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A meta-analysis of baseline characteristics in trials on mite allergen avoidance in asthmatics: room for improvement

A meta-analysis of baseline characteristics in trials on mite allergen avoidance in asthmatics:... Background: Evidence regarding the clinical effectiveness of mite allergen avoidance for the treatment of asthma is lacking. In previous meta‑analyses on mite allergen control, the baseline data were not discussed in detail. This study updates and extends the existing Cochrane review by Gøtzsche and Johansen (Cochrane Database of Systematic Reviews, 2008, Art. No: CD001187), with a focus on baseline asthma outcomes and allergen exposures. Methods: We used the existing trials in the original Cochrane review and included newly published studies. The baseline data for the mite allergen load from the mattress, the standardized asthma symptom score (ASS), the forced expiratory volume in 1 s percentage of predicted (FEV %pred.), and the histamine provocative concentration causing a 20% drop in FEV (PC ) were extracted. First, the mean values of the outcomes were calculated. The influence of the 1 20 mite allergen load was examined with a random‑ effect meta‑regression using the Metafor package in R. Results: Forty‑five trials were included; 39 trials reported strategies for concurrent bedroom interventions, and 6 trails reported strategies for air purification. The mite allergen load ranged from 0.44 to 24.83 μg/g dust, with a mean of 9.86 μg/g dust (95% CI 5.66 to 14.05 μg/g dust, I = 99.8%). All health outcomes showed considerable heteroge‑ neity (standardized ASS mean: 0.13, 95% CI 0.08 to 0.18, I = 99.9%; FEV %pred. mean: 85.3%, 95% CI 80.5 to 90.1%, 2 2 I = 95.8%; PC mean: 1.69 mg/mL, 95% CI 0.86 to 2.52 mg/mL, I = 95.6%). The covariate mite allergen load did not significantly influence health outcomes. Discussion: This meta‑analysis shows that mite avoidance studies are characterized by the inclusion of patients with rather mild to moderate asthma and with varying and sometimes negligible levels of allergen exposure. Future stud‑ ies should focus on patients with severe asthma and increased levels of allergen exposure. consensus in this research field. This lack of consensus Introduction on the effectiveness of mite allergen avoidance is sum - House dust mite-allergic asthma is a prevalent disorder marized by a Cochrane review [7], which was unable to of the lower airways that affects hundreds of millions of demonstrate any clinical benefit of avoidance measures people worldwide [1, 2]. The immediate allergic reac - designed to reduce mite exposure in 55 trials. In addi- tion to mites [3] suggests that controlling exposure to tion to the substantial meta-analysis by Gøtzsche and the antigen could be an appropriate first-line therapy for Johansen [7], several other meta-analyses on mite aller- the treatment of mite-allergic asthma. However, guide- gen avoidance for the treatment of asthma report vary- lines and reviews provide ambiguous recommendations ing results for the effectiveness of avoidance [8–11]. The for mite allergen avoidance [4–6], reflecting a lack of variation in the complex interventions as well as the het- erogeneity of several study outcomes urges further explo- *Correspondence: f.vanboven5@gmail.com ration [12, 13]. Department of Internal Medicine, Section of Allergology & Clinical The baseline data are a not well reported in the meta- Immunology, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands analyses on the effectiveness of mite allergen control. Full list of author information is available at the end of the article © The Author(s) 2020. 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The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. van Boven et al. Clin Transl Allergy (2020) 10:2 Page 2 of 12 These baseline characteristics provide attributes for cific IgE antibodies (by Gøtzsche and Johansen [7]). evidence-based decision making in the daily practice of The asthma assessment included a history of asthma clinicians [14]. First, in the case of asthma, baseline char- symptoms and a pulmonary function test. acteristics are of particular interest because they reflect • The intervention was designed to reduce the expo - the level of asthma control and the asthma severity of sure to mite antigens in the home for the treatment the patient [15]. Studies still highlight the disparities of asthma (mono-trigger therapy by tertiary avoid- between the asthma severity results between clinical tri- ance). This could include one of the following (by als and those reported from patient practice [16]. Treat- Gøtzsche and Johansen [7]): able traits have been defined in severe asthma patients and may be associated with future exacerbation risk [17]. a. Chemical (acaricides); Second, baseline environmental aspects can influence the b. Physical (mattress covers, vacuum-cleaning, treatability of allergen-induced asthma [18]. Third, base - heating, ventilation, freezing, washing, air-filtra - line characteristics provide statistical independence in tion, and ionisers); the asthma outcomes of interest. This quantitative factor c. A combination of chemical and physical. relates to the possible relationship between exposure and asthma outcomes; for example, in the paradigm of the The flow chart of the updating search was made by use bedding site introduced in the 1990s [19]. In such cases, of the PRISMA diagram [22]. the quantitative evaluation of the clinical effectiveness of the treatment of asthma in a meta-analysis differs from Data extraction that of the traditional two-sample test [20]. These aspects The data extraction was elaborated by the first author demonstrate that baseline characteristics in a meta- (FvB); the extracted data included the study popula- analysis are important for the interpretation of the study tion, the type of intervention and control (the strategy of results [21]. avoidance [13]), the study methodology (randomization This study updates and extends the existing Cochrane and blinding), and outcomes. The outcomes included the review by Gøtzsche and Johansen [7], with a focus on main outcomes and the additional outcomes. baseline asthma outcomes and allergen exposures. Main outcomes Methods • Mite allergen load from the mattress (μg/g dust). Searches and selections • Asthma symptom score diaries (e.g. ASS/ACQ). The starting point for this protocol was the Cochrane • Forced expiratory volume in 1  s percentage of pre- review by Gøtzsche and Johansen [7]. This meta-analysis dicted (%) (FEV %pred.) includes 55 trials. An updating search was performed 1 • Histamine or methacholine concentration that in the EMBASE, Medline, and Cochrane databases causes a 20% reduction in the FEV (PC ). (see Additional file  1: Appendix S1). The