Systematic review

The sensitivity and specificity of the mannitol bronchial challenge test to identify asthma in different populations: a systematic review

DOI: https://doi.org/10.4414/smw.2019.20100
Publication Date: 02.09.2019
Swiss Med Wkly. 2019;149:w20100

Kernen Philippa, Steveling-Klein Esther H.b, Saccilotto Ramon T.c, Raatz Heikec, Briel Matthiasce, Koller Michael T.ce, Westwood Maried, Bucher Heiner C.bce, Miedinger Davidae, Leuppi Jörg D.ae

a University Clinic of Medicine, Cantonal Hospital Baselland, Liestal, Switzerland

b Allergy Unit, Department of Dermatology, University Hospital Basel, Switzerland

c Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital and University of Basel, Switzerland

d Kleijnen Systematic Reviews Ltd, York, United Kingdom

e Medical Faculty, University of Basel, Switzerland

Summary

OBJECTIVE

Asthma is associated with bronchial hyperresponsiveness, assessed by bronchial provocation tests such as the mannitol test. We aimed to assess the data on sensitivity and specificity of the mannitol test in diagnosing asthma.

DATA SOURCES

We searched electronically the Medline, Embase and Central databases from 1997 to 2019.

STUDY SELECTION

Inclusion criteria were the assessment of the validity of the mannitol test. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2). Data were extracted according to a prespecified list and analysed qualitatively.

RESULTS

A total of 27 studies (4589 individuals, age 6–85 years, cross-sectional [n = 18] and case-controlled [n = 9] study design) were included. Overall sensitivity and specificity ranged from 8% (95% confidence interval [CI] 1–27) to 100% (95% CI 93–100) and 75% (95% CI 67–82) to 100% (95% CI 85–100). Excluding case-controlled design, studies conducted in a clinical setting showed a range from 19% (95% CI 14–27) to 91% (95% CI 59–100) for sensitivity and from 75% (95% CI 67–82) to 100% (95% CI 80–100) for specificity. Heterogeneity was high owing to differences in the populations examined and the methods used.

CONCLUSIONS

Studies on the accuracy of the mannitol test were heterogeneous. Overall specificity was higher than sensitivity and therefore the mannitol test seems to be a suitable diagnostic tool to confirm asthma. However, the high level of heterogeneity among the included studies makes a conclusive statement on the accuracy of the mannitol test difficult and further research is needed. As bronchial provocation tests can be especially useful in patients with an intermediate probability of asthma diagnosis, further studies are needed that include subjects with asthma symptoms but intermediate probability of asthma diagnosis.

Keywords: mannitol, bronchial challenge test, asthma, bronchial hyperresponsiveness, Aridol, athletes, fire fighters

Abbreviations

GINA: Global Initiative for Asthma

BPT: bronchial provocation tests

EVH: eucapnic voluntary hyperpnoea

QUADAS: Quality Assessment of Diagnostic Accuracy Studies

ATS: American Thoracic Society

ERS: European Respiratory Society

HSROC: hierarchical summary receiver operating characteristic

CI: confidence interval

FEV1: forced expiratory volume in 1 second

TP: true positive

FP: false positive

FN: false negative

TN: true negative

ROC: receiver operating characteristic

COPD: chronic obstructive pulmonary disease

Introduction

Asthma is a chronic inflammatory airway disease with an estimated 300 million affected individuals worldwide [1]. The chronic inflammation of the airways is associated with airway hyperresponsiveness with recurrent episodes of wheezing, breathlessness, chest tightness, coughing and provocation by typical triggers [1].

A correct diagnosis of asthma is essential if appropriate drug therapy is to be given. The diagnosis of asthma should not be based on respiratory symptoms alone as the symptoms may be unspecific [1, 2]. According to the Global Initiative for Asthma (GINA) guidelines, the diagnosis of asthma is made by the presence of variable respiratory symptoms and a confirmed variable expiratory airflow limitation with objective pulmonary function tests [1].

Bronchial provocation tests (BPTs) are particularly useful for the detection of airway hyperresponsiveness and diagnosing asthma on occasions where the lung function testing shows normal results. Two different methods for bronchial provocation tests exist, the ´direct´ and the “indirect” method. “Direct” bronchial provocation tests cause airway narrowing by acting “directly“ on their respective receptors on bronchial smooth muscle, causing contraction [1, 3, 4]. The “direct” tests are very sensitive for identifying airway hyperresponsiveness. A limitation of direct tests is that they act directly on the smooth muscle, and can show airway hyperresponsiveness even without any active airway inflammation. This direct effect may cause false positive test results and thus reduce specificity [1, 3, 5].

In contrast to this, “indirect“ challenge tests such as the mannitol test cause airway narrowing by releasing a wide variety of mediators of bronchoconstriction from inflammatory cells within the walls of the airways [3]. Because of this mechanism indirect tests are more specific for identifying asthma that is currently active [1, 3, 5, 6]. The mannitol test has the advantage of a standardised protocol, ease of administration, shortness of procedure and good safety profile due to a progressive dose-response challenge. The test can be stopped before severe falls of FEV1 occur, making it an attractive alternative to the “direct” test methods where different protocols exist [3, 6, 7]. In 2007, mannitol was included as a bronchoprovocation test in the GINA guidelines [1].

Several studies have investigated the accuracy of the mannitol test to identify asthma. However, the results from these studies differ substantially [813]. This systematic review aims to clarify this point. Our objective was to investigate the sensitivity and specificity of the mannitol test to diagnose asthma compared to accepted reference standards (GINA) in children and adults with and without asthma symptoms. We included cross-sectional, cohort and case-controlled studies. Characteristics (reference standard, different settings, populations) were recorded. Methodological quality of the studies was assessed with QUADAS-2 [14].

Methods

Protocol

The methods of data extraction and inclusion criteria were specified in advance and documented in a protocol, which is available upon request.

Search strategy and data sources

We performed a systematic search of three electronic databases to identify studies evaluating the accuracy of the mannitol BPT for the diagnosis of asthma. A research librarian experienced in literature searches for systematic reviews developed a search strategy in collaboration with the investigators (see appendix 1). We systematically searched Medline (through Ovid or PubMed), Embase (through Ovid) and Central databases from January 1997, as the mannitol BPT was originally described by Anderson et al. in 1997 [15], to February 2019. Participants of any age were considered. No publication status restrictions were imposed. We checked the reference lists of the identified studies as well as the reference lists of identified narrative reviews, published on diagnostic tests for asthma after 1997, and visited the Aridol website (accessed February 2019) to identify other relevant studies. A hand-search for conference proceedings of the American Thoracic Society (ATS), European Respiratory Society (ERS), and Chest and World Allergy Congress was performed to search for possible additional studies.

