varicella infections in patients with end stage renal

RESEARCH ARTICLE Open Access

Varicella infections in patients with endstage renal disease: a systematic reviewChong Yau Ong1* , Sher Guan Low2,3, Farhad Fakhrudin Vasanwala1,3, Shashidhar Baikunje4,5

and Lian Leng Low6,3

Abstract

Background: End stage renal disease (ESRD) is on the rise globally. Varicella infection among adult patients withESRD has been reported to lead to multiple complications and even death. While varicella vaccination has beenrecommended in paediatric renal patients; recommendation on varicella vaccination among adult patients withESRD remained sparse. This review is aimed at evaluating the impact of varicella infection among adult patientswith ESRD and make a recommendation for vaccination.

Methods: Three databases (PubMed, Embase and Cumulative Index to Nursing and Allied Health Literature (CINAHL))were searched in April 2018 with keywords ‘varicella, chronic kidney failure, chronic kidney disease, renal replacementtherapy, kidney transplantation, end stage renal disease, end stage renal failure, chicken pox, vaccine, vaccinationand complications’.

Results: 29 articles were selected for review. The studies were mainly case reports, and they included measuredoutcomes: prevalence of seronegativity, impact (morbidity, length of stay, and mortality) of varicella amongpatients with ESRD, seroconversion rates and safety of varicella vaccination. The prevalence of seronegativity amongvaricella-infected ESRD adults was found to be at 42 to 100%. Nineteen deaths were reported. At least 54 patients havehad complications from varicella infection. Seroconversion rate post vaccination was found to be around 64–94%.

Conclusion: Varicella is associated with significant morbidity and mortality rates in adult patients with ESRD. Varicellavaccination should be considered for the vulnerable, seronegative patients.

Keywords: Varicella, Chickenpox, End stage renal failure, End stage renal disease, Varicella vaccine, Impact, Morbidity,Mortality

BackgroundEnd stage renal disease (ESRD) is a prevalent chronic con-dition in many countries. ESRD incident rate in developedcountries had largely stabilized in the past one decade,although incident rates rose for many developing coun-tries during the same period [1]. The lifetime risk for anindividual to develop chronic kidney disease (CKD) ishigh, with more than half the adults aged 30–64 years inthe United States likely to develop CKD [2]. About 2.6million people were on dialysis in 2010; 93% in high orupper-middle-income countries [3]. By 2030, worldwideuse of renal replacement therapy (RRT) is projected to

more than double, with a most projected increase inAsia [3].Patients with ESRD have impaired immune system

and therefore are susceptible to infections [4]. The dis-turbance to the immunity system is caused by uraemia,haemodialysis procedure, complications of CKD andtherapeutic interventions for their treatment. Fehr et al.’sliterature review on cases of disseminated varicella infec-tion in adult renal allograft recipients, showed an overallmortality of 34% [5]. The mortality rate from pulmonaryinfections was 14 to 16-fold higher in dialysis patientsand about two-fold higher in renal transplant recipientscompared to general population [6]. One large cohortobservational study showed hazard ratio of hospitalisa-tion due to infection among patients with CKD or ESRD* Correspondence: [email protected]

1Department of Family Medicine, Sengkang General Hospital, 110 SengkangEast Way, Singapore 544886, SingaporeFull list of author information is available at the end of the article

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Ong et al. BMC Nephrology (2018) 19:185 https://doi.org/10.1186/s12882-018-0976-4

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to be as high as 2.55 with a corresponding hazard ratioof 3.76 for infection-related deaths [7].Varicella (chickenpox) is a primary infectious disease

that is caused by varicella-zoster virus (VZV), an alphaherpes virus belonging to the Herpesviridae family. Thesecondary household attack rate of over 90% showedthat varicella is highly contagious [8]. Transmissions aremostly airborne and by direct contact with vesicularfluids. The course of the disease is usually benign amongpaediatric patients; however, this is not so with adultpatients. When it occurs in adult renal transplant recipi-ents, it follows a virulent course and carries a very highrisk of morbidity and mortality [9, 10]. Pneumonia,pneumonitis, acute obstructive respiratory disease, en-cephalitis, meningitis, neutropenia, thrombocytopenia,Henoch-Schonlein purpura, synovitis, Reye’s syndrome,secondary bacterial infections (sepsis, cellulitis, impetigo,abscesses, necrotizing fasciitis, and toxic skin syndrome)- the list of possible complications from varicella infec-tion are numerous.Since the advent of varicella vaccination, it had been