titles and/or 1 20 abstracts of the retrieved updated studies were screened in Endnote by the first author to identify randomized tri - Additional outcomes als that met the inclusion criteria. Searches and selections were checked by a second author (NWJ). We selected all • Medication usage (use of inhaled corticosteroids: yes trials by applying the following inclusion criteria; where or no). possible, criteria derived from Gøtzsche and Johansen [7] • Type of patient (child or adult). was applied. • Presence of co-sensitization. • The study was published in the English language. Missing data were requested from the study authors. • The study was a peer-review publication with full text A second author (NWJ) validated the selections and (no abstracts). the data extraction by the first author. Any ambiguities • The study was a randomized controlled trial with in the selections and the extractions were resolved by blinding. discussion. • The control included a placebo or no treatment (by The mite allergen load in trials was measured by the Gøtzsche and Johansen [7]). allergen content, the number of mites or the guanine • The participants were physician-diagnosed with content. A rapid colorimetric test such as the Acarex bronchial allergic asthma. These included partici - test can be used to measure the latter. Mite allergen pants who underwent a mite sensitization assess- exposure measured by Acarex or an equivalent test was ment with either a skin test or serum assay for spe- van Boven et al. Clin Transl Allergy (2020) 10:2 Page 3 of 12 the data synthesis. The trials selected for the updated excluded from the analysis; the Acarex test is poorly analysis were assessed similarly for the risk of bias by correlated with allergen content [23]. To estimate the the first author (FvB) using the Cochrane checklist [32]. allergen load from the number of mites in mattresses, A second author (NWJ) validated the assessment by the the mean number of mites can be divided by a factor of first author. Any ambiguities in the assessed risk of bias 50. This ratio is adapted from a nonsensitization thresh - were resolved by discussion. We also did not include the old for allergens and for mites [24]. However, confidence assessments in the data synthesis, as we did not hypoth- limits for this calculation are unknown. We therefore also esize that the risk of bias or the quality of trials would excluded mite counts. The most reliable way to meas - affect the baseline characteristics. ure the allergen content is with a chemical assay; the Enzyme-Linked Immuno Sorbent Assay (ELISA). In an ELISA the house dust mite allergens in the dust extract Statistical and sensitivity analyses binds to an antibody, and are consequently linked to an The effect size was set as the mean for the physiological enzyme, producing a detectable signal correlating to the outcomes. The ASSs were standardized. First, the over - antigen concentration in the extract [25]. This assay has all effect of the three health outcomes was estimated been the most acceptable assay since 1989 [26]. We lim- using a random-effects meta-analysis. Additionally, the I ited the studies to those measuring the mass (μg/g dust) value was calculated to examine heterogeneity in the out- of the mite allergen loads in mattresses with ELISA. Early comes. A random-effect meta-regression and subgroups epidemiologic studies defined a threshold level of 10.0 μg were introduced for all medical outcomes showing at mite allergen per gram of dust, above which asthmatic least moderate heterogeneity. Covariates and subgroups patients are in risk of asthma attacks [24]. Confidence of interest included the mite allergen load from the mat- boundaries were absent, reducing the threshold to a rule tress at baseline and possible confounding by the use of of thumb. Since then, there is a lack of papers on this inhaled corticosteroids, the type of patient (child/adult), threshold level, and thus never updated. and the presence of co-sensitization. Random-effects Questionnaires have been developed to measure meta-regressions and subgroups were tested for a pre- asthma symptom scores and the adequacy of asthma ferred minimum of ten trials [32]. Another sensitivity control, regarding shortness of breath, wheeze, woken by analysis yielded the exclusion of possible outliers as well asthma, severity of asthma in the morning, limiting activ- as the results of the updated reference search. All calcu- ities because of asthma, use of a short-acting bronchodi- lations were performed with the Metafor 2.0.0 package lator [27]. A limitation of the ASSs is that are no validated in R 3.5.3. [33, 34]. The level of significance was set to cut-off points indicating severity or level of control. In α = 0.05. the validated questionnaire by Juniper, an ACQ of 1.50 (maximum 6) relates to inadequately controlled asthma, Results [28], corresponding to a standardized cut-point of 0.25. Selection of references The FEV measures the obstruction in the airways dur- The selection and inclusion of studies resulted in two ing a forced expiratory flower using a spirometer [15]. groups of publications. The first group included the tri - An FEV   %pred. of 50 to 79% refers to moderate airflow als from the Gøtzsche and Johansen [7] analysis (fifty-five obstruction, and < 50% to (very) severe obstruction [29]. trials published until July 2011 [35–89]). We excluded In a standardized bronchoprovocation test, the dose his- twelve of these trials for being only abstracts, being pub- tamine or methacholine is determined causing a 20% fall lished in a non-English language, not reporting data on in FEV, PC or PD [30]. A P C < 1  mg/mL is consid- 1 20 20 20 the treatment of mite-allergic asthma, or containing ered a severe airway hyper responsiveness, and > 8  mg/ non-usable data (outcomes not of prior interest; incom- mL as being a normal responsiveness [31]. plete data) [35–45, 87]. One of the excluded trials was a The analysis was limited to the main health outcomes large trial by Woodcock et al. [87], which dominated the with the most reported units. In the case of the ASS, we a meta-analysis by Gøtzsche and Johansen (weight > 40%). priori standardized (SMN) the mean (MN) score by divid- Woodcock et  al. [87] reported incomplete data in the ing it by the maximum number of the score (MAX). The subset of the mite load as well as the ASS. Further, the variance was standardized in the same way (SD standardized research team did not report the FEV or the PC data. 1 20 2 2 = SD /(MAX * number of patients)). extracted The remaining forty-three trials were included for data extraction. The second group included studies identified Risk of bias assessment in our updated search starting in July 2011 (Fig.  1). We Gøtzsche and Johansen [7] judged the adequacy of the found a total