Study selection

To be eligible for inclusion in the systematic review, studies had to fulfil the following criteria:

  1. Population: Patients with suspected or diagnosed asthma, healthy participants of population studies, or participants of studies investigating asthma in the workplace.
  2. Index test: The index test was the mannitol bronchial provocation test using the protocol originally described by Anderson et al. or the Aridol package leaflet [7].
  3. Reference standard: We accepted the following reference standards to diagnose asthma: “clinical diagnosis of asthma” (physician makes diagnosis based on respiratory symptoms of asthma in conjunction with the results of the clinical examination and a bronchial provocation test); or “physician diagnosed asthma” (physician had diagnosed asthma but it was unclear how he did it). Another accepted reference standard was a test result in an exercise challenge, eucapnic voluntary hyperpnoea or specific inhalation test, performed in patients who were included if they had respiratory symptoms. A positive bronchial provocation or exercise test in subjects without respiratory symptoms was not considered sufficient to diagnose asthma.
  4. Study types: We included cross-sectional, cohort and case-controlled studies.
  5. Outcome measure: We included studies that reported the diagnostic accuracy (sensitivity and specificity) of the mannitol BPT.

We excluded animal studies and “dose-finding studies”, as well as studies in which a two-by-two table could not be established even after contacting the relevant investigators. We took care to exclude duplicate studies.

In a first step, two reviewers independently screened titles and abstracts. Any articles that were deemed to be potentially relevant by one of the reviewers were marked. Studies that were judged to be ineligible by both reviewers based on the title and abstract were not assessed further. In a second step, the full texts of all the potentially eligible articles were retrieved so that they could be screened, again independently and in duplicate by two reviewers. Study eligibility was evaluated using pre-piloted forms with the above mentioned inclusion and exclusion criteria. Any disagreement was resolved by consensus. If consensus was not achieved, a third reviewer had the decisive vote.

Assessment of risk of bias of studies

The methodological quality and risk of bias of the selected studies was assessed independently and in duplicate by two reviewers with the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2; see appendix 2), which assessed common sources of bias in diagnostic studies.

Data extraction

From all the eligible studies after full text screening, two reviewers extracted predefined data independently and in duplicate using an extraction form (see appendix 3). Further data were extracted post hoc, including FEV1, atopy status and stopping of medication prior to testing. In cases of missing information from the articles, we contacted the authors of the respective studies to provide further details. If it was not possible to construct two-by-two tables, the studies were excluded from the final analysis. Controversies were resolved by discussion. If consensus was not achieved, a third reviewer had the decisive vote.

Data synthesis and analysis

For each included study, we constructed two-by-two tables by comparing the results of the mannitol BPT with the respective reference standard. Sensitivity and specificity were the main measures of accuracy of the mannitol test, which we calculated using the data of the two-by-two tables. The true and false negative and positive rates were recorded. Sensitivity and specificity were plotted in receiver operating characteristic space. To explore the different populations, we grouped studies according to study design, study setting and age group in a forest plot.

Results

Study selection

The literature search provided a total of 836 citations after removing duplicates. After those in which the subject of this review was not addressed were excluded, 221 remained potentially relevant and were retrieved for full text screening (fig. 1). Finally, 27 studies [810, 12, 13, 1536] met the inclusion criteria for our systematic review, all of them published in English between 1997 and 2018.

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Figure 1
Identification of studies.

Study and population characteristics

Eighteen of the included studies were cross-sectional studies [810, 12, 1620, 2630, 32, 3436], nine studies used a case-controlled design [13, 15, 16, 2529, 35], including asthmatics and a healthy control group.

The included studies involved a total of 4589 participants. The age range was from 6 to 85 years, and the percentage of males ranged from 25 to 100%. Most studies included only adults [8, 12, 15, 16, 21, 2328, 3033], eight studies included adults and children [9, 10, 13, 17, 18, 21, 23, 33], three studies included only children [19, 24, 26]. Twelve studies were conducted in a clinical setting [10, 13, 15, 17, 2124, 28, 29, 32, 36], with participants attending any kind of clinical institution. The other studies used a nonclinical setting [8, 9, 12, 16, 1820, 2527, 30, 31, 3335]; most of these included elite athletes as their study population, and two studies specifically investigated military conscripts and fire fighters [8, 12].

In most of the studies, having symptoms consistent with asthma was an inclusion criterion. However, in some studies, all of them in a nonclinical setting, having asthma symptoms was not required. Most of the case-controlled studies included a population that already had a diagnosis of asthma and a healthy control group.

In eight studies, it was mentioned that smokers were excluded [10, 15, 18, 2629, 34]. Nine studies showed the numbers of current smokers included in the study [8, 9, 12, 16, 25, 31, 32, 35, 36], and in ten studies, no information was given on the smoking status of the participants [13, 17, 1924, 30, 33].

In all the included studies, the mannitol challenge test was conducted according to the protocol by Anderson et al. or by the Aridol package leaflet.

The following reference standards were used. Twelve studies used “clinical diagnosis” as a reference standard [810, 12, 13, 17, 21, 23, 24, 32, 35, 36], eight studies used “test result” [15, 17, 20, 23, 24, 26, 31, 33], and seven studies used “physician diagnosed asthma” [16, 22, 29, 30, 32, 34, 35]. In eight studies, anti-asthmatic therapy was appropriately stopped prior to the tests [10, 20, 23, 25, 27, 3335]. The individual characteristics of the included studies and their population are summarised in tables 1 and 2, including information about atopy status and FEV1.

Table 1

Study and population characteristics of all studies included in the systematic review – I.

