Bachert, Claus

Berings, Margot

De Ruyck, Natalie

Derycke, Lara

Dullaers, Melissa

Ellis, J

Gevaert, Philippe

Ghekiere, P

Jult, Anton

Lambrecht, Bart

Temmerman, R

Ucar, H

Vermeulen, Hanne

Ghent University Academic Bibliography

R E S E A R CH L E T T E RProbiotics-impregnated bedding covers for house dust miteallergic rhinitis: A pilot randomized clinical trialM. Berings1,2 | A. Jult3 | H. Vermeulen3 | N. De Ruyck1 | L. Derycke1 | H. Ucar4 |P. Ghekiere4 | R. Temmerman5 | J. Ellis6 | C. Bachert1 |B. N. Lambrecht2,7 | M. Dullaers2,7,8* | P. Gevaert1*1Upper Airways Research Laboratory, Ghent University, Ghent, Belgium2Laboratory of Immunoregulation, VIB Inflammation Research Center, Ghent, Belgium3Ghent University, Ghent, Belgium4BekaertDeslee Innovation bvba, Waregem, Belgium5Chrisal NV, Lommel, Belgium6Devan Chemicals NV, Ronse, Belgium7Department of Internal Medicine, Ghent University, Ghent, Belgium8Clinical Immunology Research Lab, Department of Respiratory Medicine, Ghent University Hospital, Ghent, BelgiumCorrespondenceMargot Berings, MD, Upper Airways Research Laboratory, Department of Otorhinolaryngology, Ghent University Hospital, Ghent, Belgium.Email: margot.berings@ugent.beFunding informationThis is an investigator-initiated trial supported by an unrestricted grant provided by BekaertDeslee Innovation bvba. Margot Berings is a PhD fellow of theResearch Foundation–Flanders (FWO, grant numbers FWO.3F0.2013.0004.01 and FWO.3F0.2013.0004.02), and Philippe Gevaert is a senior clinicalinvestigator of the Research Foundation–Flanders (FWO).1 | INTRODUCTIONAllergic rhinitis (AR) affects up to one-third of the adult populationand causes illness and disability world-wide.1 Main symptoms includesneezing, rhinorrhea and nasal obstruction. AR is often accompaniedwith conjunctivitis, characterized by watery, itchy and sometimes redor swollen eyes. House dust mite (HDM) allergens are one of themost relevant indoor allergy triggers.2 Treatment of AR consists ofsymptomatic medications (mainly antihistamines and nasal corticos-teroids) and allergen-specific immunotherapy (in more severe cases).1Although HDM avoidance is generally recommended, there is littleevidence of beneficial effects on allergy symptoms. Several studiesevaluated the effect of HDM avoidance in patients with AR, how-ever, to date only nine studies fulfil the criteria of randomized clini-cal trials (RCTs).3 Five of these studies evaluated the use ofimpermeable bedding covers, alone or in combination with otheravoidance measures. Based on these studies, especially the study byTerreehorst et al.4, it is concluded that the isolated use of imperme-able bedding is unlikely to be effective.3 The use of high efficiencyparticulate air (HEPA) filters is poorly investigated (two smallstudies), and results are not convincing.3 Two small RCTs in the early1990s suggested some beneficial effects of acaricides as a HDMavoidance measure, but to date, no larger, well-designed RCTs haveconfirmed the results.3As current evidence for existing HDM avoidance measures is low,new methods are being developed. Purotex is a probiotics-based tex-tile treatment, which contains five different probiotic and natural bac-terial strains of Bacillus species (strains of Bacillus subtilis, Bacillusamyloliquefaciens and Bacillus pumilus). In laboratory setting, Purotex-treated fabric showed a reduction of 89.3% of Der p 1 levels comparedwith untreated fabric (BMA-Labor GbR, Bochum, Germany). However,up to now, the effect of these probiotics-impregnated covers had notbeen tested in a clinical trial. Therefore, we set out to perform the firstpilot RCT to evaluate the effectiveness of Purotex covers to reduceHDM allergen levels in bedding, and to improve allergy symptoms andquality of life (QoL) of patients with AR to HDM.2 | METHODSAll patients were recruited via the Department of Otorhinolaryngol-ogy in Ghent University Hospital (Belgium). Prior to patient*Melissa Dullaers and Philippe Gevaert contributed equally.