and no bronchial hyperreactivity (PC20 > 8mg/ml), *According to GINA 2000 [30], SPT= skin prick test
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175 In total, 4.8% of the patients with asthma were in remission with a remission rate of 0.8/100/year.

176 More strict criteria of remission were fulfilled only by 3% of asthmatics. Higher mean FEV1% at

177 visit 1, absence of both smoking and rhinitis and negative skin prick test were more common among

178 remitters. Among those with active asthma 65% were using inhaled steroids. Age, sex or BMI were

179 not significantly different between those in remission and those with active disease.

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180 Severity grade according to GINA 2000 guideline [30] varied considerably between the visits. The

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181 percentage of patients classified as having mild intermittent or mild persistent asthma increased,

182 whereas the percentage of patients having either moderate or severe asthma decreased (Table 1B).

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183 Factors that predicted severe asthma were low FEV1 at visit 1 and weight gain during the study

184 period [32]. No data was reported on mortality, asthma control or annual FEV1 decline.

185
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186 Studies evaluating the prognosis of asthma diagnosed mainly at adult age (set 2)
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187 The basic details and the main results of the six studies included in the set 2 are summarized in

188 Tables 2A and B. None of these studies were based only on questionnaires. Three of the studies are
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189 presented in Tables 2A and B as two separate subgroups for clarity (33-35) because the data in the
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190 original articles was presented in such manner and was best extracted for the subgroups.

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192

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194

195

196

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197 Table 2A Details of the study populations at visit 1 in studies evaluating the prognosis of asthma diagnosed mainly at adult age.
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Study Follow- Number of Age at Child-onset Age at Duration of Inclusion criteria (objective Exclusion criteria
(subgroup) up years subjects asthma (<18 years) visit 1 asthma, years basis of physician diagnosed
(range) visit1/visit2 onset asthma (%) years (range) before asthma)

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(response years (range) visit 1
rate %) (range)
Almind 1992 [33]
343/144 Possibly none Spirometry and reversibility
39¶ 52¶ 13¶

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(Non-allergic) 7 NR
(NR)# (NR) test, PEF-follow-up§
Almind 1992 [33]
343/69 Possibly none Spirometry and reversibility

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(Allergic) 7 22¶ 36¶ 14¶ NR
(NR)# (NR) test, PEF-follow-up§
Cibella 2002 [35]
55/55 Possibly 5.5+
31¶ 40¶

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(Male) 5 ATS 1987* Smoking
(100) (NR) (1-44)

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Cibella 2002 [35]
87/87 Possibly 8.8+
(Female) 5 31¶ 42¶ ATS 1987* Smoking
(100) (NR) (1-45)
Prior anti-inflammatory

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Kauppinen 2011 162/122 43¶& None 43¶&
10 ≤1 ATS 1987* medication, COPD****,
[36] (75) (18-79) (0) (18-79)
smoking >10 pack-years

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Panhuysen 1997 4+ Included 24+ 14 Age ≤ 45yr, symptoms*, Specific respiratory or
25 426/181
[28] (0-39) (NR) (13-44) (0-42) positive histamine challenge** other serious disease

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COPD****, specific
Porpodis 2009 282/163 Included 26¶
12 NR 4.6a ATS 1987* and GINA 1992*** respiratory or other
[37] (58) (28)∫ (6-55)
serious disease
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Ulrik 1992 [34]
10 180/94 Included Spirometry and reversibility
(Intrinsic) NR 44+ 23+ NR
(9-12) (NR)# (NR) test
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Ulrik 1992 [34]

10 180/49 Included Spirometry and reversibility
(Extrinsic) NR 31+ 23+ NR
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(9-12) (NR)# (NR) test

