Self-collected nasal swabs to detect infection and colonization: a useful tool for population-based epidemiological studies?

Pe spec i e Sel -collec ed nasal swabs o de ec in ec ion and coloniza ion: a use ul ool o popula ion-based epidemiological s udies? M.K. Akma o a, *, F. Pessle a,b a Depa men o In ec ion Gene ics, P ojec G oup Epidemiology, Helmhol z Cen e o In ec ion Resea ch, Inho ens aße 7, D-38124 B aunschweig, Ge many b Uni e si y Child en’s Hospi al, Di ision o Rheuma ology and Immunology, Technical Uni e si y D esden, D esden, Ge many 1. In oduc ion Why a e he e so ew la ge popula ion-based epidemiological s udies on isk ac o s o in ec ious diseases? Indeed, in ec ious diseases ha e been all bu excluded om he la ge popula ion- based coho s udies ha a e cu en ly in a ious s ages o e olu ion wo ldwide. This is he mo e su p ising since en i on- men al, li es yle, and hos gene ic ac o s clea ly con ibu e o acquisi ion, ansmission, clinical cou se, and ou come o essen- ially all in ec ious diseases known o da e. Hos gene ic ac o s in pa icula may play impo an oles in many acu e in ec ious diseases, as exemplified by influenza 1,2 and no o i us in ec ion. 3 This pauci y o popula ion-based app oaches o in ec ious diseases/in ec ions may be explained, a leas in pa , by me hodological limi a ions. In con as o he common ch onic diseases ha a e usually ea u ed in popula ion-based s udies (e.g., ca dio ascula , me abolic, neoplas ic, o neu odegene a i e dis- eases), in ec ious diseases o en ollow an acu e cou se and he pa hogen may only be de ec able du ing a na ow ime-window. Fo ins ance, maximal shedding o influenza i us occu s in he fi s 3 days o in ec ion in humans, and he a e o i al de ec ion by PCR declines apidly a e 5 days. 4 Mo eo e , in ec ious diseases may ollow a mild o e en asymp oma ic cou se, and some indi iduals may be colonized wi h mic obial pa hogens (e.g., S aphylococcus au eus) wi hou displaying any symp oms. Thus, heal hca e u iliza ion by hese indi iduals is low and hei iden ifica ion in he con ex o popula ion-based s udies is di ficul . Consequen ly, esea ch on in ec ious diseases is o en hospi al-based, esul ing in an o e sampling o diseases cha ac- e ized by compa a i ely high mo bidi y and heal hca e u iliza- ion. The e o e, di e en me hods o sample collec ion a e needed o iden i y asymp oma ic ca ie s o indi iduals wi h acu e in ec ions no se e e enough o necessi a e a isi o a medical ca e p o ide . As exemplified by s udies on influenza in ec ion, a ained membe o he field eam may collec he diagnos ic specimen by pe o ming a nasal swab on he s udy pa icipan du ing a house call. 5 Howe e , o his app oach o unc ion, he subjec s need o no i y he s udy cen e p omp ly and eliably a he onse o symp oms. An addi ional d awback is ha he cos o his app oach sky ocke s when la ge numbe s o inciden cases need o be iden ified, e.g., o a genome-wide associa ion s udy (GWAS). An a ac i e al e na i e app oach would be o ask he pa icipan s o pe o m he swabs hemsel es (‘sel -swabbing’). The e is ample e idence om a ious clinical scena ios demon- s a ing he easibili y o sel -swabbing among specific isk g oups and pa ien popula ions. 6–10 Sel -swabbing has se e al ad an ages o e he collec ion o samples by s udy pe sonnel. Fi s , inciden cases o acu e in ec ions ha ea u e a sho du a ion o mild symp oms can be iden ified mo e easily. Thus, his me hod may imp o e