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction inany medium, provided the original work is properly cited and is not used for commercial purposes.© 2017 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons LtdDOI: 10.1111/cea.129371092 | wileyonlinelibrary.com/journal/cea Clin Exp Allergy. 2017;47:1092–1096.enrolment, the trial was registered at clinical.trials.gov (NCT01997606).Patients aged 18-65 years were considered eligible if they hada clinical history consistent with AR to HDM for at least 1 year, apositive skin prick test to D.Pteronyssinus (D.pt), a positive nasalallergen provocation test (NAPT) to HDM extract (Alyostal, Staller-genes) and sIgE to D.pt of at least 0.7 kU/L (ImmunoCAP; Phadia,Uppsala, Sweden) at screening. Moreover, subjects were random-ized only when Der p 1 was detectable (≥0.488 ng/mL dustextract, corresponding to ≥9.76 ng/g dust) in dust samples col-lected from their mattress and/or pillow at screening. This trial wasdesigned as an explorative pilot study with an intended sample sizeof 20 patients.Purotex textile treatment contains five different probiotic andnatural (not genetically modified) bacterial strains of Bacillus species.The probiotic spores are encapsulated in microcapsules (2-3 lm),which are diffusely inserted in the textile. Upon friction forcesbetween the cover and the sleeper’s body, a small number of themicrocapsules rupture and release their probiotic bacteria.The probiotics-impregnated covers and the untreated (placebo)covers were indistinguishable from one another: they were identicalin colour, feeling and smell.The study was designed as a pilot double-blind, randomized, pla-cebo-controlled, crossover trial (see Figure S1). The study consistedof four periods: (i) a run-in period of 4 weeks (without study cover),(ii) a first study period of 8 weeks (with probiotics-impregnated cov-ers, resp. placebo covers), (iii) a washout period of at least 4 weeks(without study cover) and (iv) a second study period of 8 weeks (withplacebo covers, resp. probiotics-impregnated covers).Der p 1 levels in mattress and pillow dust samples were the pri-mary outcome measures. Dust samples were collected by thepatients every 2 weeks (day 0, 14, 28, 42, 56).Symptoms, QoL and use of reliever medication were secondaryoutcome measures. Questionnaires (Visual Analogue Scales, VAS5;Rhinoconjunctivitis Quality of Life Questionnaire, RQLQ6; NocturnalRhinoconjunctivitis Quality of Life Questionnaire, NRQLQ7) werecompleted weekly.Additional descriptions of the methods can be found inAppendix S1.3 | RESULTSOf 34 screened subjects, 24 subjects met all inclusion and exclusioncriteria and were randomized. Four randomized subjects discontin-ued the trial, and finally, 20 patients were retained for analysis (pa-tient enrolment and dropout are summarized in Figure S2). Patientcharacteristics at screening are shown in Table S1.Der p 1 levels, symptom and QoL scores at baseline of the Puro-tex period and the placebo period were comparable (see Table 1).A significant and comparable decrease in Der p 1 levels wasobserved with the placebo covers and the probiotics-impregnatedcovers (both for mattress and pillow dust samples) (see Figure 1).With the probiotics-impregnated covers, there was a significantoverall improvement compared to baseline of several symptoms andQoL scores (see Figure 1 and Figure S3): VAS for subjective controlof AR symptoms (P=.001), VAS for global discomfort (P=.008), VASfor nose symptoms (P<.001), VAS for eye symptoms (P=.03), RQLQtotal score (P=.01), RQLQ nose symptoms (P=.02), RQLQ eye symp-toms (P=.02) and NRQLQ total score (P=.02). Improvement of symp-toms and QoL with the probiotics-impregnated covers occurredmainly during the second half of the study period (week 5-8). Bycontrast, there was not any significant overall change from baselinewith the placebo covers. However, the differences in effect betweenthe probiotics-impregnated covers and placebo were not significant.The only significant P-value (P=.048 for NRQLQ sleeptime) for differ-ence in effect