of 942 titles and abstracts. Nine hundred allocation concealment according to the Cochrane and fifteen titles were excluded for not reporting a rand - guidelines [32]. Their assessment was not included in omized blinded trial on the effectiveness of tertiary mite van Boven et al. Clin Transl Allergy (2020) 10:2 Page 4 of 12 Records idenfied through Addional records idenfied database searching through other sources (n = 942 ) (n = 0 ) Records aer duplicates removed (n = 942 ) Records screened Records excluded (n = 942 ) (n = 915 ) Full-text arcles assessed Full-text arcles excluded; for eligibility -only abstract (n=4) (n = 28 ) - duplicate (n=4) - not terary prevenon (n=3) - not a RCT (n=9) - not paents with mite allergic asthma (n=4) -protocol issue (n=2) Studies included in quantave synthesis (meta-analysis) (n = 2 ) Fig. 1 Flow chart of the updating literature search and selection of studies allergen avoidance. Twenty-eight potentially relevant Twenty-one trials reported on the treatment of children titles were selected for inclusion [90–117]. Twenty-six with allergic asthma, the other twenty-four reported on full-text articles were excluded for not meeting our inclu- the treatment of adults; some trials included both chil- sion criteria (see Additional file  1: Appendix S1). Two dren and adults. In nineteen trials, co-sensitization at full-text articles were included in the analysis [97, 115]. baseline was reported. Gøtzsche and Johansen [7] pre- Finally, forty-five full-text articles were included in the viously reported that eight of the included trials had a analysis. low risk of bias. Seven trials were judged to have a high risk of bias. The bias in the remaining twenty-eight tri - als was deemed unclear by Gøtzsche and Johansen [7]. Description of the included trials We judged the trial by El-Ghitany and El-Salam [97] to Thirty-nine trials reported avoidance using concur - have an unclear risk of bias (no information on conceal- rent bedroom intervention strategies, and six trials ment was included). The trial by Murray et al. [115] was reported air purification strategies. In twenty-five trials judged to have a low risk of bias (use of a computer- (56%), patients used inhaled corticosteroids at baseline. based minimization procedure). van Boven et al. Clin Transl Allergy (2020) 10:2 Page 5 of 12 Mean characteristics at baseline ASSs: P = 0.13; FEV   %pred.: P = 0.81; PC : P = 0.75, 1 20 Seventeen of the forty-five trials reported on the mite see Additional file  1: Appendix S1). We calculated allergen load from the mattress at baseline, as measured the FEV   %pred. in the adult subgroup (FEV   %pred.; 1 1 by ELISA (mean 9.86 μg/g dust; 95% CI 5.66 to 14.05 μg/g adults = 84.2%, 95% CI 79.2 to 89.2%; 11 trials). All other dust; range 0.44 to 24.83  μg/g dust; n = 1066; I = 99.8%; subgroups included less than ten trials. Finally, the ran- Fig.  2). The standardized ASSs at baseline were reported dom-effects models for the health outcomes were unal - in twelve trials with high heterogeneity (standardized tered when excluding the updated trials (symptom score symptom score = 0.13; 95% CI 0.08 to 0.18; range: 0.03 to 0.12; FEV  %pred.: 85.4%; PC : 1.69 mg/mL). 1 20 0.29; n = 703; I = 99.9%; Fig. 3). Sixteen studies reported the outcome FEV   %pred. by measuring the percentage predicted value (FEV   %pred. = 85.3%; 95% CI 80.5 to Discussion 90.1%; range 68.5 to 102.2%; n = 816; I = 95.8%; Fig.  4). This study contributes to the existing Cochrane review Fifteen trials reported P C values at baseline, expressed by Gøtzsche and Johansen [7] by generating hypotheses as mg/mL. The mean PC was 1.69 mg/mL (95% CI 0.86 on the characteristics of asthma outcomes according to to 2.52 mg/mL; n = 599; I = 95.6%, Fig. 5). baseline data as well as possible dependencies for asthma outcomes. We observed considerable heterogeneity in Dependence, subgroups and sensitivity analysis the mite allergen load in the mattresses (17 trials), the The covariate mite allergen load at baseline did not sig - standardized ASSs (12 trials), the FEV   %pred. values nificantly influence the health outcomes (standardized (16 trials), and the PC values (15 trials). We judged Fig. 2 Forest plot of the mite allergen load of the mattress at baseline van Boven et al. Clin Transl Allergy (2020) 10:2 Page 6 of 12 Fig. 3 Forest plot of the standardized asthma symptom scores at baseline the mean mite allergen load from the mattress at base- [119]. Compatible with the situation of pharmacological line to be moderate (9.86  μg/g dust). Overall, the stand- treatments [16], it remains unknown whether the results ardized ASSs and the percentage predicted FEV   %pred. found by Gøtzsche and Johansen [7] are generalizable to suggested a mild to moderate disease. The PC at base- patients with uncontrolled asthma. In one trial [55], we line predominantly indicated moderate to severe air- extracted a median symptom score at daytime of zero way hyperresponsiveness according to the definition by for the treatment group. Since the score was already zero Cockroft [31]. We did not observe a relationship between at baseline, it was probably clear that there would be no the mite allergen load from the mattress at baseline and clinical benefit observed in this subset. The asthma out - health outcomes. The number of trials available did not comes showed more notable levels, such as a FEV  %pred. allow for comparisons between the child and adult sub- above 100%, as reported by Carswell et al. [51]. The mod - groups, the inhaled corticosteroid use or no use sub- erate asthma status at baseline was possibly related to the groups, or the presence or absence of co-sensitization use of inhaled corticosteroids, as reported in more than subgroups. half of the included trials (56%). However, the number of In this study, we observed several factors related to the trials available did not allow for testing this hypothesis. three attributes of prior interest. The first attribute was A second attribute is the magnitude of the expo- asthma severity. We observed a mild to moderate mag- sure at baseline, which relates to the environmental nitude of asthma severity at baseline. We were, how- treatability. In four of the included trials [51–53, 115], ever, limited in our evaluation of asthma severity by the we observed that the mean mite allergen load from absence of appropriate instruments to assess asthma the mattress at baseline was quite low (range 0.44 to control [27, 118] and the asthma-related quality of life 1.91  μg/g dust). Only one of these four trials included van Boven et al. Clin Transl Allergy (2020) 10:2 Page 7 of 12 Fig. 4 Forest plot of the FEV percentage of predicted at baseline an evaluation of the treatability of mite allergen expo- As far as we know, this is the first systematic review