iden ifica ion o inciden cases and he eby educe disease misclassifica ion. Second, a la ge numbe o s udy subjec s can be included in a gi en s udy due o he lowe cos and simple logis ics. Fo In e na ional Jou nal o In ec ious Diseases 15 (2011) e589–e593 A R T I C L E I N F O A icle his o y: Recei ed 17 No embe 2010 Recei ed in e ised o m 1 Ma ch 2011 Accep ed 22 Ap il 2011 Co esponding Edi o : J. Pe e Donnelly, Nijmegen, he Ne he lands. Keywo ds: Sel -collec ed nasal swabs Bac e ial and i al in ec ions Epidemiological s udies S U M M A R Y Popula ion-based epidemiological s udies on in ec ious diseases a e limi ed by me hodological p oblems ha may no be encoun e ed in o he fields o epidemiology. The acu e o asymp oma ic na u e o many in ec ions hinde s a imely diagnosis by ained pe sonnel in a s udy cen e, indica ing he need o new collec ion me hods o biological specimens. One al e na i e app oach is o ha e he pa icipan s collec he specimens hemsel es, o ins ance nasal swabs o he de ec ion o bac e ial o i al pa hogens. Al hough sel -collec ion is widely accep ed in clinical s udies o specific popula ions (e.g., sel -collec ion o aginal swabs by young women o diagnose sexually ansmi ed in ec ions), i has no been employed much in popula ion-based s udies. He e, we e iew ecen expe ience wi h sel - collec ion o nasal swabs o he de ec ion o mic oo ganisms and discuss u u e p ospec s and applica ions o his echnique. ß 2011 In e na ional Socie y o In ec ious Diseases. Published by Else ie L d. All igh s ese ed. * Co esponding au ho . Tel.: +49 0 531 6181 1112; ax: +49 0 531 6181 1199. E-mail add ess: [email p o ec ed] (M.K. Akma o ). Con en s lis s a ailable a ScienceDi ec In e na ional Jou nal o In ec ious Diseases jou nal h o mep ag e: w ww .else ie .co m /loc a e/ijid 1201-9712/$36.00 – see on ma e ß 2011 In e na ional Socie y o In ec ious Diseases. Published by Else ie L d. All igh s ese ed. doi:10.1016/j.ijid.2011.04.009 example, o a planned GWAS on gene ic ac o s o influenza in ec ion (de ec ed in nasal swabs) in an u ban/subu ban popula ion, we compa ed he cos o swabbing by s udy pe sonnel o he cos o sel -swabbing. In o de o de ec an odds a io o 1.5 (assuming 10% clinical a ack a e, 80% powe , and 5  10 8 ype 1 e o accoun ing o mul iple hypo hesis es ing), 1000 cases would be needed. Expec ing an in ec ion a e o app ox. 25%, a disco e y sample o n = 4000 pa icipan s would be needed o yield 1000 cases. Assuming an a e age o wo acu e espi a o y in ec ions (ARI) pe indi idual pe yea , 11 app ox. 8000 home isi s a a cos o a leas 20 eu os/ isi (pe sonal communica ion, Thomas Beh ens, B emen Ins i u e o P e en ion Resea ch and Social Medicine; based on cu en cos o pe sonnel ime and a el in Ge many) would be equi ed, cos ing upwa d o 160 000 eu os. Including pa icipan s om u al o emo e a eas would esul in e en highe cos s due o highe a el expenses. On he o he hand, he cos o sel -collec ion o swabs would be app ox. 32 000 eu os, mos ly o packaging and pos age. He e, we e iew he li e a u e on sel -collec ion o nasal swabs o he de ec ion o mic oo ganisms and discuss u u e p ospec s and applica ions o his p omising new ool o in ec ious disease field esea ch. 2. S a e o he a 2.1. Sample collec ion in an unsupe ised se ing A summa y o all s udies ha ha e used sel -collec ed nasal swabs is p esen ed in Table 1. 