proven to be effective in seroconverting paediatrics pa-tients (including children with leukaemia), adolescentsand adults, with a low occurrence of vaccine-associatedrash among immunocompetent patients [11]. Similarly,seroconversion rates in adults have been encouraging,although adults respond less effectively than childrengroup. In adults with ESRD, there are few studies on theefficacy of varicella vaccination in seroconverting thisgroup of patients who are known to respond less effi-ciently to vaccinations. This is followed by lack of con-sensus and guidelines recommendation on vaccinatingESRD patients with VZV vaccines. This review is aimedat identifying the prevalence of seronegativity among pa-tients with ESRD, evaluating the impact of varicella in-fection to adult patients with ESRD, and synthesizingcurrent recommendations on VZV vaccination.

MethodsData sources and search termsThe relevant papers published were collected through acomputerised search on three databases (PubMed, Embaseand Cumulative Index to Nursing and Allied Health Litera-ture, CINAHL) using the keywords: chronic kidney failure,renal replacement therapy, kidney transplantation, end stagerenal disease, end stage renal failure, chicken pox, varicella,vaccine, vaccination and complication. For PubMed search,the Boolean search of (Kidney Failure, Chronic [MedicalSubject Heading (MeSH) Terms]) OR Renal ReplacementTherapy [MeSH Terms]) OR kidney transplantation [MeSHTerms]) OR end stage renal disease) OR end stage renalfailure)) AND (“Chickenpox”[MeSH Terms]) OR “Vari-cella”) AND (Complicat* OR vaccin*) was used. The samesearch terms were used for Embase and CINAHL database

searches. For CINAHL only academic journals were in-cluded, periodics and bulletins were not included. Thesearch was conducted in April 2018. There was no timeframe limitation applied for the inclusion of the studies.

Study selection and eligibility criteriaTwo reviewers, O.C.Y and L.S.G, independently evalu-ated the articles for eligibility through screening of thetitle and abstract first, followed by full text. Consensuson the eligibility of the articles was sought, and F.F.Vwas involved if there was disagreement and would act asan adjudicator.A study is included if it is found to be relevant with

regards to varicella infection in ESRD: the prevalence ofseronegativity, the complications of the infection, or safetyand efficacy of varicella vaccination to adult patients withESRD or CKD. Case reports and cohort were included ifmeasurable outcomes of death, complications, or lengthof stay were described. Records on herpes zoster, acyclovir,and non-renal solid organ transplants were excluded.Records on paediatric/ child populations were excluded.

Data analysisSelected studies were summarised in Table 1. The datawas grouped into themes of seroprevalance, impact ofthe disease, immunogenicity and safety of the varicellavaccination. Each article was graded for quality of studybased on the Strength of Recommendation Taxonomy(SORT); which was introduced by the United States fam-ily medicine and primary care journals (i.e., AmericanFamily Physician, Family Medicine, The Journal of Fam-ily Practice, Journal of the American Board of FamilyPractice, and British Medical Journal-USA) and the Fam-ily Practice Inquiries Network (FPIN) [12]. The SORTwas used because it can be applied to many sources ofevidence and therefore suitable for our review which in-cluded studies with heterogeneous designs. Study qualitywas included in Tables 2, 3, 4, and 5. Risks of bias ofeach study were not accessed directly as most studieswere of grade three in qualities based on the SORT. Nostatistical analysis was performed.

Results610 studies were retrieved from the search strategy.After removal of duplications, 536 records remained.Screening of title and abstract narrowed down the num-ber of records to 83 which were then assessed for eligi-bility. Twenty-nine studies were included in this reviewafter study selection process (Fig. 1). More than half ofthe studies were case reports; the remaining studiescomprised of retrospective data collection, prospectivecohort, and cross-sectional studies (Table 1).

Ong et al. BMC Nephrology (2018) 19:185 of 14

Table 1 Characteristics of selected studies

Study Region Design Study population Outcomes measured

Prevalence ofdisease/immunity

Morbidity/Mortality

Efficacy Safety

Crespo JF, et al.(2002) [16]

Spain Prospective cohort Single centre.336 candidates for renaltransplant.Follow-up 4 years.

+ + +

Geel AL, et al.(2006) [17]

Netherlands Prospective cohort Single centre.854 transplants patients. 286waitlist patients.Follow-up 13 weeks.