sure at baseline in their methods [52]. Environmentally, of baseline characteristics in trials on mite allergen whether such low values of exposure are considered avoidance for the treatment of asthma. This study was treatable remains a question. An exposure level of executed a priori to generate hypotheses for a new meta- 0.44  μg/g dust is quite similar to the exposure level analysis on the treatment of mite-allergic asthma by observed in the “low-allergen” region of Davos in the environmental control. Generating hypotheses to define European Alps (approximately 0.02 to 0.2  μg/g dust; a protocol for a meta-analysis prevents misleading con- assessed from [120]). In addition, Pingitore and Pinter clusions [32]. We could not generate a hypothesis on a [121] noted that in many trials, there was no success in possible relationship with asthma outcomes, particularly reducing the mite allergen load. Overall, it seems that considering the mite allergen exposure covariate. The multiple clinical trials on avoidance paid little atten- mite allergen load from the mattress covariate was lim- tion to the environmental issue of the treatability of the ited to the data obtained from ELISA. This limitation exposure. can be considered a rigorous selection factor to prevent Furthermore, the attribute of dependence was of inter- bias in this covariate of prior interest. It is possible that est in this study. None of the medical baseline data could some of the covariates we used were still unrefined. For be related to mite allergen exposure from the mattress. instance, the covariate co-sensitization was introduced as This indicates that from a meta-viewpoint, at baseline, a binary value (presence yes or no); we believe the next there was no clinical potential for reducing the mite aller- step is to introduce the number of co-sensitizations as an gen load in the bedding. ordinal covariate. van Boven et al. Clin Transl Allergy (2020) 10:2 Page 8 of 12 Fig. 5 Forest plot of the PC at baseline The main limitation of this study was that we had to Murray et al. [115] are explained by a more severe asthma exclude the large trial by Woodcock et  al. [87] because status at baseline than those in the participants in the tri- their data was not usable data for the purpose of this als included by Gøtzsche and Johansen [7]. study. Woodcock et al. did probably not include patients The baseline characteristics in a meta-analysis have with uncontrolled asthma. Their publication included been the subject of methodological studies, emphasiz- only adult patients with asthma who were undergo- ing the careful consideration of this topic in the defi - ing routine management with inhaled corticosteroids nition of the protocol [21, 122]. Advanced statistical in primary care. Though not a limitation, another large methods to evaluate underlying risk have been devel- trial also worth noting is the recently published study oped for cases in which the baseline characteristics or by Murray et  al. [115]. Murray et  al. found that only the the severity of the disease among the participants varies use of single covers prevented asthma exacerbations in [123]. The definition of the types of participants is con - the hospital setting. In a post hoc analysis, Murray et al. sidered a key factor in reviews [32]. A positive example reported that relatively younger children (P = 0.006), of the explicit (a priori) consideration of baseline char- those mono-sensitized to mites (P = 0.04), those with acteristics was demonstrated in the Cochrane review severe asthma (P = 0.03), and those not exposed to smok- on the treatment of asthma by sublingual immunother- ing (P = 0.02) explained the reduced number of hospital apy [124]. In contrast, the current meta-analyses on the admissions in the 123 participants. No information was treatment of asthma using avoidance were commonly presented on the selection of significant covariates or characterized by no baseline characteristic reporting on the power of the calculations. Possibly, the results by [7–11]. Gøtzsche and Johansen [7] stated that adjusting van Boven et al. Clin Transl Allergy (2020) 10:2 Page 9 of 12 Ethics approval and consent to participate for baseline differences would risk biasing the review, Not applicable. “since investigators are inclined to show baseline dif- ferences and adjust for them when this procedure Consent for publication Not applicable. favours the experimental treatment”. By limiting their meta-analysis to the changes and final values, Gøtzsche Competing interests and Johansen [7] did not account for the types of par- The authors declare that they have no competing interests. ticipants they reviewed. Other Cochrane reviews on the Author details treatment of asthma or rhinitis by mite allergen avoid- Department of Internal Medicine, Section of Allergology & Clinical Immu‑ ance [125, 126], recognized for their rigorous method- nology, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Department of Pulmonology, Sint Franciscus Vlietland Groep, ology, do not account for the types of participants, as P.O. Box 10900, 3004 BA Rotterdam, The Netherlands. Department of Pulmo‑ they did not describe their baseline characteristics. This nology, Erasmus Medical Center, Rotterdam, The Netherlands. Department suggests that there is room for improvement in the of Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands. Depart‑ ment of Psychology, Education & Child Studies, Erasmus University Rotterdam, multiple Cochrane reviews and other meta-analyses on P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. avoidance. In conclusion, this systematic review demonstrates Received: 24 July 2019 Accepted: 13 December 2019 that many previous mite avoidance studies are charac- terized by the inclusion of patients with rather mild to moderate asthma and with varying and sometimes neg- ligible levels of allergen exposure. Most likely, the use of References asthma medication modified the baseline asthma out - 1. Backman H, Räisänen P, Hedman L, Stridsman C, Andersson M, Lindberg comes in these studies, leaving less room to improve. A, et al. Increased prevalence of allergic asthma from 1996 to 2006 In future studies, we suggest focusing on patients with and further to 2016—results from three population surveys. Clin Exp Allergy. 2017;47(11):1426–35. partially controlled or uncontrolled asthma and assess- 2. Mincheva R, Ekerljung L, Bossios A, Lundbäck B, Lötvall J. High preva‑ ing asthma control with the appropriate instruments lence of severe asthma in a large random population study. 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A meta-analysis of baseline characteristics in trials on mite allergen avoidance in asthmatics: room for improvement

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Copyright © 2020 by The Author(s)