Study author, year of publicationCountryStudy designPopulation settingNo. of participants analysedMale, n (%)Mean age, yearsAge range, yearsHealth inclusion criteriaMannitol test: protocol, definition of positive testReference standardSensitivity, % (95% CI)Specificity, % (95% CI)TPFPFNTN
Anderson, 1997 [15]AustraliaCase-controlClinical: local community50Asthmatics: 11 (26%), non-asthmatics: not reported2418–39Asthma diagnosis with current response to hypertonic saline and a healthy control groupProtocol by Anderson, FEV1 fall >20% (PD15 calculated)Test result: 4.5% NaCl*99.0 (88.0–100.0)99.0 (52.0–100.0)43007
Anderson, 2009 [10]USACross-sectionalClinical: university hospital375182 (49%)24.36–50Asthma symptomsPackage leaflet, FEV1 fall >15% or dFEV1>10% between consecutive dosesClinical diagnosis55.8 (49.3–62.2)74.8 (66.6–81.9)13434106101
Brannan, 2005 [13]AustraliaCase-controlClinical: general population and from pulmonary function clinics592272 (46%)34.76–83With or without Asthma symptomsProtocol by Anderson, FEV1 fall >15%Clinical diagnosis59.8 (55.2–64.1)95.2 (89.2–98.4)2915196100
Clearie, 2010 [22]Scotland, UKCross-sectionalNonclinical: elite swimmers59Not reported15.2Not reportedAthletes with and without physician diagnosed asthmaPackage leaflet, FEV1 fall >15% or dFEV1>10% between consecutive dosesPhysician diagnosed30.0 (6.7–65.2)89.8 (77.8–96.6)35744
Holzer, 2003 [23]AustraliaCross-sectionalNonclinical: elite athletes5015 (30%)2116–42Asthma symptoms or doctors diagnosis of asthmaprotocol by Anderson, FEV1 fall >15%Test result: eucapnic voluntary hyperpnoea challenge test*76.0 (55.0–91.0)92.0 (74.0–99.0)192623
Koskela, 2003 [25]FinlandCase-controlClinical: patients from outpatient clinic and healthy volunteers4726 (55%)Asthmatics: 49, non-asthmatics: 4119–85Patients with recently diagnosed asthma and healthy control groupProtocol by Anderson, FEV1 fall >15%Clinical diagnosis51.4 (34.4–68.1)100 (69.2–100)1901810
Lund, 2009 [16]DenmarkCase-controlNonclinical: elite athletes and general population11164 (58%)Asthmatics: 24–27.8, non-asthmatics 20.4–25.118–35Elite athletes with and without asthma and non-athletes with and without asthmaProtocol by Anderson, FEV1 fall >15%Physician diagnosed53.7 (37.4–69.3)95.7 (88–99.1)2231967
Miedinger, 2007 [12]SwitzerlandCross-sectionalNonclinical: full time fire fighters9494 (100%)4123–64Fire fighters with and without physician diagnosed asthmaProtocol by Anderson, FEV1 fall >15%Clinical diagnosis92.9 (66.1–99.8)97.5 (91.3–99.7)132178
Miedinger, 2010 [8]SwitzerlandCross-sectionalNonclinical: military conscripts235235 (100%)Not reported18–20Conscripts with and without physician diagnosed asthmaPackage leaflet, FEV1 fall >15% or dFEV1>10% between consecutive dosesClinical diagnosis40.5 (25.6–56.7)92.7 (88.1–96.0)171425179
Sverrild, 2009 [9]DenmarkCross-sectionalNonclinical: general population23896 (40%)18.914–24None specifiedProtocol by Anderson, FEV1 fall >15%Clinical diagnosis58.8 (44.2–72.4)98.4 (95.4–99.7)30321184
Aronsson, 2011 [28]SwedenCase-controlClinical: outpatient department at a university hospital and control group4923 (47%)3521–65Asthma diagnosis and healthy control groupPackage leaflet, FEV1 fall >15% or dFEV1>10% between consecutive dosesClinical diagnosis38.2 (22.2–56.4)100 (78.2–100)1302115
Subbarao, 2000 [26]CanadaCase-controlClinical: general population3421 (60%)106–13Asthma diagnosis and healthy control groupProtocol by Anderson, FEV1 fall >20% (PD15 calculated)Test result: Methacholine test*87.5 (67.6–97.3)100 (69.2–100)210310
Barben, 2011 [19]SwitzerlandCross-sectionalClinical: outpatient clinic9963 (64%)126–17Asthma symptomsPackage leaflet, FEV1 fall >15% or dFEV1>10% between consecutive dosesClinical diagnosis43.5 (31–56.7)94.6 (81.8–99.3)2723535
Stenfors, 2010 [30]SwedenCross-sectionalNonclinical: cross-country skiing or biathlon athletes4624 (52%)2119–31None specifiedProtocol by Anderson, FEV1 fall >15%Physician diagnosed8.3 (1.0–27.0)95.5 (77.2–99.9)212221
McClean, 2011 [29]AustraliaCase-controlNonclinical: workers at a research institute, hospital, university and volunteers6731 (46%)Asthmatics: 39.4, non-asthmatics: 3418–66Asthma diagnosis and healthy control groupProtocol by Anderson, FEV1 fall >15%Physician diagnosed61.5 (47.0–74.7)86.7 (59.5–98.3)3222013
Romberg, 2012 [17]SwedenCross-sectionalNonclinical: elite swimmers9755 (54%)1613–17None specifiedProtocol by Anderson, FEV1 fall >15%Test result: exercise test*50.0 (18.7–81.3)78.2 (68.0–86.3)519568
Andregnette-Roscigno, 2012 [24]SpainCross-sectionalNonclinical2314 (61%)12.97–17Asthma symptomsProtocol by Anderson, FEV1fall >15%Test result: methacholine test*55.6 (30.8–78.5)100 (47.8–100)10085
Ulrik, 2012 [18]DenmarkCross-sectionalNonclinical: elite canoe and kayak athletes2924 (83%)25.117–43None specifiedProtocol by Anderson, FEV1 fall >15%Clinical diagnosis42.9 (9.9–81.6)100 (84.6–100)30422
Kim, 2014 [27]KoreaCase-controlClinical: university hospital and control group10430 (29%)43.818–70Asthma diagnosis and healthy control groupProtocol by Anderson, FEV1 fall >15%Clinical diagnosis48.0 (33.7–62.6)92.6 (82.1–98.0)2442650
Toennesen, 2014 [20]DenmarkCross-sectionalNonclinical: elite athletes5742 (74%)27.5not reportedElite athletes participating at the Olympic Games 2008 with or without asthma symptomsProtocol by Anderson, FEV1 fall >15%Test result: mannitol or methacholine test*50.0 (26.0–74.0)92.3 (79.0–98.4)93936
De Menezes, 2018 [31]BrazilCross-sectionalNonclinical: workers at a university811326 (40%)32.4not reportedContact with laboratory animalsProtocol by Anderson, FEV1 fall >15%Test result: Mannitol test*99.9 (93.1–99.9)96.7 (95.1–97.8)66240721
White, 2017 [32]AustraliaCross-sectionalClinical: wheezing population and general population920Not reported2221–23Wheezing population: wheezing, general population: no wheezingProtocol by Anderson, FEV1fall >15%Physician diagnosis19.5 (13.6–26.6)97.1 (95.7–98.2)3022124744
Cancelliere, 2013 [33]SpainCross-sectionalClinical: university hospital287 (25%)3215–54Asthma-like symptoms (shortness of breath, wheezing, cough)Protocol by Anderson, FEV1 fall >15%Test result: Methacholine test and/or Mannitol test*87.5 (51.6–97.9)99.7 (75.0–100.0)100117
Osthoff, 2013 [34]SwitzerlandCross-sectionalNonclinical: Elite athletes (Swiss paralympic team)4430 (68%)34.4not reportednon specified (Swiss paralympic team)Protocol by Anderson, FEV1 fall >10%Physician diagnosed55.0 (23.4–83.3)94.0 (79.8–99.3)62531
Backer, 2015 [21]DenmarkCross-sectionalClinical: university hospital19082 (43%)32.115–not reportedSymptoms suggesting asthmaProtocol by Anderson, FEV1 fall >15%Clinical diagnosis38.0 (34.0–44.0)82.0 (71.0–89.0)46117657
Porpodis, 2016 [36]GreeceCross-sectionalClinical: university hospital8841 (47%)38.6not reportedAsthma-like symptoms (shortness of breath, wheezing, cough)Protocol by Anderson, FEV1 fall >15%Clinical diagnosis64.0 (51.5–75.5)95.0 (76.2–99.9)4312420
Vakali 2016 [35]Greece, UKCase-controlNonclinical: elite athletes200100 (50%)Asthmatics: 20.4, non-asthmatics: 22.120.7–22.5Athletes with and without physician diagnosed asthmaProtocol by Anderson, FEV1 fall >15%Physician diagnosed21.8 (12.0–35.0)95.0 (89.4–97.6)12843137