4,12–20 Only wo s udies we e uly popula ion-based and ea u ed sel -collec ion ou side o a s udy cen e. 4,19 an Clee e al. examined he p e alence o li es ock- associa ed me hicillin- esis an S aphylococcus au eus (MRSA) in he Ne he lands. 19 In his s udy, swabbing supplies we e sen by mail o indi iduals who had ag eed o pa icipa e in he s udy (n = 644). App oxima ely 90% e u ned he swabs, indica ing ha sel -collec ion may be highly easible in he gene al popula ion. In ano he popula ion-based s udy o espi a o y in ec ions, pa en s we e asked o collec nasal and pha yngeal swabs om hei child en. 4 The main ou come in his s udy was he p opo ion o swabs ha we e posi i e o any one o se en espi a o y pa hogens. By compa ing esul s o (1) nasal and h oa swabs and (2) swabs collec ed by pa en s who wo ked in heal hca e s. pa en s who did no , i was ound ha nasal swabs we e mo e o en posi i e han pha yngeal swabs, bu ha he e was no di e ence in he p opo ion o posi i e swabs when compa ing Table 1 Summa y o published s udies using sel -collec ed nasal swabs Au ho /yea S udy design S udy popula ion To al sample size Ou come Sel -swabbing Mos ele an esul s Gilbe e al. 2007 18 C oss-sec ional (pa ien -based) Adul s (ma ginalized u ban popula ion, e.g., d ug use s) 271 MRSA coloniza ion Sel -collec ed nasal swabs MSSA was de ec ed in 95 o 271 (36%) swabs, any MRSA s ain in 13 (4.8%), and MRSA USA300 in 10 (3.7%) Coope e al. 2008 16 C oss-sec ional (pa ien -based) Adul s 296 Influenza i us de ec ion Sel -collec ed nasal swabs 142 o 296 (48%) swabs we e e u ned by mail No di ficul ies in sel -swabbing epo ed Mean ime be ween he phone call and sel -swabbing 7.4 days No di e ences in mean imes be ween posi i e and nega i e samples Lambe e al. 2008 4 Coho s udy (communi y-based) Child en 234 De ec ion o espi a o y i uses Pa en -collec ed nasal swabs Highe posi i i y a es o nasal samples o any i us (78%) compa ed o samples om h oa (71%) No di e ences in he posi i i y a es be ween pa en s who did and did no wo k in heal hca e Time om symp om onse o sel - swabbing o less han 5 days i espec i e o ime om sel - swabbing o labo a o y analysis did no influence he posi i i y a e Time om symp om onse o sel - swabbing o mo e han 6 days combined wi h ime om sel - swabbing o labo a o y analysis o 2 and mo e days dec eased he posi i i y a e High accep ance (e.g., 87% o pa icipan s ag eed o pa icipa e in u he s udies) Di ficul ies wi h h oa swab (58%) Lu e al. 2008 15 Con enience sample o labo a o y s a Adul s 4 Rhino i us Se ial sel -collec ed nasal swabs Samples we e used o de elop a eal- ime PCR assay o de ec ion o human hino i uses Ellio e al. 2009 13 C oss-sec ional (pa ien -based) Adul s 3129 Influenza su eillance Sel -collec ed nasal swabs 1783 swabs o 3129 (57%) we e e u ned by mail 1076 swabs o 1346 (80%) we e ecei ed wi hin 7 days o symp om onse M.K. Akma o , F. Pessle / In e na ional Jou nal o In ec ious Diseases 15 (2011) e589–e593 e590 pa en al p o ession (heal hca e s. non-heal hca e wo ke s). These esul s a e a fi s indica ion ha – a leas in his se ing o pa en al swabbing – lay pe sons can collec swabs as e ficien ly as heal hca e wo ke s. The i al de ec ion a e emained cons an as long as he ime ha elapsed be ween he onse o illness and collec ion o he specimen was 5 days o less. Howe e , i dec eased when he ime om illness onse o labo a o y analysis exceeded 8 days, unde sco ing he impo ance o imely e u n o sel -collec ed swabs o he s udy cen e. Sel -sampling has also been ound o imp o e symp oma ic su eillance by p o iding addi ional labo a o y-based in o ma- ion. 13,16 Fo example, du ing he 2004–2005 influenza seasons, he UK Na ional Heal h Se ice es ablished a elephone ho line (‘NHS Di ec ’). 