Herpes virus seroepidemiology in the adult Swedish population

RESEARCH Open Access He pes i us se oepidemiology in he adul Swedish popula ion Jan Olsson 1* , Eloise Kok 2 , Rol Adol sson 3 , Hugo Lö heim 4 and F ed ik Elgh 1 Abs ac Backg ound: He pes i uses es ablish a li e-long la ency and can cause symp oms du ing bo h i s - ime in ec ion and la e eac i a ion. The aim o he p esen s udy was o desc ibe he se oepidemiology o He pes simplex ype 1 (HSV1), He pes simplex ype 2 (HSV2), Cy omegalo i us (CMV), Va icella Zos e i us (VZV) and Human he pes i us ype 6 (HHV6) in an adul Swedish popula ion (35–95 yea s o age). Me hods: P esence o an ibodies agains he espec i e i uses in se um om indi iduals in he Be ula s udy was de e mined wi h an enzyme-linked immunoso ben assay (ELISA). Singula samples om 535 pe sons (53.9% women, mean age a inclusion 62.7 ± 14.4 yea s) collec ed 2003-2005 we e analyzed o he i e HHVs men ioned abo e. In addi ion, samples including ollow-up samples collec ed 1988–2010 om 3,444 pe sons we e analyzed o HSV. Resul s: P e alence o HSV1 was 79.4%, HSV2 12.9%, CMV 83.2%, VZV 97.9%, and HHV6 97.5%. He pes i us in ec ions we e mo e common among women (p= 0.010) and a lowe age-adjus ed HSV se op e alence was ound in la e bi h coho s (p< 0.001). The yea ly incidence o HSV in ec ion was es ima ed a 14.0/1000. Conclusion: Women a e mo e o en se oposi i e o HHV, especially HSV2. Age-adjus ed se op e alence o HSV was lowe in la e bi h coho s indica ing a dec easing childhood and adolescen isk o in ec ion. Keywo ds: He pes, He pes simplex, Cy omegalo i us, Va icella zos e i us, Se op e alence, Epidemiology In oduc ion Human he pes i uses (HHV1-8) a e ubiqui ous human pa hogens wi h a global dis ibu ion. Epidemiological s udies ha e iden i ied geog aphic loca ion, socioeconomic s a us, and age as p ima y ac o s o acquisi ion o HHV in ec ion [1]. The in ec ion cycle in ol es a p ima y in ec- ion, ollowed by a la ency phase ha may be in e up ed by episodes o eac i a ed in ec ion [1]. Al hough his pa - e n o in ec ion is sha ed by all HHVs, a ia ion among he included i al species exis s e.g. conce ning he issue in ol ed in he la ency phase o he in ec ion. HHV1-3 (HSV1, HSV2 and VZV) es ablish la ency in senso y gan- glia, while he o he HHVs (EBV, CMV, HHV6-8) employ lymphocy es, monocy es, and some imes also epi helium o la ency. When eac i a ed, HHV1-3 sp ead along ne es, HHV4 (EBV), HHV7 and HHV8 expand in lymphocy e popula ions, while HHV5 (CMV) and HHV6 o en sp ead sys emically [1]. HHVs ha e been a ibu ed a ole in he de elopmen o ch onic diso de s, such as Alzheime ’s disease [2–6], ca dio ascula disease [7–9], cogni i e impai men [10, 11], and dep ession [12–14]. We, and o he s esea ching he ield o la e neu ological sequela om HHV in ec ions ha e had g ea use o se ological sc eening in coho s o adul and elde ly indi- iduals [5, 6, 15–18]. Al hough li e a u e on he se oepide- miology o HHV in ec ions is ex ensi e, mos s udies ocus on young indi iduals o selec ed popula ions posing al eady known isks om HHV in ec ions [19–22]. We he e o e pe o med he p esen s udy wi h he aim o es ima e he p e alence o HHV1 (HSV1), HHV2 (HSV2), HHV3 (VZV), HHV5 (CMV), and HHV6 in se um samples e ie ed om indi iduals in he Be ula s udy [23], e lec ing a popula ion o adul s, including he eld- e ly, in Sweden. Fo HSV1&2 combined, we u he ana- lyzed a la ge coho wi h longi udinal samples allowing o es ima ion on he end in yea ly incidence. * Co espondence: [email p o ec ed] 1 Depa men o Clinical Mic obiology, Vi ology, Umeå Uni e si y, Umeå, Sweden Full lis o au ho in o ma ion is a ailable a he end o he a icle © The Au ho (s). 