¶
199 NR = not reported, # response rates to the subgroups were not reported, mean, PEF = peak expiratory flow, §in 8 % of the patients, no objective lung function measurement
200 basis for diagnosis is met; diagnosis based on characteristic history of asthma, +median, *According to American Thoracic Society (ATS) 1987 [38], &See reference [39], **At
∫
201 diagnostic phase, the objective basis for diagnosis remains unknown, percentage of those with onset of asthma at age < 16 years, ***According to GINA 1992 [40],
202 ****Exact definition of COPD not reported.
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203

204 Table 2B Results of the follow-up in studies evaluating the prognosis of asthma diagnosed mainly at adult age

Study Current Outcome variables Factors related to outcome

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(subgroup) smokers at
visit 2 (%)
Remission Mortality Asthma control& / FEV1 decline
Severity&

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(%) (ml/year)
Almind 1992 [33] ¶
75# NR Men: 1.55 NR 89
(Non-allergic)

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(1.12;1.98) Death (males): pulmonary reasons
¶
Women 1.24 FEV1 decline: smoking
Almind 1992 [33]
75# NR (0.69;1.86) NR 95
(Allergic)

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Cibella 2002 [35]

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0 NR NR NR
(Male) FEV1 decline: steeper in younger male subjects.
41 FEV1 variability was associated with increased
Cibella 2002 [35] rate of FEV1 decline.
0 NR NR NR

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(Female)

Kauppinen 2011 Controlled 24% Better asthma control: better PEF and health
8 NR NR NR

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[36] Uncontrolled 25% related quality of life at visit 1

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Panhuysen 1997 Remission: younger age and less severe
27 11§ NR NR NR
[28] obstruction at visit 1
mild 58% → 66%
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Porpodis 2009 Positive changes in severity: younger age, male,
36 NR NR moderate 28% → 27% NR
[37] rhinitis, less smoking
severe 14% → 7%
Ulrik 1992 [34] 50 FEV1 decline: age, reversibility at visit 1 and
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21 NR NR NR
(Intrinsic) (45;62)+ high blood eosinophils
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FEV1 decline: age, inversely with FEV1,

Ulrik 1992 [34] 22.5
16 NR NR NR FEV1/VC at enrollment and need for
(Extrinsic) (1;32)+
corticosteroids
¶
205 NR=not reported, PEF = peak expiratory flow, VC = vital capacity, #Non-allergic and allergic groups are combined, standard mortality rate (95% CI), &asthma control
206 according to GINA 2008 [31] and asthma severity according to GINA 1992 [40], +95% confidence interval (CI)
§
207 no symptoms, no bronchial hyperreactivity (PC20 > 16 mg/ml), FEV1 > 90%
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208 One study in set 2 [36] definitely included only patients with both adult-onset and new-onset

209 asthma. In the other studies, child-onset patients were included or time of onset remained unclear

210 and the mean/median duration of asthma before visit 1 varied between 4.6 and 23 years and at

211 individual level between 0 and 45 years. Thus, all these studies cannot be considered to represent

212 patients with new-onset asthma. In all study patients were referred to pulmonary clinics due to

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213 respiratory symptoms and the diagnosis of asthma or inclusion criteria to the follow-up included

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214 objective pulmonary function measurements and changes typical to asthma. Study of Kauppinen

215 and co-workers [36] most clearly represented the target population of this review, i.e. new-onset

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216 asthma beginning at adult age.

217 In the longest follow-up study of 25 years, population consisted largely of child-onset patients and

218
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only patients below 45 years were included [28]. Eleven percent of the patients were in remission as
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219 defined by strict criteria based on clinical evaluation (no symptoms, no BHR, FEV1 > 90%).
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220 Remission was predicted by younger age and less severe obstruction at visit 1. In the other studies,

221 natural course of asthma was measured by different outcome variables such as mortality, asthma
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222 control or changes in asthma severity, or annual decline in FEV1. Increased mortality among men
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223 was reported in one follow-up study of heavily smoking population [33] and was considered to be