+ + +

Rodríguez-MorenoA, et al. (2006) [13]

Spain Retrospective datacollection

Single centre.812 adult renal transplantpatients.(From 1995 to 2004).

+ +

Kaul A, et al. (2012) [9] India Retrospective datacollection

Single centre.1546 adult renal transplantspatients.(From June2000-June 2010)

+ +

Talebi-Taher M, et al.(2013) [18]

Iran Cross sectional Single centre.VZV IgG acquisition from 187haemodialysis patients(aged 18 to 88).(March–July 2010).

+

Abad CL, et al.(2016) [14]

USA Retrospective datacollection

Not available.Review of all cases withdisseminated VZV amongrenal transplant recipients56 cases in adults.(From 1985 to 2011).

+

Ong CY, et al.(2018) [15]

Singapore Retrospective datacollection

Single centre.Review of all cases with varicellaamong ESRD patients.66 cases in adults.(From 2005 to 2016).

+ +

Errasti P, et al.(1999) [19]

USA Case reports fromretrospective datacollection

Single centre.Review of 476 renal transplantrecipients revealed 4 casesof chickenpox.(Renal transplant done from1969 to 1998).

+

Ishikawa N, et al.(2000) [20]

Japan Case reports 2 patients described. +

Fehr T, et al.(2002) [5]

i)not mentionedii) Switzerland

i) Review of literature.ii)Case reports

i) Not available.Review of literature 1981–2000.34 cases disseminated varicellaidentified.ii) 4 cases reported.

+

Lauzurica R, et al.(2003) [21]

USA Retrospective datacollection

Single centre.Review of kidney transplantrecipients.1 patient described.(Oct 1985 to Aug 2002).

+

Sinha S, et al.(2003) [46]

India Case reports 2 patients described. +

Robertson S, et al.(2006) [22]

Scotland, UK Case report 1 patient described. +

Shahabazian H,et al. (2007) [47]

Iran Case report Report of chickenpox outbreakin renal transplant recipients. 3patients described.

+

Crowther N,et al. (2009) [31]

Australia i) Retrospective datacollection.

Single centre. +


Prevalence of varicella seronegativity among patientswith ESRDOut of the seven studies on the prevalence of seronegativeresults; four studies were on the prevalence of seronegativ-ity among ESRD patients upon presentation of the vari-cella disease [9, 13–15]. The results showed that 42 to100% of the patients who contracted varicella had no priorimmunity to varicella. Three studies examined the preva-lence of seronegativity among ESRD patients before con-traction of primary varicella. Of the three, the first studiedon transplant recipients [16], the second on both trans-plant recipients and candidates on waitlist [17], and thethird on haemodialysis patients [18]. The latter three stud-ies, however, showed that prevalence of seronegativity waslow (2.1 to 9.8%).

The prevalence of VZV seronegativity varies amongrenal transplant recipients, haemodialysis patients, andrenal transplant candidates awaiting transplant (Table 2).There was no mention of whether the candidates waitingtransplant was on renal replacement therapy or not.Among transplant patients (n = 935), there was a hugerange of prevalence seronegativity from 2.1 to 100% [9,13, 14, 17]. Among haemodialysis patients (n = 187), theprevalence of seronegativity was 2.1% [18]. As for candi-dates awaiting transplant (n = 622), 3.2 to 9.8% was sero-negative to VZV [16, 17].

Impact of the disease (mortality and morbidity)23 articles reported on the impact of the disease; includingcomplications from varicella, length of stay, and mortality

Table 1 Characteristics of selected studies (Continued)

Study Region Design Study population Outcomes measured

Prevalence ofdisease/immunity

Morbidity/Mortality

Efficacy Safety

ii) Case report Review of renal allograft recipientsrevealed 1 patient developedvaricella.(From Dec 1972 to July 2010)

Kandasamy R,et al. (2009) [48]

USA Case report 1 patient described. +

Sato A, et al.(2009) [27]

Japan Case report 1 patient described. +

Assi M, et al. (2011)[29]


Mustapic Z, et al.(2011) [49]

Croatia Case report 2 patients described. +

Chiang E, et al. (2012)[50]


Inokuchi R, et al. (2013)[23]

Japan Case report 1 patient described. +

Low LL, et al. (2014)[30]

Singapore Case report 1 patient described. +

Nabi S, et al. (2014)[26]


Sampathkumar K, et al.(2015) [24]

India Case report 1 patient described. +

Depledge DP, et al.(2016) [25]

UK Case report 1 patient described. +

Chhabra P, et al.(2017) [51]

India Case report 1 patient described +

Momani H, et al.(2017) [52]

Jordan Retrospective datacollection.