CI = confidence interval; FEV1 = forced expiratory volume in 1 second; TP = true positive; FP = false positive; FN = false negative; TN = true negative
* A positive test result was only accepted as a reference standard when the included subjects had respiratory symptoms

Table 2

Study and population characteristics of all included studies in the systematic review – II.

Study author, year of publicationSmoking statusAppropriate stop of antiasthmatic therapy prior to test*Asthma related symptomsTime between asthma diagnosis and mannitol testFEV1 (L) asthmaFEV1(% pred) asthmaFEV1 (L) controlFEV1 (% pred) controlFEV1 (L) allFEV1 (% pred) allAtopy in asthmaticsAtopy in controlsAtopy in allPublication status
Anderson, 1997 [15]All non-smokersNoAsthmatics: yes, non-asthmatics: no symptomsNot reportedNot reported82.9 (SD 12.9)Normal valuesNormal valuesNot reportedNot reported100%43%92%Peer-reviewed
Anderson, 2009 [10]All non-smokersYesYes, currentCouple of weeksNot reportedNot reportedNot reportedNot reported3.32 (SD 0.82)93.6 (SD 10)Not reportedNot reported16% to 50%Peer-reviewed
Brannan, 2005 [13]Not reportedNoAsthmatics: yes, current, non-asthmatics: no symptomsSimultaneouslyNot reportedNot reportedNot reportedNot reported3.0 (SD 0.9)95.0 (SD 14.5)Not reportedNot reportedNot reportedPeer-reviewed
Clearie, 2010 [22]Not reportedNoYes, 26 (43%) with exercise induced symptoms3 daysNot reportedNot reportedNot reportedNot reportedNot reportedNot reportedNot reported1424%Peer-reviewed
Holzer, 2003 [23]Not reportedYesYes, current1 weekNot reportedNot reportedNot reportedNot reportedWithin normal limits (>80% of predicted)103.6 (SD 10.8)Not reportedNot reportedNot reportedPeer-reviewed
Koskela, 2003 [25]Current smokers: 6; former smokers: 14; never smoked: 27YesAsthmatics: yes, current, non-asthmatics: no symptoms2 weeks2.9 (95% CI 2.6–3.1)81 (95% CI 76–86)3.9 (95% CI 3.1–4.7)99 (95% CI 95–104)Not reportedNot reported38%10%Not reportedPeer-reviewed
Lund, 2009 [16]Current smokers: 7Elite athletes: no, non-athletes: yesAll athletes (54): yesSimultaneously4.37 (SD 0.19) for elite athletes; 3.73 (SD 0.14) for non-elite athletes98.2 (SD 1.94) for elite athletes; 82.6 (SD 2.63) for non-elite athletes4.91 (SD 0.15) for elite athletes, 3.87 (SD 0.13) for non-elite athletesElite: 105.4 (SD 2.10); non-elite: 96.9 (SD 1.82)Not reportedNot reportedElite athletes: 21%; non-elite athletes: 100%Elite athletes: 51%; non-elite athletes: 29%Not reportedPeer-reviewed
Miedinger, 2007 [12]Current smokers: 33Not reportedAsthmatics: yes, in the past 12 months, non-asthmatics: unclear1 weekNot reportedRange of 42–105Not reportedNot reportedNot reported103 (SD 12)86%Not reported51%Peer-reviewed
Miedinger, 2010 [8]Current smokers: 77Not reportedAsthmatics: yes, in the past 12 months, non-asthmatics: unclear48 hoursNot reported95 (IQR 88;102)Not reported98 (IQR 91;105)Not reportedNot reported74%36%42%Peer-reviewed
Sverrild, 2009 [9]Current smokers: 52NoAsthmatics: yes, in the past 12 months, non-asthmatics: unclearNot reportedNot reportedNot reportedNot reportedNot reportedNot reported96.92 (SD 10.60)Not reportedNot reported42%Peer-reviewed
Aronsson, 2011 [28]All non-smokersNoAsthmatics: current exercise induced symptoms 27 (79%), non-asthmatics: no symptomsA couple of weeks3.7 (SD 1.0)95.5 (SD 14.2)3.6 (SD 0.8)98.6 (SD 6.8)Not reportedNot reported82%0%Not reportedPeer-reviewed
Subbarao, 2000 [26]All non-smokersNoAsthmatics: yes, current, non-asthmatics: no symptomsNot reportedNot reportedNot reportedNot reportedNot reportedNot reportedNot reported87%0%Not reportedPeer-reviewed
Barben, 2011 [19]Not reportedNoYes, currentA few daysNot reportedNot reportedNot reportedNot reportedNot reported97 (IQR 88;104)Not reportedNot reported89.0%Peer-reviewed
Stenfors, 2010 [30]Not reportedNoIn 17% classical Symptoms of exercise induced asthmaNot reported4.7 (SD 1.1)97.7 (SD 14.0)4.5 (SD 0.5)101.4 (SD 7.5)Not reportedNot reported55%50%Not reportedPeer-reviewed
McClean, 2011 [29]All non-smokersNoAsthmatics: were well controlledNot reportedNot reported87 (SD 13.0)Not reported104 (SD 14.4)Not reportedNot reported83%53%Not reportedPeer-reviewed
Romberg, 2012 [17]Not reportedNoExercise induced symptoms 75 (77.3%), current asthma symptoms 60 (62.0%), current asthma symptoms with exercise induced symptoms 54 (55.7%): past 12 monthsNot reportedNot reportedNot reportedNot reportedNot reportedNot reported112 (IQR 104;118)Not reportedNot reported54%Peer-reviewed