224 mainly of pulmonary reasons. Asthma control was the outcome in one study, only 24 % of the
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225 patients were found to be in control after ten years of follow-up [36]. In the study of Porpodis et al.,

226 asthma turned out to be milder after 12 years of follow-up in the majority of patients (see Table 2B)
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227 [37]. Rate of lung function decline was the only or one of the outcome variables in three studies

228 [33-35]. An accelerated decline in FEV1 was seen in the group of intrinsic but not in extrinsic

229 asthma [34]. Controversially, no difference was found between the outcomes in another study [33]

230 comparing patients with allergic and non-allergic asthma, where accelerated annual FEV1 decline

231 was associated with smoking. Taken together, factors related to better outcome at visit 2 (i.e. after

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232 follow-up) in at least two different studies were younger age, non-smoking (or less smoking) and

233 better pulmonary function level at the visit 1.

234

235 DISCUSSION

236 Age at asthma onset seems to be a major factor in differentiating phenotypes of asthma. We

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237 undertook a systematic review to identify studies that evaluated the long-term prognosis of new-

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238 onset asthma diagnosed at adult age. Criteria used were physician-diagnosed lung function based

239 asthma, diagnosed at adult age, not more than one year earlier, and followed at least for five years.

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240 The main result of this systematic review is that the amount of evidence on the prognosis of new-

241 onset asthma diagnosed at adult age is very limited. Only one study (n=250) fulfilled all the

242
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inclusion criteria measuring the prognosis of new-onset asthma diagnosed at adult age after
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243 relatively short period of follow-up (5.8 years) [32]. This study suggests that the prognosis of adult-
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244 onset asthma is not good, only 3-4.8% of patients being in remission. Furthermore, an explorative

245 analysis of six other studies including patients with adult asthma suggested that the prognosis of
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246 these patients may not be favorable [28,33-37].

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247

248 Methodological issues

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249 There are a number of methodological issues that need to be addressed with regard to this review.

250 Firstly, one may question, whether all relevant studies were included. To overcome this problem,
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251 we used very broad-range search terms such as “asthma”, “adult”, “prognosis” or “follow-up” and

252 did not restrict the search to newer phenotype-specific term such as “adult-onset”. In addition, we

253 went through a vast number of relevant literature in the field. Thus, we believe that no significant

254 studies remained undetected.

255 Cross-sectional trials were excluded because they only describe the current situation among a group

256 of asthmatic patients, but usually do not provide enough information on factors such as precise age
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257 of asthma onset or duration of the disease, which are critical determinants affecting the probability

258 of remission. In addition, they do not report other aspects (e.g. smoking, atopy, lung function, etc)

259 at the time of the disease onset. In addition, the time from diagnosis varies making it difficult to

260 assess the prognosis at a certain time-point. Furthermore, most of the cross-sectional studies are

261 based on self-reported asthma without reporting the diagnostic grounds i.e. objective lung function

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262 tests.

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263 In this systematic review, we searched for studies reporting the prognosis of new-onset asthma

264 diagnosed at adult age. We chose an arbitrary definition of ≥ 18 years to represent adult or adult-

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265 onset asthma, while there is no uniform definition of the cut-off age of adult-onset asthma either

266 evidence how the prognosis of different age groups differ. According to the recent GINA report

267
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[41] the diagnosis of asthma should be based on the history of characteristic symptom patterns and
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268 evidence of variable airflow limitation. For this reason, we limited our search to studies in which
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269 asthma diagnosis was based on both symptoms and objective lung function assessments. In many

270 follow-up studies asthma prognosis has been evaluated only by questionnaires [42, 43]. In the
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271 present review, requirement for objective lung function measurements also at follow-up visit was
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272 required for several reasons. Firstly, the current GINA report [41] advocates that determination of

273 risk factors of poor asthma outcomes also includes assessment of lung function. Secondly, asthma
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274 severity has been shown to be biased when based on self-report [44] and patients’ perception of