2017 Open Access This a icle is dis ibu ed unde he e ms o he C ea i e Commons A ibu ion 4.0 In e na ional License (h p://c ea i ecommons.o g/licenses/by/4.0/), which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided you gi e app op ia e c edi o he o iginal au ho (s) and he sou ce, p o ide a link o he C ea i e Commons license, and indica e i changes we e made. The C ea i e Commons Public Domain Dedica ion wai e (h p://c ea i ecommons.o g/publicdomain/ze o/1.0/) applies o he da a made a ailable in his a icle, unless o he wise s a ed. Olsson e al. Immuni y & Ageing (2017) 14:10 DOI 10.1186/s12979-017-0093-4 Me hods Pa icipan s The Be ula s udy is an ongoing longi udinal, p ospec i e coho s udy wi h he o e all aim o in es iga ing how memo y unc ion and heal h de elop ac oss he adul li e span [23]. The s udy is designed as a mixed coho and c oss-sec ional s udy, modeled a e Schaie [24, 25], o enable he sepa a ion o age, coho and ime o meas- u emen e ec s. The Be ula s udy s a ed in 1988 by ec ui ing 1,000 pe sons om he municipali y o Umeå –a municipali y o abou 120,000 inhabi an s loca ed in No he n Sweden. The pa icipan s we e andomly selec ed om he Swedish Popula ion Regis y, and we e in- i ed o pa icipa e ia an in oduc o y le e and a ollow-up elephone call. Rec ui men con inued un il pa icipan s wi hin all age g oups we e ully en olled. In he i s wa e, 1,976 pe sons we e con ac ed o ob- ain 1,000 pa icipan s. To ul ill he p ima y s udy aims, pe sons wi h se e e isual o audi o y de ici s, cogni i e de ici s due o in ellec ual disabili y, se e e psychia ic illness, suspec ed demen ia, and hose who did no speak and unde s and he Swedish language we e excluded. The i s coho (sample 1; S1) o 1,000 pe sons was in es iga ed in 1988 –1990 ( ime-poin 1; T1), and was ollowed-up e e y i e yea s he ea e un il 2008 – 2010 (T2 o T5). Addi ional coho s, om he same geog aphical egion we e included a each subsequen wa e o in es iga ion (T2 o T5). A T2 (1993 –1995) wo coho s (S2, n=997, and S3, n=966)we een olled, a T3 (1998 –2000) one coho o 563 pe sons (S4), and T4 (2003 –2005) ano he coho o 562 pe sons (S5) was en olled. S1 and S2 comp ised pe sons aged 35, 40, 45, 50, 55, 60, 65, 70, 75 and 80 yea s a inclusion, wi h up o 100 indi iduals in each age g oup. The S3 coho comp ised pe sons aged 40 o 85 a inclusion, up o 100 in each age g oup, and he S4 and S5 coho s comp ised people in 12 di e en age g oups om 35 o 95 yea s old a inclu- sion, wi h up o 50 in each g oup. The p opo ion o men and women in each coho and age g oup was equal, oughly co esponding o he gende dis ibu ion in he gene al popula ion. The S3 coho , like S1, was ollowed wi h epea ed examina ions e e y i e yea s un il T5. A pa o he S2 coho was e-examined a T3 bu no he ea e , whe eas S4 (1998 –2000) and S5 (2004 –2006) we e examined only a he ime o inclusion. Samples included o he c oss-sec ional analysis o an i-HSV1, an i-HSV2, an i-VZV, an i-CMV and an i- HHV6 we e all s o ed se um samples a ailable om S5T4 (n= 535, age 35-95, sampling imepoin 2003-2005). One sub-coho , sampled once, was selec ed om he Be ula s udy o make assessmen o he i e HHVs se o- p e alence a o dable, and his pa icula coho (S5T4) was ound sui able because i s samples a e ela i ely ecen , and i con ains pa icipan s o a wide age- dis ibu ion. Samples included in he addi ional