Single centre.20 renal transplants patientsrevealed 1 patient developedvaricella.(From April 2015–June 2016)

+

Kho MML, et al.(2017) [32]

Netherlands Prospective cohort Not available.52 kidney transplants patients.Follow-up two years.

+ +

Scanlon-Kohlroser CA,et al. (2002) [28]


+Outcomes measures available


Table

2Prevalen

ceof

serone

gativeresults

Reference

MainResults

Timingof

serology

taken

Mainconclusion

sStud

yqu

ality

Renaltransplantpatients/recipien

tsHaemod

ialysispatients

Renaltransplantcand

idates

+

CrespoJF,etal.

(2002)

[16]

Amon

g336renaltransplant

cand

idates,33(9.8%)were

serone

gative.

Before

contractionof

prim

aryvaricella

–Level2

GeelA

L,et

al.

(2006)

[17]

Amon

g854transplant

recipien

ts,

2.1%

wereserone

gative.

Amon

g286patientson

the

waitlist,3.2%

patientswere

serone

gative

Before

contractionof

prim

aryvaricella

-Low

prevalen

ceof

serone

gativity.

-Atriskof

severe

complications

aftercontactwith

chickenp

ox.

Level2

Rodríguez-Moren

oA,etal.

(2006)

[13]

Amon

gthefour

patientsthat

develope

dprim

aryvaricella

infection,allw

eretested

negativeforVZ

VIgG.

Presen

tatio

n/on

set

ofprim

aryvaricella

-Varicellainfectionam

ongrenal

allograftrecipien

tsisun

usualb

utcarriesahigh

morbidity

and

mortality.

Level3

Kaul

A,etal.(2012)[9]

Amon

g23

renalallograftpatientsthat

develope

dvaricellainfection,

allw

astested

negativeforVZ

VIgG.

Presen

tatio

n/on

set

ofprim

aryvaricella

–Level3

Talebi-Taher

M,etal.

(2013)

[18]

Amon

g187patientson

haem

odialysis,2.1%

were

serone

gative.

Before

contractionof

prim

aryvaricella

-Nocorrelationbe

tweenpatient’s

self-repo

rted

historyof

VZVinfection

andseroprevalen

cestatus

(p=0.6).

-Serolog

icscreen

ingforVZ

Vfor

transplant

cand

idates

isessential.

-Con

side

rthispo

pulatio

nas

atarget

grou

pforfuture

natio

nal

immun

isationprog

ram.

Level2

AbadCL,et

al.(2016)[14]

Amon

g54

casesof

varicellain

transplant

recipien

ts,b

aseline

serology

availablein

32patients,

19(59.4%

)wereserone

gative.

Presen

tatio

n/on

set

ofprim

aryvaricella

Baselineserologies

before

transplantationremains

useful

asmarkersforpriorexpo

sure

and

latent

infection.

Italso

guides

VZVvaccination.

Level3

Ong

CY,et

al.(2018)[15]

Amon

g66

casesof

varicellain

patientswith

ESRD

(dialysis,transplant,con

servative),b

aseline

serology

availablein

19patients.42.1%

wereserone

gative.

Presen

tatio

n/on

set

ofprim

aryvaricella

-Immun

ityto

varicellashou

ldbe

screen

edam

ongESRD

patients.

-Seron

egativepatientsto

beconsidered

forvaricellavaccination.

Level3

+Inform

ationon

whe

ther

rena

lrep

lacemen

tor

norena

lrep

lacemen

ttherap

ygivenwhile

awaitin

gtran

splant

wereno

tmen

tione

d


Table

3Im

pact

ofthedisease:mortalityandmorbidity

Reference

Patient’spresen

tatio

nResults

Elaborations

onresults

Mainconclusion

sStud

yqu

ality

Com

plication

Leng

thof

stay

(LOS)

Mortality

Ong

CY,et

al.

(2018)

[15]

-66patientsde

velope

dvaricellain

the12-yearreview

ofallESRDpatients.

-Age

rang

e:19–89yearsold(m

edian:53)

-37malepatients.

-Tim

ingof

infection:

6to

19yearspo

stdiagno

sisof

ESRD

.

++

+-24patientsde

velope

dat

leaston

ecomplication.