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Medicine & Public Health; Allergology; Immunology; Pneumology/Respiratory System
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2045-7022
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10.1186/s13601-019-0306-3
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Abstract

Background: Evidence regarding the clinical effectiveness of mite allergen avoidance for the treatment of asthma is lacking. In previous meta‑analyses on mite allergen control, the baseline data were not discussed in detail. This study updates and extends the existing Cochrane review by Gøtzsche and Johansen (Cochrane Database of Systematic Reviews, 2008, Art. No: CD001187), with a focus on baseline asthma outcomes and allergen exposures. Methods: We used the existing trials in the original Cochrane review and included newly published studies. The baseline data for the mite allergen load from the mattress, the standardized asthma symptom score (ASS), the forced expiratory volume in 1 s percentage of predicted (FEV %pred.), and the histamine provocative concentration causing a 20% drop in FEV (PC ) were extracted. First, the mean values of the outcomes were calculated. The influence of the 1 20 mite allergen load was examined with a random‑ effect meta‑regression using the Metafor package in R. Results: Forty‑five trials were included; 39 trials reported strategies for concurrent bedroom interventions, and 6 trails reported strategies for air purification. The mite allergen load ranged from 0.44 to 24.83 μg/g dust, with a mean of 9.86 μg/g dust (95% CI 5.66 to 14.05 μg/g dust, I = 99.8%). All health outcomes showed considerable heteroge‑ neity (standardized ASS mean: 0.13, 95% CI 0.08 to 0.18, I = 99.9%; FEV %pred. mean: 85.3%, 95% CI 80.5 to 90.1%, 2 2 I = 95.8%; PC mean: 1.69 mg/mL, 95% CI 0.86 to 2.52 mg/mL, I = 95.6%). The covariate mite allergen load did not significantly influence health outcomes. Discussion: This meta‑analysis shows that mite avoidance studies are characterized by the inclusion of patients with rather mild to moderate asthma and with varying and sometimes negligible levels of allergen exposure. Future stud‑ ies should focus on patients with severe asthma and increased levels of allergen exposure. consensus in this research field. This lack of consensus Introduction on the effectiveness of mite allergen avoidance is sum - House dust mite-allergic asthma is a prevalent disorder marized by a Cochrane review [7], which was unable to of the lower airways that affects hundreds of millions of demonstrate any clinical benefit of avoidance measures people worldwide [1, 2]. The immediate allergic reac - designed to reduce mite exposure in 55 trials. In addi- tion to mites [3] suggests that controlling exposure to tion to the substantial meta-analysis by Gøtzsche and the antigen could be an appropriate first-line therapy for Johansen [7], several other meta-analyses on mite aller- the treatment of mite-allergic asthma. However, guide- gen avoidance for the treatment of asthma report vary- lines and reviews provide ambiguous recommendations ing results for the effectiveness of avoidance [8–11]. The for mite allergen avoidance [4–6], reflecting a lack of variation in the complex interventions as well as the het- erogeneity of several study outcomes urges further explo- *Correspondence: f.vanboven5@gmail.com ration [12, 13]. Department of Internal Medicine, Section of Allergology & Clinical The baseline data are a not well reported in the meta- Immunology, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands analyses on the effectiveness of mite allergen control. Full list of author information is available at the end of the article © The Author(s) 2020. 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The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. van Boven et al. Clin Transl Allergy (2020) 10:2 Page 2 of 12 These baseline characteristics provide attributes for cific IgE antibodies (by Gøtzsche and Johansen [7]). evidence-based decision making in the daily practice of The asthma assessment included a history of asthma clinicians [14]. First, in the case of asthma, baseline char- symptoms and a pulmonary function test. acteristics are of particular interest because they reflect • The intervention was designed to reduce the expo - the level of asthma control and the asthma severity of sure to mite antigens in the home for the treatment the patient [15]. Studies still highlight the disparities of asthma (mono-trigger therapy by tertiary avoid- between the asthma severity results between clinical tri- ance). This could include one of the following (by als and those reported from patient practice [16]. Treat- Gøtzsche and Johansen [7]): able traits have been defined in severe asthma patients and may be associated with future exacerbation risk [17]. a. Chemical (acaricides); Second, baseline environmental aspects can influence the b. Physical (mattress covers, vacuum-cleaning, treatability of allergen-induced asthma [18]. Third, base - heating, ventilation, freezing, washing, air-filtra - line characteristics provide statistical independence in tion, and ionisers); the asthma outcomes of interest. This quantitative factor c. A combination of chemical and physical. relates to the possible relationship between exposure and asthma outcomes; for example, in the paradigm of the The flow chart of the updating search was made by use bedding site introduced in the 1990s [19]. In such cases, of the PRISMA diagram [22]. the quantitative evaluation of the clinical effectiveness of the treatment of asthma in a meta-analysis differs from Data extraction that of the traditional two-sample test [20]. These aspects The data extraction was elaborated by the first author demonstrate that baseline characteristics in a meta- (FvB); the extracted data included the study popula- analysis are important for the interpretation of the study tion, the type of intervention and control (the strategy of results [21]. avoidance [13]), the study methodology (randomization This study updates and extends the existing Cochrane and blinding), and outcomes. The outcomes included the review by Gøtzsche and Johansen [7], with a focus on main outcomes and the additional outcomes. baseline asthma outcomes and allergen exposures. Main outcomes Methods • Mite allergen load from the mattress (μg/g dust). Searches and selections • Asthma symptom score diaries (e.g. ASS/ACQ). The starting point for this protocol was the Cochrane • Forced expiratory volume in 1  s percentage of pre- review by Gøtzsche and Johansen [7]. This meta-analysis dicted (%) (FEV %pred.) includes 55 trials. An updating search was performed 1 • Histamine or methacholine concentration that in the EMBASE, Medline, and Cochrane databases causes a 