16 Calle s who oiced a conce n o su e ing om an influenza-like illness we e sen swabbing supplies by mail and we e asked o sel -collec a nasal swab and mail i o a cen al e e ence labo a o y. Mos s udy pa icipan s pe o med he swab and e u ned i wi hin he eques ed ime: he ime in e als be ween he phone call and sel -swabbing and be ween he phone call and labo a o y analysis we e 4.1 and 7.4 days, espec i ely. The majo i y o pa icipan s epo ed no di ficul ies wi h sel - sampling. 2.2. Sample collec ion in a supe ised se ing In a ecen pa ien -based s udy o influenza in ec ion in child en, esea che s compa ed he e ficiency o nasal swabs collec ed by pedia icians and pa en s. 14 Sensi i i y (89%) and specifici y (98%) o pa en -collec ed swabs (compa ed o pedia i- cian-collec ed swabs) o he de ec ion o influenza i us by eal- ime PCR we e high, and he mean i al copy numbe pe posi i e swab did no di e be ween pa en - and pedia ician-collec ed samples. The pa en s epo ed ha he child en we e mo e sa isfied when nasal swabs we e aken by he pa en s han by he pedia icians. 14 In a e y ecen s udy, a newly de eloped flocked nasal swab was e alua ed o he de ec ion o espi a o y in ec ions. 17 Ini ially, symp om- ee pa icipan s we e asked o collec swabs om one nos il. A he same ime, swabs we e collec ed by s udy pe sonnel wi h a ayon nasopha yngeal swab (gold s anda d) om he o he nos il. The sel -collec ed nasal swabs yielded be e esul s han he gold s anda d (based on a highe epi helial cell coun and de ec ion o highe le els o human b -ac in gene coding sequences, which we e used as p oxy endpoin s). Fu he mo e, espi a o y i al in ec ions we e de ec ed in symp oma ic sub- jec s; among he 108 symp oma ic subjec s any one o se e al ARI was de ec ed in 42 sel -collec ed swabs (39%). Howe e , his endpoin was no compa ed wi h he gold s anda d me hod. The majo i y o subjec s (87% o 55) had no o mino di ficul ies wi h sel -swabbing. Six y-fi e pe cen o subjec s epo ed no o only mino discom o om sel -swabbing, 31% epo ed mode a e discom o , and 4% se e e discom o . A fi s glance, nasal swabbing does no appea o be a echnically demanding p ocedu e, bu specific aspec s such as he applied p essu e and he numbe o e olu ions du ing swabbing, he dep h o inse ion owa d he u bina es, o e en which nos il o p obe, a e all pa ame e s ha could po en ially a ec he e ficiency o de ec ion. Hence, i mus be no ed ha he s udy on pa en -collec ed swabs is he only one whe e he de ec ion a e o sel -collec ed nasal swabs was compa ed di ec ly o samples ob ained by ained pe sonnel. 14 Howe e , pa en s collec ed he swabs in he p esence o s udy pe sonnel and may ha e el mo e confiden , esul ing in be e swabbing. In he abo e-men ioned s udy by Smieja e al., 17 he numbe o nasal epi helial cells and he Table 1 (Con inued ) Au ho /yea S udy design S udy popula ion To al sample size Ou come Sel -swabbing Mos ele an esul s Loeb e al. 2009 12 Randomized ial (con enience sample o hospi al s a ) Adul s 446 Influenza i us ansmission Sel -collec ed nasal swabs Compa ison o a su gical mask (g oup 1) and an N95 espi a o (g oup 2) o p e en ansmission o influenza A o B i us Influenza i us was de ec ed in 2.8% o