c oss- sec ional and longi udinal analysis o an i-HSV we e all s o ed se um samples a ailable om S1-5 T1-5. The o al numbe o pa icipan s was 3,444, om which 2,213 con ibu ed one sample, and 1,231 p o ided wo o mo e samples om di e en sampling imepoin s (1988 –1990, 1993 –1995, 1998 –2000, 2003 –2005, and 2008 –2010). Se um analyses F ozen se um samples we e hawed and analyzed o an i-HSV, an i-VZV, an i-CMV, and an i-HHV6 IgG an ibodies using Enzyme-linked immunoso ben assays (ELISA). In a p ocedu e o sepa a e an i-HSV posi i e samples in o an i-HSV1, an i-HSV2, o an i-HSV1 + 2 posi i e, an i- HSV posi i e samples we e u he ana- lyzed o p esence o an i-HSV2 IgG, a e which an i- HSV2 posi i e samples we e analyzed o p esence o an i-HSV1 IgG. Fo an i-HSV, an i-VZV, and an i-CMV, ELISA assays de eloped in-house we e used [26–28], o an i-HSV1 and an i-HSV2 He peSelec ®-assays (Focus diagnos ics) we e u ilised, and o an i-HHV6 he HHV-6 IgG An ibody ELISA Ki (Ad anced bio- echnologies inc.) was used. Fo he in-house me hods, an igens agains HSV, VZV, and CMV we e acqui ed by g ow h o HSV1 Umeå clinical isola e 3458-13 on GMK cells, VZV s ain SMI 1197 on Ve oE6 cells, and CMV s ain Ad169 on HumB cells, espec i ely. Plasma incuba ion on an igen-coa ed ELISA pla es was pe o med a 4 °C o e nigh . Analyses we e pe o med in duplica e using unin ec ed cell ex ac as a nega i e con ol. In each ELISA un, high and low posi i e con ols and a nega i e con ol we e included o moni o he quali y o indi idual uns and in e -assay a ia ion. Plasma we e dilu ed 1/420 in phospha e bu e ed saline supplemen ed wi h 0.05% ( / ) Tween-20 and 1% d ied milk. IgG an ibodies we e iden i ied using goa F(ab)2 an i-human IgG, alkaline phospha ase conjuga e (In i ogen) dilu ed 1/6000, and de eloped using p-ni ophenyl phospha e disodium subs a e (Sigma-Ald ich). The IgG an ibody ac i i y o he indi idual sample was exp essed in a bi a y uni s (AU) as a pe cen age o he ne -abso bance a 405 nm (abso bance o i us-coa ed well minus abso bance o con ol an igen well) o he posi i e con ol. Samples wi h IgG alues o 5 AU o abo e we e ega ded as posi i e o HHV IgG an ibody con en . All se ological me hods we e un acco ding o ou ine analyses pe o med in he clinical diagnos ics lab, which is a pa o No lands Uni e si e ssjukhus (NUS). The Olsson e al. Immuni y & Ageing (2017) 14:10 Page 2 o 6 me hods a e acc edi ed by Swedac acco ding o ISO 17025 s anda ds. S a is ics Chi-2 es , independen sample - es , and Pea son co el- a ion we e used o uni a ia e analyses as app op ia e. A mul iple logis ic eg ession model was used o di e en i- a e be ween he e ec o he a iables age, sex, and bi h yea o HSV IgG se op e alence. To plo HSV se op e a- lence in ela ion o age, a linea eg ession model was used o i eg ession lines. The HSV incidence was calcula ed by di iding he num- be o new cases wi h he o al ollow-up ime (pe son- yea s) among HSV nega i e pa icipan s. New cases we e calcula ed as he numbe o se ocon e an s sub ac ed by he numbe o se o e e an s. P< 0.05 was ega ded as s a is ically signi ican . The SPSS 20.0 so wa e o Mac was used o s a is ical calcula ions. Resul s The se op e alence o IgG an ibodies owa ds i e com- mon human he pes i uses was c oss-sec ionally in es i- ga ed in a ep esen a i e sample (T5 S4) om an adul Swedish popula ion. The sample included 535 people (274 women and 261 men) aged 35 o 95 yea s (mean age 60.7 ± 16.2 yea s). The se op e alence o IgG an i- bodies agains HSV1, HSV2, VZV, CMV and HHV6 