20% reduction in the FEV (PC ). (see Additional file  1: Appendix S1). The titles and/or 1 20 abstracts of the retrieved updated studies were screened in Endnote by the first author to identify randomized tri - Additional outcomes als that met the inclusion criteria. Searches and selections were checked by a second author (NWJ). We selected all • Medication usage (use of inhaled corticosteroids: yes trials by applying the following inclusion criteria; where or no). possible, criteria derived from Gøtzsche and Johansen [7] • Type of patient (child or adult). was applied. • Presence of co-sensitization. • The study was published in the English language. Missing data were requested from the study authors. • The study was a peer-review publication with full text A second author (NWJ) validated the selections and (no abstracts). the data extraction by the first author. Any ambiguities • The study was a randomized controlled trial with in the selections and the extractions were resolved by blinding. discussion. • The control included a placebo or no treatment (by The mite allergen load in trials was measured by the Gøtzsche and Johansen [7]). allergen content, the number of mites or the guanine • The participants were physician-diagnosed with content. A rapid colorimetric test such as the Acarex bronchial allergic asthma. These included partici - test can be used to measure the latter. Mite allergen pants who underwent a mite sensitization assess- exposure measured by Acarex or an equivalent test was ment with either a skin test or serum assay for spe- van Boven et al. Clin Transl Allergy (2020) 10:2 Page 3 of 12 the data synthesis. The trials selected for the updated excluded from the analysis; the Acarex test is poorly analysis were assessed similarly for the risk of bias by correlated with allergen content [23]. To estimate the the first author (FvB) using the Cochrane checklist [32]. allergen load from the number of mites in mattresses, A second author (NWJ) validated the assessment by the the mean number of mites can be divided by a factor of first author. Any ambiguities in the assessed risk of bias 50. This ratio is adapted from a nonsensitization thresh - were resolved by discussion. We also did not include the old for allergens and for mites [24]. However, confidence assessments in the data synthesis, as we did not hypoth- limits for this calculation are unknown. We therefore also esize that the risk of bias or the quality of trials would excluded mite counts. The most reliable way to meas - affect the baseline characteristics. ure the allergen content is with a chemical assay; the Enzyme-Linked Immuno Sorbent Assay (ELISA). In an ELISA the house dust mite allergens in the dust extract Statistical and sensitivity analyses binds to an antibody, and are consequently linked to an The effect size was set as the mean for the physiological enzyme, producing a detectable signal correlating to the outcomes. The ASSs were standardized. First, the over - antigen concentration in the extract [25]. This assay has all effect of the three health outcomes was estimated been the most acceptable assay since 1989 [26]. We lim- using a random-effects meta-analysis. Additionally, the I ited the studies to those measuring the mass (μg/g dust) value was calculated to examine heterogeneity in the out- of the mite allergen loads in mattresses with ELISA. Early comes. A random-effect meta-regression and subgroups epidemiologic studies defined a threshold level of 10.0 μg were introduced for all medical outcomes showing at mite allergen per gram of dust, above which asthmatic least moderate heterogeneity. Covariates and subgroups patients are in risk of asthma attacks [24]. Confidence of interest included the mite allergen load from the mat- boundaries were absent, reducing the threshold to a rule tress at baseline and possible confounding by the use of of thumb. Since then, there is a lack of papers on this inhaled corticosteroids, the type of patient (child/adult), threshold level, and thus never updated. and the presence of co-sensitization. Random-effects Questionnaires have been developed to measure meta-regressions and subgroups were tested for a pre- asthma symptom scores and the adequacy of asthma ferred minimum of ten trials [32]. Another sensitivity control, regarding shortness of breath, wheeze, woken by analysis yielded the exclusion of possible outliers as well asthma, severity of asthma in the morning, limiting activ- as the results of the updated reference search. All calcu- ities because of asthma, use of a short-acting bronchodi- lations were performed with the Metafor 2.0.0 package lator [27]. A limitation of the ASSs is that are no validated in R 3.5.3. [33, 34]. The level of significance was set to cut-off points indicating severity or level of control. In α = 0.05. the validated questionnaire by Juniper, an ACQ of 1.50 (maximum 6) relates to inadequately controlled asthma, Results [28], corresponding to a standardized cut-point of 0.25. Selection of references The FEV measures the obstruction in the airways dur- The selection and inclusion of studies resulted in two ing a forced expiratory flower using a spirometer [15]. groups of publications. The first group included the tri - An FEV   %pred. of 50 to 79% refers to moderate airflow als from the Gøtzsche and Johansen [7] analysis (fifty-five obstruction, and < 50% to (very) severe obstruction [29]. trials published until July 2011 [35–89]). We excluded In a standardized bronchoprovocation test, the dose his- twelve of these trials for being only abstracts, being pub- tamine or methacholine is determined causing a 20% fall lished in a non-English language, not reporting data on in FEV, PC or PD [30]. A P C < 1  mg/mL is consid- 1 20 20 20 the treatment of mite-allergic asthma, or containing ered a severe airway hyper responsiveness, and > 8  mg/ non-usable data (outcomes not of prior interest; incom- mL as being a normal responsiveness [31]. plete data) [35–45, 87]. One of the excluded trials was a The analysis was limited to the main health outcomes large trial by Woodcock et al. [87], which dominated the with the most reported units. In the case of the ASS, we a meta-analysis by Gøtzsche and Johansen (weight > 40%). priori standardized (SMN) the mean (MN) score by divid- Woodcock et  al. [87] reported incomplete data in the ing it by the maximum number of the score (MAX). The subset of the mite load as well as the ASS. Further, the variance was standardized in the same way (SD standardized research team did not report the FEV or the PC data. 1 20 2 2 = SD /(MAX * number of patients)). extracted The remaining forty-three trials were included for data extraction. The second group included studies identified Risk of bias assessment in our updated search starting in July 2011 (Fig.  1). We