he 212 swabs om g oup 1 s. 1.9% o he 210 swabs om g oup 2 O he espi a o y i uses we e de ec ed in 9.4% (g oup 1) and 10.5% (g oup 2) o he swabs Esposi o e al. 2010 14 Coho s udy (pa ien -based) Child en 203 Influenza i us de ec ion Pa en -collec ed nasal swabs High sensi i i y (89%) and specifici y (98%) o he sel - collec ed swabs (gold s anda d: pedia ician-collec ed swabs) Highe sa is ac ion o child en wi h pa en - han pedia ician-collec ed swabs No di e ence in i us de ec ion a e be ween pa en - and pedia ician- collec ed swabs Smieja e al. 2010 17 C oss-sec ional s udy (con enience sample o hospi al s a and isi o s) Adul s 250 Respi a o y i al in ec ions Sel -collec ed nasal swabs 108 pa icipan s o 250 (44%) sel - swabbed wi hin 4 days o symp om onse and e u ned he swabs wi hin 5 days Van Clee e al. 2010 19 C oss-sec ional s udy (communi y-based) Adul s 644 MRSA coloniza ion Sel -collec ed nasal swabs 583 swabs o 644 (91%) we e e u ned by mail Ammons e al. 2010 20 C oss-sec ional s udy (con enience sample o s uden popula ion) Young adul s 375 a MRSA coloniza ion Sel -collec ed nasal swabs S aphylococcus au eus was de ec ed in 7 o 375 swabs (1.9%); 6 o which we e MRSA MRSA, me hicillin- esis an S aphylococcus au eus; MSSA, me hicillin-sensi i e S aphylococcus au eus. a Numbe o swabs. M.K. Akma o , F. Pessle / In e na ional Jou nal o In ec ious Diseases 15 (2011) e589–e593 e591 p esence o DNA sequences encoding he human b -ac in gene we e used o quan i y hos issue in which i uses o o he pa hogens migh be de ec ed. Howe e , he i al de ec ion a e was no compa ed be ween sel -collec ed and pe sonnel-collec ed swabs. Thus, he diagnos ic equi alence o sel -collec ed swabs by adul s has no been es ablished o mally. We a e cu en ly conduc ing such a s udy, in which sel -collec ed and ained pe sonnel-collec ed nasal swabs a e being compa ed in e ms o hei accu acy in he de ec ion o i al espi a o y pa hogens. In wo s udies, nasal swabs we e sel -collec ed by labo a o y 15 and hospi al s a . 12 In hese selec ed popula ions, sel -swabbing should be easible since unde s anding o he swabbing p ocedu e and compliance wi h i s echnical aspec s should be good. The abo e-men ioned s udies indica e ha sel -swabbing was highly accep able among he s udied popula ions. I also appea s o be a easible me hod o he diagnosis o a ious mic oo ganisms, as long as he ime in e als om onse o symp oms o sample collec ion and hen o a i al in he labo a o y, a e moni o ed ca e ully. Fu he alida ion s udies a e needed o in es iga e he e ficacy o sel -collec ed nasal swabs o de ec espi a o y pa hogens, pa icula ly by compa ing sel -swabbing wi h he espec i e gold s anda d me hod, e.g. s a -collec ed nasal swabs. 3. Challenges The abo e-men ioned s udies show ha sel -swabbing may be a iable and cos -e ec i e al e na i e me hod o he pu pose o collec ing nasal swabs o epidemiological s udies. Howe e , he e a e some challenges ha ha e o be conside ed p io o using his me hod. Fi s , an inadequa e sampling echnique will undoub edly comp omise he alue o any labo a o y analysis. E en hough i appea s ob ious ha s udy pa icipan s should be in i ed once o a s udy cen e whe e s udy pe sonnel can explain and demons a e he co ec sel -swabbing echnique, i has no ye been de e - mined whe he his is eally necessa y. In coun ies wi h well- unc ioning mail deli e y sys ems, swabbing supplies ha e also been p o ided by mail. 