a e p esen ed in Table 1. The ela ionship be ween age and sex, and he p es- ence o he pes i us an ibodies was in es iga ed (Table 2). Women we e se oposi i e o on a e age 3.8 ± 0.7/5 o he analyzed an ibodies, compa ed o 3.6 ± 0.7/5 o men, p= 0.010. Women we e mo e likely o be HSV2- posi i e compa ed o men (p= 0.013). Age co ela ed posi i ely wi h CMV- and HSV1-IgG p es- ence (p< 0.001 and p< 0.001 espec i ely), bu nega i ely wi h HHV6-IgG p esence (p= 0.034). A ela ionship be- ween he p esence o an i-HSV1 IgG and an i-CMV IgG was ound (Pea son’s 0.167, p< 0.001), bu no be ween any o he combina ion. A la ge sample o 3,444 pa icipan s om all i e co- ho s (S1-5 T1-5) (sampled 1988-2010) was in es iga ed o HSV IgG se op e alence wi h an ELISA de eloped in-house. The 535 people in he analyses abo e we e a subsample o he 3,444. All singula samples and he i s sample om pe sons ha con ibu ed mul iple samples we e included. The age anged be ween 35 and 95 yea s, and he mean age was 62.7 ± 14.4. The e we e 1,860 (54%) women. The an i-HSV IgG se op e alence was 3,038/3,444 = 88.2%. In his sample HSV was sig- ni ican ly mo e common among women (1,671 (89.8%) e sus 1,367 men (86.3%), p = 0.001), and he mean age o HSV posi i e indi iduals was highe , when compa ed o HSV nega i e (63.9 ± 14.0 yea s e sus 53.6 ± 14.0 yea s, p<0.001). In a mul iple linea eg ession model wi h age and sex as independen a iables, and an i-HSV IgG se o- posi i i y as he ou come a iable, he calcula ed in- c ease in an i-HSV se op e alence o each subsequen yea o age was 0.0051. This alue hus co esponds o 0.0051 x 3,444 = 17.6 es ima ed new cases each yea . The age, sex, and yea o bi h o he pa icipan s we e included in a logis ic eg ession model o indi idually in es iga e he e ec s o hese h ee a iables on he ou - come a iable an i-HSV IgG se oposi i i y (Table 3). Female sex and ea lie yea o bi h was associa ed wi h a highe an i-HSV IgG p e alence, while inc easing age was no . The bi h coho e ec , gi ing lowe age-speci ic an i- HSV IgG p e alence in la e bi h coho s, is illus a ed in Fig. 1 showing HSV IgG se op e alence in ela ion o age in wo empo ally sepa a ed s udy coho s (S1T1: 1988- 1990 and S5T4: 2003-2005). Samples om 1,231 people who con ibu ed one o se e al ollow-up sample(s) we e included in a longi u- dinal analysis. These people con ibu ed in o al 14,089.83 pe son-yea s (PY) o ollow-up ime, de ined as he imespan om i s sample un il he las sam- ple, o which pa icipan s who we e an i-HSV IgG ee a he beginning o each pe iod con ibu ed 1,289.83 PY ollow-up ime. Du ing he ollow-up pe iod, 28 people se ocon e ed while 10 people se o e e ed, hence 28 –10 = 18 was ega ded as he numbe o inciden HSV cases. We ea ed se o e e an s as alse nega i es and assumed a simila equency o alse- posi i es. HSV incidence was hence calcula ed as 18/ 1,289.83 = 14.0/1000 PY. In o de o disc imina e he incidence a e om bi h coho e ec s, he calcula ed incidence, 14.0/1000 PY, was compa ed o he igu e o yea ly inc ease o he whole s udy coho (17.6). The 14.0/1000 PY incidence mul iplied wi h 406 an i- HSV IgG nega i e pa icipan s a baseline would p edic 5.7 new an i-HSV IgG posi i e cases du ing he o hcom- ing yea . New inciden cases hence would accoun o Table 1 He pes i us se op e alence, N= 535 Vi us IgG an ibodies N posi i e /N o al % 95% con idence in e al He pes simplex ype 1 425/535 79.4 76.0 –82.9 He pes simplex ype 2 69 a /535 12.9 10.1 –15.8 Va icella zos e i us 524/535 97.9 96.7 –99.1 Cy omegalo i us 445/535 