Gøtzsche and Johansen [7] judged the adequacy of the found a total of 942 titles and abstracts. Nine hundred allocation concealment according to the Cochrane and fifteen titles were excluded for not reporting a rand - guidelines [32]. Their assessment was not included in omized blinded trial on the effectiveness of tertiary mite van Boven et al. Clin Transl Allergy (2020) 10:2 Page 4 of 12 Records idenfied through Addional records idenfied database searching through other sources (n = 942 ) (n = 0 ) Records aer duplicates removed (n = 942 ) Records screened Records excluded (n = 942 ) (n = 915 ) Full-text arcles assessed Full-text arcles excluded; for eligibility -only abstract (n=4) (n = 28 ) - duplicate (n=4) - not terary prevenon (n=3) - not a RCT (n=9) - not paents with mite allergic asthma (n=4) -protocol issue (n=2) Studies included in quantave synthesis (meta-analysis) (n = 2 ) Fig. 1 Flow chart of the updating literature search and selection of studies allergen avoidance. Twenty-eight potentially relevant Twenty-one trials reported on the treatment of children titles were selected for inclusion [90–117]. Twenty-six with allergic asthma, the other twenty-four reported on full-text articles were excluded for not meeting our inclu- the treatment of adults; some trials included both chil- sion criteria (see Additional file  1: Appendix S1). Two dren and adults. In nineteen trials, co-sensitization at full-text articles were included in the analysis [97, 115]. baseline was reported. Gøtzsche and Johansen [7] pre- Finally, forty-five full-text articles were included in the viously reported that eight of the included trials had a analysis. low risk of bias. Seven trials were judged to have a high risk of bias. The bias in the remaining twenty-eight tri - als was deemed unclear by Gøtzsche and Johansen [7]. Description of the included trials We judged the trial by El-Ghitany and El-Salam [97] to Thirty-nine trials reported avoidance using concur - have an unclear risk of bias (no information on conceal- rent bedroom intervention strategies, and six trials ment was included). The trial by Murray et al. [115] was reported air purification strategies. In twenty-five trials judged to have a low risk of bias (use of a computer- (56%), patients used inhaled corticosteroids at baseline. based minimization procedure). van Boven et al. Clin Transl Allergy (2020) 10:2 Page 5 of 12 Mean characteristics at baseline ASSs: P = 0.13; FEV   %pred.: P = 0.81; PC : P = 0.75, 1 20 Seventeen of the forty-five trials reported on the mite see Additional file  1: Appendix S1). We calculated allergen load from the mattress at baseline, as measured the FEV   %pred. in the adult subgroup (FEV   %pred.; 1 1 by ELISA (mean 9.86 μg/g dust; 95% CI 5.66 to 14.05 μg/g adults = 84.2%, 95% CI 79.2 to 89.2%; 11 trials). All other dust; range 0.44 to 24.83  μg/g dust; n = 1066; I = 99.8%; subgroups included less than ten trials. Finally, the ran- Fig.  2). The standardized ASSs at baseline were reported dom-effects models for the health outcomes were unal - in twelve trials with high heterogeneity (standardized tered when excluding the updated trials (symptom score symptom score = 0.13; 95% CI 0.08 to 0.18; range: 0.03 to 0.12; FEV  %pred.: 85.4%; PC : 1.69 mg/mL). 1 20 0.29; n = 703; I = 99.9%; Fig. 3). Sixteen studies reported the outcome FEV   %pred. by measuring the percentage predicted value (FEV   %pred. = 85.3%; 95% CI 80.5 to Discussion 90.1%; range 68.5 to 102.2%; n = 816; I = 95.8%; Fig.  4). This study contributes to the existing Cochrane review Fifteen trials reported P C values at baseline, expressed by Gøtzsche and Johansen [7] by generating hypotheses as mg/mL. The mean PC was 1.69 mg/mL (95% CI 0.86 on the characteristics of asthma outcomes according to to 2.52 mg/mL; n = 599; I = 95.6%, Fig. 5). baseline data as well as possible dependencies for asthma outcomes. We observed considerable heterogeneity in Dependence, subgroups and sensitivity analysis the mite allergen load in the mattresses (17 trials), the The covariate mite allergen load at baseline did not sig - standardized ASSs (12 trials), the FEV   %pred. values nificantly influence the health outcomes (standardized (16 trials), and the PC values (15 trials). We judged Fig. 2 Forest plot of the mite allergen load of the mattress at baseline van Boven et al. Clin Transl Allergy (2020) 10:2 Page 6 of 12 Fig. 3 Forest plot of the standardized asthma symptom scores at baseline the mean mite allergen load from the mattress at base- [119]. Compatible with the situation of pharmacological line to be moderate (9.86  μg/g dust). Overall, the stand- treatments [16], it remains unknown whether the results ardized ASSs and the percentage predicted FEV   %pred. found by Gøtzsche and Johansen [7] are generalizable to suggested a mild to moderate disease. The PC at base- patients with uncontrolled asthma. In one trial [55], we line predominantly indicated moderate to severe air- extracted a median symptom score at daytime of zero way hyperresponsiveness according to the definition by for the treatment group. Since the score was already zero Cockroft [31]. We did not observe a relationship between at baseline, it was probably clear that there would be no the mite allergen load from the mattress at baseline and clinical benefit observed in this subset. The asthma out - health outcomes. The number of trials available did not comes showed more notable levels, such as a FEV  %pred. allow for comparisons between the child and adult sub- above 100%, as reported by Carswell et al. [51]. The mod - groups, the inhaled corticosteroid use or no use sub- erate asthma status at baseline was possibly related to the groups, or the presence or absence of co-sensitization use of inhaled corticosteroids, as reported in more than subgroups. half of the included trials (56%). However, the number of In this study, we observed several factors related to the trials available did not allow for testing this hypothesis. three attributes of prior interest. The first attribute was A second attribute is the magnitude of the expo- asthma severity. We observed a mild to moderate mag- sure at baseline, which relates to the environmental nitude of asthma severity at baseline. We were, how- treatability. In four of the included trials [51–53, 115], ever, limited in our evaluation of asthma severity by the we observed that the mean mite allergen load from absence of appropriate instruments to assess asthma the mattress at baseline was quite low (range 0.44 to control [27, 118] and the asthma-related quality of life 1.91  μg/g dust). Only one of these four trials included van Boven et al. Clin Transl Allergy (2020) 10:2 Page 7 of 12 Fig. 4 Forest plot of the FEV percentage of predicted at baseline an evaluation of the treatability of mite