275 their asthma control has been shown to differ from the actual control [45, 46]. Patients considered to
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276 be in remission may still have obstruction and hyperresponsiveness [47]. Thirdly, approximately 10

277 - 30% of asthmatics in different countries smoke [48, 49]. Long-term smoking may lead to the

278 development of simultaneous COPD. In COPD, the quality of life does not correlate with lung

279 function [50] leading to a possibility that the patient is presenting with mild severity or good asthma

280 control, even though his / hers lung function is severely impaired. Taken together, we consider that

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281 the criteria used in the present systematic review are accurate enough to objectively answer the

282 questions of the clinician on the prognosis of new-onset asthma diagnosed at adult age.

283

284 Main findings

285 In this review only one prospective study fulfilled the main inclusion criteria evaluating the long-

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286 term (≥ 5 years) prognosis of new-onset asthma at adult age. Rönmark et al reported the long-term

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287 outcome of physician-diagnosed adult-onset asthma almost six years after diagnosis [32]. Less than

288 five percent of patients reached remission. Mild asthma at visit 1 with absence of rhinitis, atopy and

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289 smoking predicted remission. Even though remission was rare six years after diagnosis, asthma

290 severity declined, which was explained by recent onset of asthma and introduction of anti-

291 inflammatory treatment.

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292 In studies included in the set 2, evaluating the prognosis of asthma diagnosed mainly at adult age,
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293 remission of asthma was determined in one study. In this study, one tenth of the patients was found

294 to be in remission (Tables 2A and B) [28]. However, a large part of the patients had child-onset
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295 asthma; median age at onset was four years [28] and thus the study does not represent adult-onset
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296 asthma very well. In a very recent study, adult asthma patients were followed for seven years with a

297 remission rate of 11% [51]. Younger age, earlier onset, atopy, allergic rhinitis and fewer
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298 comorbidities predicted remission. However, there seems to be a bias in the patient selection; 90%

299 were females and smoking history was exceptionally rare (81% never smokers). In the study of
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300 Porpodis et al., the severity of asthma turned out to be milder after 12 years of follow-up but 34% of

301 the patients were still considered to have either moderate or severe asthma [37]. In a Finnish study

302 [36] of new-onset asthma diagnosed at adult age, 76% of asthmatics were not in control after ten

303 years of follow-up. In three out of six studies the main or the only outcome variable was the annual

304 FEV1 decline which varied between 25 and 95 ml/year [33-35]. With regards to lung-function, the

305 outcome of adult-onset asthma seems to be worse when compared to the outcome of early-onset
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306 disease [52]. The studies included in this review are in line with other reports suggesting that

307 patients with later asthma onset tend to have a worse lung function in follow-up [17, 18]. Finally,

308 increased mortality among males was reported in a Danish study of heavily smoking population

309 [33] which was suggested to be mainly of pulmonary reasons.

310 Taken together, the current systematic review, with a very limited amount of evidence, indicates

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311 that the five-year prognosis of new-onset asthma diagnosed at adult age is not favorable,

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312 approximately half of them is having moderate to severe asthma and the proportion of patients

313 being in remission is less than 5%. Furthermore, evidence from the six follow-up studies including

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314 mainly patients with adult-onset asthma usually diagnosed several years earlier supports these

315 findings.

316
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317 Open questions and future research directions
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318 All the follow-up studies included in this systematic review were carried out before identification of

319 the currently recognized phenotypes [3-6]. Two of the studies [33, 34] evaluating the prognosis of
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320 adult asthma separated the allergic and non-allergic phenotypes of asthma providing information on
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321 the natural course of those features. The results were controversial which may partially be explained

322 by different proportion of smokers included in these populations [33, 34]. The current systematic
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323 review did not find any evidence to evaluate the prognosis of the described phenotypes [3-5] such

324 as late-onset eosinophilic, exercise-induced, obesity-related or neutrophilic asthma. Some of the

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325 adult-onset asthma phenotypes show poor response to traditional treatment modalities [7], which

326 might explain the low remission rate and poor outcome in the studies of this review. Stability of

327 phenotypes in adult-onset asthma is uncertain, only few follow-up studies have been carried out so

328 far [53, 54].