83.2 80.0 –86.4 Human he pes i us ype 6 517/530 b 97.5 96.2 –98.9 No e: a Among he 69 HSV2 posi i e, 50 we e HSV1 posi i e and 16 we e HSV1 nega i e b Fi e samples we e una ailable o HHV-6 analysis Olsson e al. Immuni y & Ageing (2017) 14:10 Page 3 o 6 5.7/17.6 = 32.2% o he obse ed e ec o age o an i- HSV IgG se op e alence, wi h he emaining being he bi h coho e ec . Discussion We epo se op e alence es ima es o i e common human he pes i uses in he gene al adul popula ion in Sweden. The mos equen species, VZV and HHV6, bo h showed mo e han 97% p e alence. S udies om USA epo simila igu es o VZV (99%) [29]. E en HHV6 is epo ed o be p e alen almos ubiqui ously in he adul popula ion [30–33]. We no ed a lowe p e a- lence o an i-HHV6 an ibodies wi h inc easing age, in line wi h ea lie epo s [34, 35]. The p e ailing explan- a ion is ha he p ima y in ec ion, and co esponding humo al immuni y, almos exclusi ely occu s in ea ly childhood, and ha an ibody i e s decline wi h age and hus in some pa ien s goes below ou assay’s de ec ion limi [34]. The se op e alence o CMV was 83%, con- i ming he high p e alence igu es ea lie epo ed om Sweden, ega dless o egion s udied o u baniza ion s a- us [36–38]. Repo s om USA ha e shown 67%, o a younge coho [39, 40] and 87% o a coho o women aged 70––79 [41]. Inc easing age is associa ed wi h in- c eased se op e alence o CMV, in line wi h epo s o a signi ican a e o se ocon e sion in adul s [42]. Se o- p e alence o HSV1 was 79%, in good ag eemen wi h compa able s udies om Swi ze land (80%) [43], Sweden (88%) [44] and Finland (86%) [18]. The HSV2 se op e a- lence was 13%, placing ou coho in he lowe ange o compa able ea lie s udies om Sweden, (16%) [44], o USA, (17%) [45]. The p e alence was signi ican ly highe in women (16%), con i ming o he ci ed s udies. Yea o bi h a ec ed HSV se op e alence signi i- can ly. As illus a ed in Fig. 1, he age-speci ic HSV p e alence is shi ed downwa d in subjec s sampled 2003–2005 compa ed o subjec s sampled 1988–1990. When in es iga ed in a logis ic eg ession model, age pe se had no signi ican e ec on an i-HSV IgG se o- posi i i y. This su p ising ou come should be in e - p e ed in he way ha in his s udy coho - designed o allow sepa a ion o he wo connec ed a iables age and yea o bi h - he la e domina es o e he o me . By analysis o longi udinal samples, he HSV incidence was calcula ed a 14.0/1000 PY in his popula ion and his incidence a e explains app oxima ely one hi d o he inc ease in p e alence by age. The emaining inc ease can be a ibu ed o yea o bi h di e ences in he sub- coho s, in ha la e sub-coho s ha e a lowe p e a- lence. The yea o bi h di e ences could be explained by a dec easing childhood and adolescen isk o HSV, especially HSV1, in ec ion in he popula ion [46, 47]. Changing li es yle may also in luence HSV sp ead, gi en i s ou es o ansmission. The lack o analysis on he im- pac o socio-demog aphic ac o s such as le el o educa- ion and o e c owding, is a limi a ion o he p esen s udy. Fu he s udies and he inclusion o younge pa ic- ipan s would be needed o con i m he obse a ion o a Table 2 Rela ionship be ween p esence o He pes i us IgG an ibodies, and age and sex HSV1 HSV2 VZV CMV HHV6 IgG posi i e women ,n(%) 218 (79.6) 45 (16.4) 269 (98.2) 234 (85.4) 266 (98.9) IgG posi i e men ,n(%) 207 (79.3) 24 (9.2) 255 (97.7) 211 (80.8) 251 (96.2) p- alue men s. women 0.943 0.013 0.699 0.159 0.143 Age IgG posi i e , mean ± SD 62.9 ± 16.0 61.5 ± 15.3 60.7 ± 16.1 62.2 ± 16.0 60.3 ± 16.1 Age IgG nega i e , mean ± SD 52.2 ± 14.0 60.6 ± 16.3 61.3 ± 20.1 53.2 ± 15.4 69.9 ± 12.4 p- alue o di e ence in mean age <0.001 0.638 0.902 <0.001 0.034 Table 3 Mul iple bina y logis ic eg ession model o HSV posi i i y, N=3,444 Odds a io 95% con idence in e al p- alue Age (yea s) 1.009 0.989 –1.030 0.370 Female sex 1.332 1.075 –1.651 0.009 Yea o bi h ( ou digi s) 0.958 0.939 –0.978 <0.001 50% 60% 70% 80% 90% 100% 35 45 55 65 75 85 P e alence o an i-HSV IgG Age (Yea s) S1 (1988-1990) S5 (2003-2005) Fig. 1 Linea eg ession model o an i- HSV IgG se op e alence in ela ion o age in he S1 (solid line)andS5(double line) coho s. Squa es ma k hemeanp e alenceineach5-yea ageg oup. Olsson e al. Immuni y & Ageing (2017) 14:10 Page 4 o 6 dec easing p e alence and could possibly also p o ide in- sigh s on he unde lying causes. In ligh o he accumula - ing e idence o a ole o HSV1 in ec ion in Alzheime ’s disease de elopmen [3, 5, 6, 48], i is also wo h men ion- ing ha he incidence o demen ia is declining in bo h USA and Sweden [49, 50]. Well-designed compa a i e s udies o age-weigh ed ajec o ies will hope ully shed u he ligh on he impac o HHV in ec ious bu den and neu onal damage, leading o sequela such as Alzheime ’s disease. Conclusion P e alence o HSV1 was 79.4%, HSV2 12.9%, CMV 83.2%, VZV 97.9%, and HHV6 97.5%. Women we e mo e o en ound o be se oposi i e o HHV, especially HSV2. Age- adjus ed se op e alence o HSV was lowe in la e bi h coho s indica ing a dec easing childhood and adolescen isk o in ec ion. Acknowledgemen s The au ho s would like o acknowledge D . Pe Ju o o he o iginal de elopmen o ELISA me hods used in his s udy, and Emma Honkala, Julia Wig en and Ing id Ma klund o skill ul echnical assis ance. Funding This s udy was suppo ed inancially by g an s om Väs e bo en Coun y Council, Kempe ounda ions, Swedish Medical Associa ion, he Swedish Demen ia Associa ion, T olle-Wach meis e ounda ion, The No hland Demen ia Fund, Swedish Alzheime Fund, S ohne ounda ion, and Umeå Uni e si y Founda ion o Medical Resea ch. The unde s had no ole in s udy design, da a collec ion and analysis, decision o publish, o p epa a ion o he manusc ip . A ailabili y o da a and ma e ials Please con ac au ho o da a eques s. Au ho s’con ibu ions HL and FE ini ialized he s udy and ou lined he manusc ip . RA designed he sample coho . JO and FE supe ised he se ological analyses. HL, JO EK and FE analyzed he ma e ial. All au ho s con ibu ed o he manusc ip and app o ed he inal e sion. Compe ing in e es The au ho s ha e no con lic s o in e es o decla e. Consen o publica ion All included pa icipan s ha e p o ided consen o publica ion o esea ch based on s o ed se um. E hics app o al and consen o pa icipa e The Regional E hical Re iew Boa d in Umeå app o ed he s udy (2010-229-31 M). All included pa icipan s ha e p o ided consen o he use o s o ed se um o esea ch pu poses. Publishe ’sNo e Sp inge Na u e emains neu al wi h ega d o ju isdic ional claims in published maps and ins i u ional a ilia ions. Au ho de ails 1 Depa men o Clinical Mic obiology, Vi ology, Umeå Uni e si y, Umeå, Sweden. 2 Depa men o Fo ensic Medicine, Uni e si y o Tampe e, Tampe e 33520, Finland. 3 Depa men o Clinical Sciences, Psychia y, Umeå Uni e si y, Umeå, Sweden. 4 Depa men o Communi y Medicine and Rehabili a ion, Ge ia ic Medicine, Umeå Uni e si y, Umeå, Sweden. Recei ed: 18 Janua y 2017 Accep ed: 5 May 2017 Re e ences 1. A in A, e al. Human He pes i uses Biology, The apy, and Immunop ophylaxis. 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