allergen expo- As far as we know, this is the first systematic review sure at baseline in their methods [52]. Environmentally, of baseline characteristics in trials on mite allergen whether such low values of exposure are considered avoidance for the treatment of asthma. This study was treatable remains a question. An exposure level of executed a priori to generate hypotheses for a new meta- 0.44  μg/g dust is quite similar to the exposure level analysis on the treatment of mite-allergic asthma by observed in the “low-allergen” region of Davos in the environmental control. Generating hypotheses to define European Alps (approximately 0.02 to 0.2  μg/g dust; a protocol for a meta-analysis prevents misleading con- assessed from [120]). In addition, Pingitore and Pinter clusions [32]. We could not generate a hypothesis on a [121] noted that in many trials, there was no success in possible relationship with asthma outcomes, particularly reducing the mite allergen load. Overall, it seems that considering the mite allergen exposure covariate. The multiple clinical trials on avoidance paid little atten- mite allergen load from the mattress covariate was lim- tion to the environmental issue of the treatability of the ited to the data obtained from ELISA. This limitation exposure. can be considered a rigorous selection factor to prevent Furthermore, the attribute of dependence was of inter- bias in this covariate of prior interest. It is possible that est in this study. None of the medical baseline data could some of the covariates we used were still unrefined. For be related to mite allergen exposure from the mattress. instance, the covariate co-sensitization was introduced as This indicates that from a meta-viewpoint, at baseline, a binary value (presence yes or no); we believe the next there was no clinical potential for reducing the mite aller- step is to introduce the number of co-sensitizations as an gen load in the bedding. ordinal covariate. van Boven et al. Clin Transl Allergy (2020) 10:2 Page 8 of 12 Fig. 5 Forest plot of the PC at baseline The main limitation of this study was that we had to Murray et al. [115] are explained by a more severe asthma exclude the large trial by Woodcock et  al. [87] because status at baseline than those in the participants in the tri- their data was not usable data for the purpose of this als included by Gøtzsche and Johansen [7]. study. Woodcock et al. did probably not include patients The baseline characteristics in a meta-analysis have with uncontrolled asthma. Their publication included been the subject of methodological studies, emphasiz- only adult patients with asthma who were undergo- ing the careful consideration of this topic in the defi - ing routine management with inhaled corticosteroids nition of the protocol [21, 122]. Advanced statistical in primary care. Though not a limitation, another large methods to evaluate underlying risk have been devel- trial also worth noting is the recently published study oped for cases in which the baseline characteristics or by Murray et  al. [115]. Murray et  al. found that only the the severity of the disease among the participants varies use of single covers prevented asthma exacerbations in [123]. The definition of the types of participants is con - the hospital setting. In a post hoc analysis, Murray et al. sidered a key factor in reviews [32]. A positive example reported that relatively younger children (P = 0.006), of the explicit (a priori) consideration of baseline char- those mono-sensitized to mites (P = 0.04), those with acteristics was demonstrated in the Cochrane review severe asthma (P = 0.03), and those not exposed to smok- on the treatment of asthma by sublingual immunother- ing (P = 0.02) explained the reduced number of hospital apy [124]. In contrast, the current meta-analyses on the admissions in the 123 participants. No information was treatment of asthma using avoidance were commonly presented on the selection of significant covariates or characterized by no baseline characteristic reporting on the power of the calculations. Possibly, the results by [7–11]. Gøtzsche and Johansen [7] stated that adjusting van Boven et al. Clin Transl Allergy (2020) 10:2 Page 9 of 12 Ethics approval and consent to participate for baseline differences would risk biasing the review, Not applicable. “since investigators are inclined to show baseline dif- ferences and adjust for them when this procedure Consent for publication Not applicable. favours the experimental treatment”. By limiting their meta-analysis to the changes and final values, Gøtzsche Competing interests and Johansen [7] did not account for the types of par- The authors declare that they have no competing interests. ticipants they reviewed. Other Cochrane reviews on the Author details treatment of asthma or rhinitis by mite allergen avoid- Department of Internal Medicine, Section of Allergology & Clinical Immu‑ ance [125, 126], recognized for their rigorous method- nology, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Department of Pulmonology, Sint Franciscus Vlietland Groep, ology, do not account for the types of participants, as P.O. Box 10900, 3004 BA Rotterdam, The Netherlands. Department of Pulmo‑ they did not describe their baseline characteristics. This nology, Erasmus Medical Center, Rotterdam, The Netherlands. Department suggests that there is room for improvement in the of Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands. Depart‑ ment of Psychology, Education & Child Studies, Erasmus University Rotterdam, multiple Cochrane reviews and other meta-analyses on P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. avoidance. In conclusion, this systematic review demonstrates Received: 24 July 2019 Accepted: 13 December 2019 that many previous mite avoidance studies are charac- terized by the inclusion of patients with rather mild to moderate asthma and with varying and sometimes neg- ligible levels of allergen exposure. Most likely, the use of References asthma medication modified the baseline asthma out - 1. Backman H, Räisänen P, Hedman L, Stridsman C, Andersson M, Lindberg comes in these studies, leaving less room to improve. A, et al. Increased prevalence of allergic asthma from 1996 to 2006 In future studies, we suggest focusing on patients with and further to 2016—results from three population surveys. Clin Exp Allergy. 2017;47(11):1426–35. partially controlled or uncontrolled asthma and assess- 2. Mincheva R, Ekerljung L, Bossios A, Lundbäck B, Lötvall J. High preva‑ ing asthma control with the appropriate instruments lence of severe asthma in a large random population study. 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Clinical and Translational Allergy – Springer Journals

Published: Dec 1, 2020

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