Andregnette-Roscigno, 2012 [24]Not reportedNoYesNot reportedNot reportedNot reportedNot reportedNot reportedNot reportedNot reportedNot reportedNot reported70%Peer-reviewed
Ulrik, 2012 [18]All non-smokersNoAsthmatics with previous diagnosis of asthma: yes, asthmatics with no previous diagnosis of asthma: no, non-asthmatics: not reportedSimultaneously4.5 (SD 0.6)103.3 (SD 13.3)4.8 (SD 0.9)109.1 (SD 14.8)Not reportedNot reported57%18%Not reportedPeer-reviewed
Kim, 2014 [27]All non-smokersYesAsthmatics: yes, in the past 6 months, non-asthmatic: noNot reportedNot reported91.2 (SD 12.2)Not reported95.0 (SD 19.4)Not reportedNot reportedAllergic rhinitis 66%, atopic dermatitis 18%, allergic conjunctivitis 22%allergic rhinitis 15%, atopic dermatitis 0%, allergic conjunctivitis 2%allergic rhinitis 39%, atopic dermatitis 9%, allergic conjunctivitis 12%Peer-reviewed
Toennesen, 2014 [20]Not reportedYesAsthmatics: yes (unclear if current or in the past), non-asthmatics: noNot reportedNot reported117 (SD 15)Not reported117.3 (SD 11.8)Not reported117.2 (12.7)17%18%18.00%Peer-reviewed
De Menezes, 2018 [31]Current smokers: 69 (8.5%)NoYes, in the past 12 monthsNot reported3.35 (SD 0.64)91.8 (SD 11.5)3.54 (SD 0.75)97.4 (SD 11.3)Not reportedNot reportedNot reportedNot reported47%Peer-reviewed
White, 2017 [32]Current smokers: 158NoGeneral population: unclear, wheezing population: 148 (100%) in the past 12 monthsNot reportedNot reportedGeneral population: 95 (SD 11.60), wheezing population: 95 (SD 11.58)Not reportedGeneral population: 98 (SD 10.76); wheezing populationd: 98 (SD 10.23)Not reportedNot reportedGeneral population: 75%, wheezing population 75%General population: 55%; wheezing population: 62%Not reportedPeer-reviewed
Cancelliere N, 2013 [33]Not reportedYesYes, currentNot reportedNot reportedNot reportedNot reportedNot reportedNot reportedNot reportedNot reportedNot reportedNot reportedPeer-reviewed
Osthoff, 2013 [34]All non-smokersYesAsthmatics: yes, current, non-asthmatics: unclearNot reportedNot reportedNot reportedNot reportedNot reported3.63Not reported32%Not reportedNot reportedPeer-reviewed
Backer, 2015 [21]Only reported that individuals older than 40 years with > 10 pack-years were excludedNoYes, current2–3 weeks3.7 (SD 0.9)97 (SD 17)3.8 (0.9)97 (SD 17)3.8 (SD 0.9)95 (SD 17)63%44%56%Peer-reviewed
Porpodis, 2016 [36]Current smokers: 17, former smokers: 16, never smoked: 55NoYes, in the last month14–20 daysNot reportedNot reportedNot reportedNot reported3.2 (SD 0.9)88.5 (SD 12.6)Not reportedNot reported43%Peer-reviewed
Vakali, 2016 [35]Smokers: 8%Yes (but refer to ATS Crapo criteria)YesNot reported4.07 (95% CI 3.9–0.2)Not reported4.29 (95%CI 4.1–4.5)Not reported4.1 (95%CI 4.1–4.2)Not reported62%44%49%Peer-reviewed

CI = confidence interval; FEV1 = forced expiratory volume in 1 second; IQR = interquartile range; SD = standard deviation
* according to Anderson et al. [10]

Risk of bias assessment of studies

Overall, the quality of the included studies was good with a low risk of bias from the procedure and interpretation of the mannitol test and the patient flow. Only nine studies mentioned that the results of the mannitol test were interpreted without knowing the results of the reference standard [8, 10, 12, 13, 17, 20, 21, 24, 34]. The domains “patient selection” and “reference standard” showed heterogeneous results concerning methodological quality (see appendix 4). The risk of bias in the patient selection was high in all the studies that used a case-controlled design [13, 15, 16, 2529, 35]. Applicability was judged to be limited for studies that included only a special population such as elite athletes, young male military conscripts or fire fighters [8, 12, 16, 18, 19, 26, 30, 31, 3335], and studies, that excluded smokers [10, 15, 18, 2629, 34]. Concerning the reference standard, the risk of bias was usually rated low in all studies that used a “clinical diagnosis of asthma” as a reference standard, and remained unclear in studies using “physician diagnosed asthma” as a reference standard. In seven studies, we observed a high risk of bias as the mannitol test was part of the reference standard and blinding of the test results was not done [8, 12, 1820, 31, 33].