between both study covers was no longer significantafter correction for multiple comparisons (Benjamini-Hochbergprocedure).TABLE 1 Outcomes: baseline levelsPurotex period(n=20)Placebo period(n=20) P-value*VAS for AR symptomscontrol, score/10051.8 (39.5-64.2) 50.8 (38.4-63.1) .86VAS for globaldiscomfort,score/10052.8 (40.5-65.0) 53.0 (40.8-65.3) .97VAS for nasalsymptoms,score/10042.8 (32.0-53.6) 40.8 (30.0-51.6) .67VAS for eyesymptoms,score/10035.2 (24.2-46.2) 28.6 (17.6-39.5) .19VAS for interferencewith sleep, score/10043.8 (31.0-56.6) 43.0 (30.1-55.8) .89VAS for lower airwaysymptoms, score/10015.7 (8.2-23.2) 17.3 (9.8-24.8) .64RQLQ total score,score/62.3 (1.8-2.7) 2.3 (1.8-2.8) .88RQLQ nose symptoms,score/62.7 (2.0-3.3) 2.6 (2.0-3.2) .81RQLQ eye symptoms,score/62.0 (1.4-2.5) 1.7 (1.2-2.2) .37NRQLQ total score,score/62.2 (1.6-2.7) 2.2 (1.7-2.8) .77NRQLQ sleep, score/6 2.0 (1.4-2.7) 2.0 (1.6-2.9) .50NRQLQ sleeptimesymptoms, score/62.1 (1.5 -2.7) 2.0 (1.5-2.6) .73Der p 1 in Mattressdust samples, ng/g336 (128-884) 386 (146-1016) .60Der p 1 in Pillowdust samples, ng/g126 (48-332) 186 (70-496) .26Variables are presented as means with 95% Confidence Intervals.*P-value for difference between Purotex and Placebo period (analysedwith Mixed models).AR, Allergic Rhinitis; NRQLQ, Nocturnal Rhinoconjunctivitis Quality ofLife Questionnaire; RQLQ, Rhinoconjunctivitis Quality of Life Question-naire; VAS, Visual Analogue Scale.RESEARCH LETTER | 1093F IGURE 1 (A) Relative (%) change from baseline of Der p 1 concentration in mattress and pillow dust samples, illustrated with line charts(error bars represent 95% CI). Mattress Der p 1: significant decrease with both the probiotics-impregnated covers (P=.02) and the placebo covers(P=.003); no difference in effect between both study covers (P=.98). Pillow Der p 1: significant decrease with both the probiotics-impregnatedcovers (P=.001) and the placebo covers (P=.007); no difference in effect between both study covers (P=.36). (B) Change from baseline of VASscores and QoL scores (RQLQ, NRQLQ), illustrated with line charts (error bars represent Standard Errors of the Mean). VAS for control of AR:significant improvement with probiotics (P=.001) and not with placebo (P=.81); no significant difference in effect between both study covers(P=.17). VAS for nose symptoms: significant improvement with probiotics (P<.001) and not with placebo (P=.36); no significant difference in effectbetween both study covers (P=.09). RQLQ total score: significant improvement with probiotics (P=.01) and not with placebo (P=.32); nosignificant difference in effect between both study covers (P=.33). NRQLQ total score: significant improvement with probiotics (P=.02) and notwith placebo (P=.30); no significant difference in effect between both study covers (P=.14).AR, Allergic Rhinitis; NRQLQ, NocturnalRhinoconjunctivitis Quality of Life Questionnaire; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire; VAS, Visual Analogue Scale1094 | RESEARCH LETTEROnly minor changes of medication intake were observed, andchanges compared to baseline were not significant in both studyperiods (P=.83 for placebo; P=.45 for probiotics; P=.71 for differencebetween both periods).4 | DISCUSSIONWe conducted the first pilot, double-blind, randomized, placebo-con-trolled clinical trial to investigate the effect of probiotics-impreg-nated covers on (i) HDM allergen levels in bedding, and (ii) allergysymptoms and QoL of patients with AR to HDM.Although no difference in effect was observed on Der p 1 levelsbetween the probiotics-impregnated covers and the placebo covers,only the probiotics-impregnated covers were associated with a sig-nificant improvement of symptoms and QoL compared to baseline.This observation may raise the hypothesis that the potentialeffect of the probiotics on symptoms and QoL may not be (solely)attributable to an effect on HDM allergen levels in bedding, but maybe related to direct effects of the probiotics on the patient. Althoughevidence is rather limited, some studies have