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
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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
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