Diagnostic accuracy of the mannitol test

Overall, sensitivity and specificity were very heterogeneous, with values ranging from 8% (95% CI 1–27%) to 100% (95% CI 93–100%) for sensitivity and 75% (95% CI 67–82%) to 100% (95% CI 85–100%) for specificity. [810, 12, 13, 1536,] We graphically presented the high level of between-study heterogeneity in the ROC space plot in figure 2. To explore the different populations, we grouped studies according to the populations (clinical vs nonclinical and children vs adults and mixed; fig. 3). As case-controlled studies represent the highest risk for bias [37], we tabulated them in a separate forest plot in figure 3.

fullscreen
Figure 2
ROC space plot of all included studies (n = 27)
fullscreen
Figure 3
Forest plot of the sensitivity and specificity of the mannitol test showing several subgroups of the included cross-sectional studies (n = 18) and case-controlled studies (n = 9).
TP = true positive; FP = false positive; FN = false negative; TN = true negative; CI = confidence interval

When all case-control studies were excluded, cross sectional and cohort studies conducted in a clinical setting showed a range from 19% (95% CI 14–27%) to 91% (95% CI 59–100%) for sensitivity and from 75% (95% CI 67–82%) to 100% (95% CI 80–100%) for specificity [10, 19, 21, 32, 33, 36]. Cross-sectional and cohort studies conducted in a nonclinical setting showed a range from 8% (95% CI 1–27%) to 100% (95% CI 95–100%) for sensitivity and from 78% (95% CI 68–86%) to 100% (95% CI 85–100%) for specificity [8, 9, 12, 16, 1820, 26, 27, 30, 34, 35]. In all studies that considered patients who had stopped asthma medication appropriately prior to testing, sensitivity and specificity ranged from 22% (95% CI 12–35%) to 91% (95% CI 59–100%) and from 75% (95% CI 67–82%) to 100% (95% CI 80–100%), respectively [10, 20, 23, 25, 27, 3335]. In the studies that did not stop asthma medication appropriately, sensitivity and specificity ranged from 8% (95% CI 1–27%) to 100% (95% CI 95–100%) and from 78% (95% CI 68–86%) to 100% (95% CI 85–100%). [9, 13, 15, 17, 18, 22, 2428, 3236]

Discussion

We found a high level of heterogeneity among the included studies and explored reasons for this by assessment of the different study designs and methods used, population characteristics such as atopy status and smoking, and risk of bias. We explored populations further by dividing them into subgroups, showing forest plots as well as giving the range of accuracy. There is no evidence that accuracy of the mannitol tests differs according to the populations examined.

Reasons for the heterogeneity in sensitivity and specificity of the mannitol test have previously been discussed and may be false negative and false positive mannitol tests. One reason for the heterogeneity in sensitivity and specificity may be current asthma treatment and lack of current asthma inflammation, which may lead to false negative results as the mannitol test just shows how many participants have active asthma at the time of assessment. A positive result for mannitol indicates the presence of inflammatory cells and a sufficient concentration of mediators to cause bronchoconstriction. A negative test result indicates that one of these elements is missing, such as is the case in treated asthmatic patients with inhaled corticosteroids (ICS), β2 agonists or leukotriene inhibitors [38, 39]. An example for this circumstance is the study of Brannan et al., who assessed that the sensitivity of the mannitol test to identify asthma was 59.8%, which rose to 88.9% when those asthmatics taking ICS, who were negative to mannitol challenge, were excluded [13]. In a later analysis of the adult data from this study, Brannan et al. reported that 49% of the asthmatic patients taking ICS daily were negative to mannitol [40]. This is confirmed by our analysis in which sensitivity was higher in studies in which asthma medication was stopped for an appropriately long time according to Anderson et al. than in those studies in which this was not the case [10].

Another case in which a mannitol test can be negative is when a trigger for asthma is taken away and no asthma inflammation is present, which has been seen for reduced exposure to house dust mites in house dust mite allergic patients [41]. Overall, the fact that the specificity was high demonstrates that there are few false positive tests. A reason for false positive results could be current smoking, which has been previously examined by Stolz et al. [42] Current smokers were excluded in several of the examined studies, a possible reason for the few false positive tests.

To a lesser degree, different reference standards may have caused heterogeneity. Even though the GINA guidelines give advice on the best diagnostic approach in asthma, a single gold-standard test does not exist [1]. We therefore accepted various reference standards.

The ROC space plot indicated that there are some studies that are clearly separate from the main group and which we would like to discuss in more detail.

In this context we need to discuss those studies in which the mannitol test was not only the index test but was also included in the reference standard, as this may lead to an overestimation of sensitivity and specificity. Looking at the studies by Miedinger [12], De Menezes [31] and Cancelliere [33], we find support for this assumption as all three show exceptionally high sensitivity. As we only included studies that combined clinical symptoms with the mannitol test result to make a diagnosis, we still assume that these are truly asthmatic patients. However, incorporation bias is of concern and we did acknowledge the risk of bias to be high (see appendix 4). An exclusion of the studies including mannitol in their reference standard may have caused an inclusion bias, as a a certain phenotype of asthma may have been selected.

In contrast, the studies by Clearie [22], Stenfors [30], Vakali [35] and White [32] showed lower sensitivity than the other studies. The studies by Clearie, Stenfors and Vakali were all conducted in nonclinical settings. They included athletes. In the study by Clearie, the fact that the elite swimmers continued to take inhaled corticosteroids before testing could be another reason for the sensitivity of only 30%, as corticosteroid treatment has been shown to inhibit indirect bronchial hyperresponsiveness, as mentioned previously [13]. In the study by Stenfors [30], the slection of asthmatic athletes were probably biased towards subjects with mild and/or well-controlled asthma, as only 21% of them had bronchial hyperresponsiveness, 29% had experienced shortness of breath post-exercise and 15% had an asthma attack in the last 12 months. Additionally, 37% were taking anti-inflammatory medicine, including steroids. As the mannitol protocol is fixed, it is not possible to administrate additional doses to elucidate a response in those with mild asthma, which may cause false negative results and thus low sensitivity in this situation [38]. In the study by White [32], the use of ICS might be a reason for the low sensitivity of 19%. However, even after participants with a negative mannitol test who were using ICS were excluded, there was no real change in sensitivity. A reason for the low sensitivity in this study might be the fact that all participants seem to have only mild asthma, showing normal pulmonary function and only a few reporting the use of ICS in the past 12 months.