suggested beneficialeffects of probiotics for treatment or prevention of atopic dermati-tis8 and AR.9However, in this trial, the measured Der p 1 levels were highlyvariable (both between-subject and within-subject observations) andmay not always have reflected the real levels in bedding. Dust sam-pling is known to be inherently variable,10 and additional variation inthis trial may have resulted from possible improper dust sampling bythe patient. It should be noted that the Der p 1 levels in this trialwere markedly lower than those previously reported, which mayexplain some of the lack of effect seen in this study. In addition, theDer p 1 levels measured in the pillow dust samples should be con-sidered less reliable, as the pillow dust samples were often inade-quate in mass (19% of samples weighed <10 mg, see Appendix S1).At last, it should be emphasized that both the placebo and the probi-otics-impregnated covers were new. Indeed, new bedding materialtends to show a lower HDM concentration, which may explain thedecrease in HDM allergen levels with both covers.To our knowledge, this study is the first clinical trial to evaluateany probiotics-based method aiming to reduce HDM allergen expo-sure. Other studies have investigated the effect of physical (heating,ventilation, freezing, washing, barrier methods, air filtration, vacuum-ing and ionizers) and/or chemical (acaricides) methods.3 Terreehorstet al.4 reported a significant reduction in HDM levels in beddingwith impermeable covers compared to non-impermeable covers.Nevertheless, this large study did not reveal a clinical effect on rhini-tis symptoms of the impermeable covers compared to the non-impermeable covers (even not a trend).In the study by Terreehorst et al.4, patients were encouraged tocarry out additional avoidance measures (including weekly washingand cleaning of bedding in water at 60°C, and ventilating the homesaccording to regular schedules). Hence, the observed improvementof rhinitis symptoms in this study may be attributed to theseadditional avoidance measures, irrespective of the use of imperme-able or non-impermeable bedding covers.In our study, no additional avoidance measures were applied.Moreover, patients were urged to use their allergy medication not asmaintenance treatment, but only when needed. Hence, the observedimprovements of symptoms and QoL are unlikely to be attributableto either additional environmental control measures or increasedintake of allergy medication.The use of the bedding covers in our study was generally well tol-erated, and no serious adverse events were considered related toPurotex. Three subjects had an airway infection during the Purotexperiod (see Appendix S1); however, it is not possible to speculate ona possible relation with Purotex based on this small pilot study.The small sample size of this pilot trial entails a restricted statisti-cal power to show significant differences in effect between the pro-biotics-impregnated covers and the placebo covers. A power analysis(in Appendix S1) revealed that a potential future large-scale studyshould include 262 patients to have 90% chance that the currentlyobserved effect of probiotics-impregnated covers on QoL (evaluatedwith RQLQ total score) would be significant compared to the pla-cebo covers. Other limitations of the current trial include the rathershort study period, the possibility of carry-over effects in this cross-over design, the possible influence of seasonal fluctuations in HDMexposure and the lack of control on dust sample collection.In conclusion, even though the probiotics-impregnated coverscompared to untreated covers did not show an effect on the pri-mary outcome measure Der p 1 levels, there was significantimprovement compared to baseline of several symptoms andallergy-related quality-of-life scores (secondary outcomes) with theprobiotics-impregnated covers and not with the placebo covers.Although the effects of probiotics-impregnated covers were notsignificant compared to untreated covers in this pilot study, thesefindings