329 We conclude that based on this systematic review our knowledge on the natural course of adult-

330 onset asthma is very limited. Few studies, so far, have unveiled adult-onset asthma as a chronic
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331 disease that rarely remits. In contrast, many studies exist on prognosis of childhood-onset asthma

332 indicating good prognosis [15, 16]. Further follow-up studies that recruit patients with new-onset adult

333 asthma are needed to understand the prognosis and prognostic factors of adult-onset asthma.

334 Recruitment of cohorts of patients with new-onset asthma at the diagnostic phase is important to be

335 able to obtain data for the identification of clinical features that are related to better or worse

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336 outcomes. In addition, outcomes such as remission, asthma control and severity, mortality and

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337 decline in lung function should be studied in a more systematic manner. To date, there is no data to

338 show the importance of any inflammatory marker on asthma control in adult-onset asthma when

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339 measured either at the diagnostic or follow-up phase. Furthermore, the future cohort studies should

340 be planned to include more than evaluation of asthma at a single time-point. The symptoms of

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asthma vary over time and in intensity and exacerbations, treatment issues and comorbidities
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342 contribute to the use of healthcare services as well as to individual burden. Thus, it will be
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343 important to perform follow-up studies, which not only compare two single time-points, but also

344 assess and gather data from the time in between as an objective marker of asthma burden and
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345 morbidity.
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346

347 Supporting information

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348 Checklist S1. PRISMA checklist. (DOC)

349
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350 SUPPORT STATEMENT

351 This work was supported by the Finnish Anti-Tuberculosis Association Foundation (Helsinki,

352 Finland), Tampere Tuberculosis Foundation (Tampere, Finland), the Competitive State Research

353 Funding of Pirkanmaa Hospital District (Tampere, Finland) and the Medical Research Fund of

354 Seinäjoki Central Hospital (Seinäjoki, Finland). None of the sponsors had any involvement in the

355 planning, execution, drafting or write-up of this systematic review.

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506

507

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508 Figure legends

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509 Figure 1. PRISMA flow diagram.

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YRMED-D-14-00853

PROGNOSIS OF NEW-ONSET ASTHMA DIAGNOSED AT ADULT AGE

A Systematic review
by Tuomisto, Ilmarinen and Kankaanranta

HIGHLIGHTS

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• Our systematic review highlights that the amount of evidence on the prognosis of new-onset
asthma diagnosed at adult age is very limited

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• Only one study fulfilled the study criteria of adult-onset asthma
• This study suggests that the proportion of patients being in remission five years after

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diagnosis was less than 5 %
• Six other studies with mixed population of child- and adult-onset asthma were included but

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variable outcomes made it difficult to compare the results
• Further follow-up studies are needed to understand the prognosis of adult, new-onset asthma
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Conflicts of interest

Dr. L. Tuomisto reports personal fees and non-financial support from Leiras-Takeda, personal fees

and non-financial support from Mundipharma, personal fees and non-financial support from

Novartis, and non-financial support from Boehringer-Ingelheim, outside the submitted work. Pinja

Ilmarinen declares that she has no conflicts of interest in relation to this protocol. Dr. H.

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Kankaanranta reports personal fees and non-financial support from Almirall, personal fees from

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AstraZeneca, personal fees from Chiesi Pharma AB, personal fees from GlaxoSmithKline, personal

fees and non-financial support from Boehringer-Ingelmheim, personal fees from Leiras-Takeda,

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personal fees from MSD, personal fees from Novartis, personal fees from Mundipharma, personal

fees from Medith, personal fees from Resmed Finland and non-financial support from Intermune,

outside the submitted work.

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