The mannitol test showed high specificity diagnosing asthma in all studied populations independent of age group or study setting.

Due to its heterogeneity, we cannot postulate a certain phenotype of asthma in which mannitol is specifically useful. Previous studies reported a higher specificity and correlation with eosinophilic asthma [38, 4346], which we cannot confirm because of the present heterogeneity of the studies. What we do see is the strength of the mannitol test to confirm asthma owing to the high specificity showed in our systematic review. This, as well as the high practicability of the mannitol test, could make it a useful diagnostic test in certain population groups such as athletes in a nonclinical setting.

As our systematic review focused on the mannitol test and we did not include a review on methacholine test, a direct comparison with a direct test such as methacholine is therefore not possible. From the literature it is known that the methacholine test shows a high sensitivity and a high negative predictive value and therefore seems to be a good test to exclude asthma. It therefore, also due to the low sensitivity of the mannitol test emphasised in our review, remains the test of choice to exclude asthma in patients with symptoms that suggest asthma, but are caused by another condition [38].

This was the first systematic review assessing the accuracy of the mannitol test in diagnosing asthma. In 2011, a systematic review assessed the accuracy of the mannitol test, but the diagnosis differed from our systematic review as this review concentrated on the diagnosis of exercise-induced bronchoconstriction, and the objective differed as it focussed on comparing eucapnic voluntary hyperpnoea and mannitol with standard exercise challenge testing [47]. Three studies were detected of which only one was also included in our systematic review [10]. Comparable to our results they found that there are only a few studies that assessed the accuracy of the mannitol test, and that heterogeneity was high [47]. Several reviews have discussed the advantages and disadvantages of indirect challenge tests, including mannitol, but no systematic review has been performed with an assessment of the risk of bias of publications [38, 39, 48, 49].

We conducted this systematic review according to a prespecified protocol, using a comprehensive literature search strategy and multiple reviewers, which strengthened the analysis by avoiding publication bias and selection bias. Another strength was the application of the Quality Assessment of Diagnostic Accuracy Studies instrument [14].

Our systematic review has limitations. There is a possibility of publication bias as we may have missed some studies despite systematic screening. There is also the risk of study selection bias, which we aimed to overcome by using two independent reviewers. Another limitation was that not all studies were designed as accuracy studies and methodological issues limited the generalisability of the results. Even though the general quality of the included studies was good, one concern was the blinding of the assessors, which was poorly reported. Studies followed a strict, predefined protocol of the mannitol test, and it was therefore deemed unlikely that a lack of blinding would have caused bias. In the studies where the methacholine test was part of the reference standard, the lack of blinding was not an important concern, as the methacholine test is an objective test. Because of selection bias, we plotted case-controlled studies separately. Our main concern about the case-controlled design was selection bias, as patients who have difficult-to-diagnose asthma are usually not included. This may lead to an overestimation of sensitivity and specificity.

Conclusions

The 27 studies included in the systematic review showed very heterogeneous results concerning the accuracy of the mannitol test in the diagnosis of asthma. This may have been caused by different study methods that resulted in false negative or false positive tests, as well as different study settings, populations and reference standards. This between-study heterogeneity hindered the formation of a conclusive statement on the accuracy of the mannitol test and there needs to be further research. In future studies, factors that may influence sensitivity and specificity such as smoking, stopping of asthma medications and current asthma symptoms, FEV1 and atopy status (information about seasonal allergies and time of assessment) should be considered and clearly stated.

Because of the high specificity the mannitol test showed in our systematic review, it seems to be a good test to confirm a diagnosis of asthma. This, and the advantage of a standardised protocol with an easy and safe test procedure, can make it a good diagnostic tool also in a nonclinical setting. To exclude asthma, however, methacholine seems to remain the test of choice as the literature shows high sensitivity, whereas in our review we could often only show low sensitivity and heterogeneous results for the mannitol test.

As bronchial provocation tests can be especially useful in patients with an intermediate probability of asthma diagnosis, further studies are needed that include subjects with asthma symptoms but an intermediate probability of asthma diagnosis. In these studies, a longitudinal follow-up would be useful in order to verify the diagnosis and establish an appropriate reference standard.

Acknowledgments

The authors would like to thank Gill Worthy for her support in data analysis and figure creation.

Author contributions

PK and EHSK contributed equally to the manuscript.

Financial disclosure

This study was supported by the Allergiestiftung Ulrich Müller-Gierok.

Potential competing interests

Prior to this study, David Miedinger and Jörg Leuppi received free mannitol bronchial provocation test kits from Pharmaxis Ltd. to perform clinical studies investigating patients with asthma/COPD or individuals in the workforce.

Correspondence

Prof. Jörg D. Leuppi, MD, PhD, University Clinic of Medicine, Cantonal Hospital Baselland, Rheinstrasse 26, CH-4410 Liestal, joerg.leuppi[at]ksbl.ch

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Appendix 1

Search strategy

The search strategy included the term (mannitol) combined with (asthma OR bronchial* OR bronchoconstrict*). In Embase the terms were: ‘mannitol’/exp OR ‘mannitol’/syn AND (‘asthma’/exp OR ‘asthma’/syn OR bronchial* OR ‘bronchoconstriction’/exp OR ‘bronchoconstriction’/syn), in PubMed/Medline they were: mannitol AND (asthma OR bronchial* OR bronchoconstrict*). For our search there was no language restriction imposed.

Appendix 2

Assessment of methodological quality

The methodological quality of the selected studies was graded independently and in duplicate by two reviewers with the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2, an improved, redesigned tool since the original QUADAS tool), a validated tool for the quality assessment of diagnostic accuracy studies [14]. The QUADAS-2 tool includes 4 domains (patient selection, index test, reference standard, and flow and timing). Each domain is assessed in terms of risk of bias, and the first 3 domains also in terms of concerns regarding applicability. Some signalling questions are included to help judge the risk of bias. We added some signalling questions to the predefined QUADAS-2 form, which seemed to be important to us judging our included studies. Disagreements were resolved by consensus. If consensus was not achieved, a third reviewer had the decisive vote.