Enceph

alitis,men

ingitis,

pneumon

ia/pne

umon

itis.

-LOS:med

ian10

days

-9died

(13.6%

)

-ESRDpatientshadsign

ificant

morbidity

andmortalityassociated

with

varicella

infection.

-Screenforserone

gativepatientsand

consider

vaccinatethem

.

Level3

ErrastiP

,etal.

(1999)

[19]

-31y.o.

Wom

an,5

yearspo

st-transplant,

admitted

foracuteep

igastricpain

with

3days

vesicularrash.

+NA

+-M

ultio

rgan

failure:

-Fulminanthe

patitis(post-

mortem

show

edmassive

hepatic

necrosis).

-Diedin

2days.

-Chicken

poxoftenfollowssevere

and

oftenfatalcou

rsein

adultswith

renal

transplantation.

-Vaccine

appe

arsto

preven

tclinical

varicellafollowingsubseq

uent

expo

sure.

Level3

-29y.o.

Man,17yearspo

st-transplant,

admitted

forconfluen

t-haem

orrhagicrash.

+NA

+-Encep

halitis(post-mortem

show

edcerebraloe

dema).

-Disseminated

intravascular

coagulation(DIC)with

multip

lebleeding

sites.

-Multio

rgan

failure.

-Secon

dary

Staphylococcus

bacteraemia.

-Patient

died

.

−59

y.o.

Man,2

yearspo

st-transplant,had

few

vesicularrash.Exposed

tohissonwho

hadvaricella4weeks

ago.

–NA

–-Nocomplication

-69y.o.

Wom

an,8

mon

thspo

st-transplant,

admitted

forvesicularrash

andfever.

–NA

–-Nocomplication

IshikawaN,

etal.(2000)[20]

-29y.o.

Man,11mon

thspo

st-ren

altransplantation.

With

papu

larand

vesicularrash

andabdo

minalpain.

+NA

–-DIC

andgastrointestinal

bleeding

.-Varicellavaccinationshou

ldbe

administeredbe

fore

transplantation

ifpatientshadno

pastvaricella

infectionbasedon

historyand

antib

odytitre

Level3

-36y.o.

Wom

anwith

avesicularrash

onface.H

adrenaltransplant3yearsago.

+NA

–-DIC

Fehr

T,et

al.

(2002)

[5]

-51y.o.

man,11yearspo

st-transplantatio

n,hadabdo

minalpain,n

ausea,vomiting

,and

gene

ralised

pustulosis.

+NA

–-Pne

umon

itisandhypo

xic

respiratory

failure.

-Failure

ofgraft6mon

thslater.

-Overallmortalityof

34%.M

ortality

after1990

with

acyclovirandredu

ction

ofim

mun

osup

pressantswere22%.

−82%

ofpatientssummarised

had

substantialm

ortality.

-Vaccinatio

niseffectiveandhasno

severe

side

effects.

-Rou

tineVZ

Vserology

testforevery

ESRD

patientsbe

fore

renaltransplant.

-Vaccinatio

nin

thosewith

negativeor

very

low

VZVantib

odytitres.

Level3

-34y.o.

Man,1.5yearspo

st-transplant,

hadacuteep

igastricpain,n

ausea,vomiting

,andvesicularrash.

+NA

–-DIC,h

epatitis.

-51y.o.

Man,6

mon

thspo

st-transplant,

admitted

forprog

ressivedyspno

ea.

++

–-Pne

umon

itiswith

respiratory

failure.

-LOS:26

days.

-23y.o.

Man,6

mon

thspo

st-transplant,

presen

tedwith

vesicles

who

lebo

dy.

++

–-Hep

atitis

-LOS:10

days

LauzuricaR,

etal.(2003)[21]

-30y.o.

Man

presen

tedwith

vesicular-pu

stular

rash,fever

+NA

+-Pne

umon

itiswith

respiratory

failure

-Detectin

gVZ

Vserone

gativepatients

before

therenaltransplantisrelevant

Level3


Table

3Im

pact


(Con

tinued)

Reference

Patient’spresen

tatio

nResults

Elaborations

onresults

Mainconclusion

sStud

yqu

ality

Com

plication

Leng

thof

stay

(LOS)

Mortality

andabdo

minalpain,3.5years

post-transplant.

-Mild

transaminitis.

-Died4days

upon

admission

dueto

multio

rgan

failure:

(hep

atitis,myocarditis,DIC)

becausevaccinationmay

minim

isethe

risks

offuture

infection.