are promising and warrant further exploration in a futurelarge-scale clinical trial.ACKNOWLEDGEMENTSOur special thanks to Charlotte Van Houtte (Clinical Trial Center,Ghent University Hospital) for her help with patient recruitment andarrangement of appointments, and to Roos Colman (Medical Infor-matics, Faculty of Medicine and Health Sciences, Ghent University)for her help with the statistical analyses. Finally, we thank allpatients for their participation in this study. The manufacturers(BekaertDeslee, Chrisal and Devan Chemicals) were involved indesigning the study, in editing the manuscript concerning productinformation, and approving the manuscript. The manufacturers hadno role in data collection, analysis and interpretation, and in thedecision to publish the manuscript.CONFLICT OF INTERESTSThis is an investigator-initiated trial supported by an unrestrictedgrant provided by BekaertDeslee Innovation bvba. M. Berings,RESEARCH LETTER | 1095A. Jult, H. Vermeulen, N. De Ruyck, L. Derycke, C. Bachert,B. Lambrecht, M. Dullaers and P. Gevaert have no conflict of inter-ests. H. Ucar and P. Ghekiere are employed by BekaertDeslee;R. Temmerman is employed by Chrisal NV; and John Ellis isemployed by Devan Chemicals NV.REFERENCES1. Bousquet J, Khaltaev N, Cruz AA, et al. Allergic Rhinitis and itsImpact on Asthma (ARIA) 2008 update (in collaboration with theWorld Health Organization, GA(2)LEN and AllerGen). Allergy.2008;63(Suppl 86):8-160.2. Platts-Mills TA. Allergen avoidance in the treatment of asthma andrhinitis. N Engl J Med. 2003;349:207.3. Nurmativ U, van Schayck CP, Hurwitz B, Sheikh A. House dust miteavoidance measures for perennial allergic rhinitis: an updatedCochrane systematic review. Allergy. 2012;67:158-165.4. Terreehorst I, Hak E, Oosting AJ, et al. Evaluation of impermeablecovers for bedding in patients with allergic rhinitis. N Engl J Med.2003;17:349.5. Hellings PW, Muraro A, Fokkens W, et al. A common language toassess allergic rhinitis control: results from a survey conductedduring EAACI 2013 Congress. Clin Transl Allergy. 2015;5:36.6. Juniper EF, Guyatt GH, Griffith LE, Ferrie PJ. Interpretation ofrhinoconjunctivitis quality of life questionnaire data. J Allergy ClinImmunol. 1996;98:843-845.7. Juniper EF, Rohrbaugh T, Meltzer EO. A questionnaire to measurequality of life in adults with nocturnal allergic rhinoconjunctivitis. JAllergy Clin Immunol. 2003;111:484-490.8. Rather IA, Bajpai VK, Kumar S, Lim J, Paek WK, Park YH. Probioticsand Atopic Dermatitis: an Overview. Front Microbiol. 2016;12:7.https://doi.org/10.3389/fmicb.2016.00507. eCollection 2016.9. Zajac AE, Adams AS, Turner JH. A systematic review and meta-analysisof probiotics for the treatment of allergic rhinitis. Int ForumAllergy Rhinol.2015;5(6):524-532doi: 10.1002/alr.21492. Epub2015Apr 20.10. Simpson A, Hassall R, Custovic A, Woodcock A. Variability of house-dust-mite allergen levels within carpets. Allergy. 1998;53:602-607.SUPPORTING INFORMATIONAdditional Supporting Information may be found online in the sup-porting information tab for this article.How to cite this article: Berings M, Jult A, Vermeulen H, et al.Probiotics-impregnated bedding covers for house dust miteallergic rhinitis: A pilot randomized clinical trial. Clin Exp Allergy.2017;47:1092–1096. https://doi.org/10.1111/cea.129371096 | RESEARCH LETTER

Probiotics-impregnated bedding covers for house dust mite allergic rhinitis : a pilot randomized clinical trial

M. Berings

A. Jult

H. Vermeulen

N. De Ruyck

L. Derycke

H. Ucar

P. Ghekiere

R. Temmerman

J. Ellis

C. Bachert

B. N. Lambrecht

M. Dullaers

P. Gevaert

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Clinical & Experimental Allergy

Probiotics-impregnated bedding covers for house dust mite allergic rhinitis: A pilot randomized clinical trial

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Probiotics-impregnated bedding covers for house dust mite allergic rhinitis : a pilot randomized clinical trial

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