Appendix 3

Data extraction

The two reviewers extracted data on characteristics of studies and patients, the index test and the reference standard as well as test results. Wherever possible, we recorded for each study: Title, author, year of publication, country and journal, conflict of interest and project funding, study aim, study design (cohort study, case-control study, cross-sectional or later follow-up, prospective or retrospective), study population (age, prevalence of asthma, severity of symptoms, co morbidity, smoking status, gender, professional sportsmen, history of asthma, atopy), Stop of anti-asthmatic therapy prior to the index test, Patient selection (consecutive, non-consecutive, random- sample, inclusion- and exclusion criteria), technical details of Mannitol bronchial provocation and reference tests regarding standardisation (protocol, definition for positive/negative test result), performance of the index test (sensitivity and specificity), number of individuals eligible and no of individuals who underwent the tests, number of individuals undergoing either the index and the reference test missing one or the other, time interval between the index and the reference test, side effects from undergoing either the Mannitol bronchial provocation test or reference standard, number of individuals in whom the test was terminated prematurely or was not analysable, reasons for exclusion from test or analysis, inter-observer variability and test reproducibility, reported results (Sensitivity, Specificity, true positive, true negative, false positive, false negative, positive predictive value, negative predictive value), Data for two-by-two table.

Appendix 4

Methodological quality of included studies

 Anderson, 1997[15]Anderson, 2009[10]Brannan, 2005[13]Clearie, 2010[22]Holzer, 2003[23]Koskela, 2003[25]Lund, 2009[16]Miedinger, 2007[12]Miedinger, 2010[8]Sverrild, 2009[9]Aronsson, 2011[28]Subbarao, 2000[26]Barben, 2011[19]Stenfors, 2010[30]McClean, 2011[29]Romberg, 2012[17]Andregnette-Roscigno, 2012[24]Ulrik, 2012[18]Kim, 2014[27]Toennesen, 2014[20]De Menezes, 2018[31]White, 2017[32]Cancelliere 2013[33]Osthoff, 2013[34]Backer, 2015[21]Porpodis, 2016[36]Vakali, 2016[35]
PATIENT SELECTION                           
Consecutive or random sample enrolment?unclearunclearunclearunclearunclearyesunclearnoyesyesunclearunclearunclearunclearunclearunclearunclearunclearunclearunclearnonoyesyesyesyesunclear
Case-control design avoided?noyesnoyesyesnonoyesyesyesnonoyesyesnoyesyesyesnoyesyesyesyesyesyesyesno
Inappropriate exclusions avoided?nonoyesyesyesyesyesyesyesyesnonoyesyesnounclearunclearnonoyesnoyesyesnonounclearno
Risk of BiasHIGHLOWHIGHLOWLOWHIGHHIGHLOWLOWLOWHIGHHIGHLOWLOWHIGHUNCLEARLOWLOWHIGHLOWLOWLOWLOWLOWLOWLOWHIGH
Applicability concernsHIGHHIGHLOWHIGHHIGHLOWHIGHHIGHHIGHLOWHIGHHIGHLOWHIGHHIGHHIGHLOWHIGHHIGHHIGHHIGHLOWLOWHIGHLOWLOWHIGH
INDEX TEST (MANNITOL)                           
Description of Index Testyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyes
Results interpreted without knowing results of the reference standard (Blinding)noyesyesunclearunclearunclearunclearunclearyesyesnounclearnounclearunclearyesyesunclearunclearyesunclearunclearnoyesyesunclearunclear
If a threshold was used, was it pre-specified?yesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesyes
Risk of BiasLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOW
Applicability concernsLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOW
REFERENCE STANDARD                           
Description of Reference standardyesyesyesnonoyesnoyesyesyesyesyesyesnonoyesyesyesyesyesyesnoyesnoyesyesno
Results interpreted without knowing results of the Mannitol test (Blinding)yesyesyesyesyesyesyesnonoyesyesyesnoyesyesunclearunclearnoyesnonounclearnounclearyesyesyes
Adequate Reference standardyesyesyesunclearyesyesunclearyesyesyesyesyesyesunclearunclearyesyesyesyesyesyesunclearyesunclearyesyesunclear
Mannitol Test was not part of the Reference standard (no incorporation bias)yesyesyesyesyesyesyesnonoyesyesyesnounclearunclearyesyesnoyesnonoyesnounclearyesyesunclear
Risk of BiasLOWLOWLOWUNCLEARLOWLOWUNCLEARHIGHHIGHLOWLOWLOWHIGHUNCLEARUNCLEARLOWLOWHIGHLOWHIGHHIGHUNCLEARHIGHUNCLEARLOWLOWUNCLEAR
Applicability concernsLOWLOWLOWUNCLEARLOWLOWUNCLEARLOWLOWLOWLOWLOWLOWUNCLEARUNCLEARHIGHLOWLOWLOWLOWLOWUNCLEARLOWUNCLEARLOWLOWUNCLEAR
FLOW AND TIMING                           
Appropriate time intervall between Mannitol test and reference standard (>24h and <1week)unclearunclearyesunclearunclearnounclearyesunclearunclearunclearyesyesunclearunclearunclearyesunclearunclearunclearnounclearnoyesunclearnounclear
Therapeutic intervention avoided between Index test and reference standardyesyesnounclearunclearyesunclearyesunclearyesunclearyesyesunclearnoyesunclearnounclearyesnononoyesunclearunclearunclear
Did all patients receive a reference standardyesyesyesyesyesyesyesyesyesyesyesyesyesyesyesnoyesyesyesyesyesyesyesyesyesyesyes
Did all patients receive the same reference standardyesyesyesunclearunclearyesunclearyesunclearyesunclearyesnounclearunclearyesyesyesyesyesyesyesyesyesyesyesyes
Were all patients included in the analysisyesunclearnonoyesnoyesnonononononoyesyesnoyesyesyesyesnoyesyesyesyesyesyes
Were reasons reported for stopping a testnot applicableyesyesyesnot applicablenot applicablenot applicableyesyesyesyesyesyesnot applicablenot applicablenot applicablenot applicablenot applicablenot applicablenot applicableyesnot applicablenot applicablenot applicablenot applicablenot applicablenot applicable
Risk of BiasLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWLOWUNCLEARUNCLEARLOWLOWLOWLOWHIGHHIGHHIGHLOWLOWLOWLOW

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