Sinh

aS,et

al.

(2003)

[46]

-22y.o.

Wom

an,42mon

ths

post-transplant,presen

tedwith

abdo

minalpain

1weekafter

thede

velopm

entof

chickenp

ox.

+NA

–-Pancreatitis.

-Acute

pancreatitisas

aconseq

uent

ofviralinfectio

niswellkno

wn

Level3

-36y.o.

Man,10days

post-transplant,

develope

dpancreatitis2weeks

afterpancreatitis.

+NA

–-M

ildacutepancreatitis

Robe

rtsonS,

etal.(2005)[22]

-30y.o.

Man

with

age

neralised

maculop

apular

rash

+NA

+-Fulminantvaricellawith

multio

rgan

involvem

ent(acute

renalfailure,acute

liver

failure)

-Diedwith

in60

hof

admission

-Alth

ough

regarded

mild

infectionin

children,

chickenp

oxcancausefatality

inadultsandin

the

immun

ocom

prom

ised

.-Screenpo

tentialren

altransplant

recipien

tsforVZ

Vsuscep

tibility

and

offervaccinationto

theserone

gative

patients.

-Testforim

mun

ityforvaricellaas

soon

asprog

ressiverenalfailure

isdiagno

sed.

Level3

Rodríguez-

Moren

oA,etal.

(2006)

[13]

-Eight

patients(1%)de

velope

dvaricella(7

men

,1wom

en).

-Age

rang

e:32–64.

-Med

iantim

efro

mtransplantation

toinfectionwas

32mths.

++

+Com

plications:

-2pn

eumon

itis,1he

patitis,1

thrombo

ticmicroangiop

athy,

1multio

rgan

failure

-LO

S:11

days

(med

ian3to

21).

-One

(12.5%

)de

athdu

eto

multio

rgan

failure

-Varicellainfectionin

adultallograft

recipien

tsisun

usualb

uthigh

lymorbid

-Vaccinatio

nof

serone

gativepre-

transplant

cand

idates

shou

ldbe

attempted

Level3

Shahbazian

H,

etal.(2007)[47]

-37y.o.

Man,a

year

post-transplant,

admitted

forsevere

abdo

minalpain.

++

–-Acute

kidn

eyinjury

-LOS:10

days

-Allrenaltransplantrecipien

tsshou

ldbe

screen

edforVZ

Vim

mun

itybe

fore

transplant

irrespe

ctiveof

previous

VZV

infection.

-Serone

gativepatientsshou

ldreceive

liveVZ

Vvaccineseveralm

onthsprior

totransplant.

Level3

-44y.o.

Man,9

yearspo

st-transplantatio

n,admitted

forlow

back

pain

of2days

duratio

n.2days

laterhe

develope

dfever

andpapu

lovesicularrash

2days

later

–+

–-LOS:15

days

-34yoman,8

yearspo

st-transplantatio

n,admitted

foracuteabdo

minalpain

with

intractablenausea

vomiting

.Papulovesicular

rash

appe

ared

ontheface

andtrun

k48

hlaterbe

fore

becamege

neralised

.

–+

–-LOS:13

days

Crowther

N,

etal.(2008)[31]

-43y.o.

Man,16yearspo

st-ren

altransplant.

Acute

renalfailure

detected

atroutineclinic

review

.Hehadscatteredskin

lesion

afterhischildrenhadchickenp

ox2weeks

ago.

+NA

–-Diagn

osis:lateacute

med

iatedrejectionpo

st-transplant

precipitatedby

recurren

tvaricellainfection.

–Level3


Table

3Im

pact


(Con

tinued)

Reference

Patient’spresen

tatio

nResults

Elaborations

onresults

Mainconclusion

sStud

yqu

ality

Com

plication

Leng

thof

stay

(LOS)

Mortality

Kand

asam

yR

etal.(2009)[48]

-58y.o.

Man

with

feverand

prog

ressiverash

+NA

–-Darrierdiseaserelatedto

dissem

inated

varicella

–Level3

Sato

A,etal.

(2009)

[27]

-36y.o.

Wom

anpresen

tedwith

anirritablecoug

h+

+–

-Varicellapn

eumon

ia-LOS:1mon

thand10

days

-One

shou

ldkeep

thepo

ssibility

ofVZ

Vreinfectionin

mind,

inIm

mun

ocom

prom

ised

patients

with

pasthistoryof

varicella.