13,16,19 I his app oach is o be used, pa icipan s should be p o ided wi h de ailed p in ed ins uc ions on how o ob ain he sample, including simple isual ma e ial. Second, o achie e imely and eliable sample collec ion (which is pa icula ly impo an in he de ec ion o ARI), pa icipan s should ecei e eminde s on a egula basis. Va ious eminde sys ems can be used, such as elephone calls, e-mail, o SMS (sho message se ice; ex ). Thi d, logis ic p oblems can a ise i sel -swabbing is o ake place ou side o a s udy cen e (e.g., a home) and he swabs a e o be e u ned by he pa icipan s in pe son o by mail. In he abo e- men ioned s udies, he swabs we e e u ned by mail, wi h e u n a es a ying be ween 48% 16 and 91%. 19 The esul s o labo a o y analyses will depend on he ime elapsed be ween sel -swabbing and labo a o y analysis; an ea ly deli e y o swabs may inc ease he sensi i i y and specifici y, bu his will a y wi h he o ganism o be de ec ed. As men ioned abo e, when a panel o pa hogenic i uses, mos ly consis ing o RNA i uses, was used, he de ec ion a e o any i us dec eased i mo e han 8 days elapsed be ween symp om onse and labo a o y analysis. 4 Concei ably, his was due o nucleic acid deg ada ion du ing anspo . In e es ingly, in a s udy o sel -collec ed aginal swabs (in which e-mail was used success ully as a eminde ool), no e ec o anspo ime on DNA quan i y was de ec ed, pe haps due o he inhe en highe s abili y o DNA compa ed wi h RNA. I he e o e appea s impo an o e alua e nucleic acid p ese a i es (e.g., RNAla e 1 , RNAp o ec 1 , and o he s) as al e na e collec ion and anspo media o scena ios in which RNA s abili y would be a conce n, and cul u e ( equi ing iable o ganisms) is no planned. Use o such media would be pa icula ly impo an in s udies in which gene exp ession pa e ns o en i e mic obial popula ions (mic obiomes) a e o be de e mined. 4. Conclusions and p ospec s o he u u e Sel -collec ion o nasal swabs may be a cos -e ficien me hod o he de ec ion o mic oo ganisms in popula ion-based epide- miological s udies. By using his me hod one may inc ease he size o he s udy popula ion, hus acili a ing in es iga ions on complex associa ions be ween in ec ious diseases/in ec ions and a ious isk ac o s. In he small numbe o s udies in which sel -swabbing was employed, i was ound o be sa e and was me wi h a high deg ee o accep ance and sa is ac ion on he pa o he pa icipan s. Howe e , i has no been es ablished whe he he de ec ion a es o a ious mic oo ganisms om sel -collec ed swabs and om swabs ob ained by ained pe sonnel a e compa able. Thus, u he alida ion s udies a e needed be o e he use o sel -swabbing can be ad oca ed wi hou ese a ions. Acknowledgemen s We hank D . Thomas Ja ¨nisch (Heidelbe g Uni e si y Hospi al), P o . Lo ha K eienb ock (Uni e si y o Ve e ina y Medicine Hanno e ) and P o . Klaus Schugha (Helmhol z Cen e o In ec ion Resea ch, B aunschweig) o c i ical eadings o he manusc ip and help ul discussions. This wo k was suppo ed by in amu al unding om he Helmhol z Associa ion (P og am In ec ion and Immuni y). Conflic o in e es : No conflic o in e es . Re e ences 1. Alb igh FS, O lando P, Pa ia AT, Jackson GG, Cannon Alb igh LA. E idence o a he i able p edisposi ion o dea h due o influenza. J In ec Dis 2008;197:18–24. 2. T ammell RA, To h LA. Gene ic suscep ibili y and esis ance o influenza in ec ion and disease in humans and mice. 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