Level3

AssiM

,etal.

(2011)

[29]

-68y.o.

man

with

kidn

eytransplant

10yearsago,

presen

tedwith

5-days

fever,confusionand

alteredsensorium

+NA

–Varicellaen

ceph

alitis,followed

byGuillain-Barre

synd

rome

(GBS).

–Level3

MustapicZ,

etal.(2011)[49]

-Tworenalallograftpatientsde

velope

dvaricella.D

etailsun

available.

NA

NA

NA

-Not

available

-VZV

infectionisarare

butpo

tentially

serio

uscomplicationin

renaltransplant

recipien

ts.

-Activeim

mun

isationforVZ

V-serone

gativepatientsbe

fore

transplantationshou

ldbe

perfo

rmed

.

Level3

ChiangE,et

al.

(2012)

[50]

-42y.o.

Wom

an,unkno

wnyearspo

stkidn

eytransplant,h

adrig

hteyeredn

ess,tearing,

and

blurredvision

for1mon

th.

+NA

–-Acute

retin

alne

crosis

–Level3

Kaul

A,etal.

(2012)

[9]

-23patientsde

velope

dvaricellain

the10-year

review

ofpo

strenaltransplant.

-Age

rang

e:21–54yearsold(m

edian:39)

-17malepatients.

-Tim

ingof

infection:

<15

days

post-transplant

to>5yearspo

st-transplant.

+NA

+-5

hadgraftdysfun

ction.

-7hadinfections

(6bacterial,

1fung

al).

-3hadsepsis

-5hadgastritis

-2haden

ceph

alitis

-2hadpancreatitis

-2hadorchitis

-2died

(8.6%)

-Prim

aryvaricella/chicken

poxisa

potentially

fatalinfectio

nin

adultrenal

transplant

recipien

ts.

-Varicellavaccinationin

thehigh

-risk

grou

ps,especially

durin

gthepre-ESRD

stage,may

redu

cethenu

mbe

rof

varicellainfection.

Level3

Inokuchi

R,et

al.(2013)[23]

-A69

y.o.

Wom

an(20yearsESRD

ondialysis,

then

1mon

thpo

strenaltransplantatio

n)presen

tedwith

gene

ralised

rash

oneday.

+NA

+-Varicellapn

eumon

iawith

respiratory

failure.

-Dem

ised

atDay

28illne

ss(despite

change

ofantiviralto

foscarne

ton

day10,

mechanicalven

tilationon

day3)

-Patientswith

VZVpn

eumon

iawith

deep

andvastulceratio

nson

bron

choscopy

hadfatalo

utcomes.

Level3

Low

LL,etal.

(2014)

[30]

-58y.o.

Man

onhaem

odialysis,presen

tedwith

feverandcoug

h.Subseq

uentlyde

velope

da

papu

lovesicularrash

onthe4thdayof

admission

.

+NA

–-Varicellapn

eumon

ia-Varicellaen

ceph

alitis

-Ren

alPh

ysicians

andFamily

Physicians

intheAsia-Pacific

region

shou

ldstud

ytheep

idem

iologicald

atain

each

coun

try.

-Con

sensus

guidelines

need

edandho

wthevaricellavaccinationprog

ram

can

betargeted

forthoseat

risk.

-Liveattenu

ated

varicellavaccineis

hasbe

enproven

tobe

safe

whe

n

Level3


Table

3Im

pact


(Con

tinued)

Reference

Patient’spresen

tatio

nResults

Elaborations

onresults

Mainconclusion

sStud

yqu

ality

Com

plication

Leng

thof

stay

(LOS)

Mortality

administeredto

adultESRD

patients

regardless

ofRR

Tmod

e.

NabiS,etal.

(2014)

[26]

-73y.o.

Wom

anwith

kidn

eytransplantation

andrecent

CMVinfection,

presen

tedwith

alteredmen

talstatus.

+NA

–-Varicellaen

ceph

alitis

-Disseminated

VZVwith

enceph

alitis

israre,b

utalife-threaten

ingcond

ition

Level3

Sampathkumar

K,et

al.(2015)[24]

-34y.o.

Man

hadkidn

eytransplant

10mon

thsago,

camewith

fever×

2weeks

andbitempo

ralh

eadache.

+NA

–-VZV

indu

cedcentraln

ervous

system

angiop

athy

–Level3

Dep

ledg

eD,

etal.(2016)[25]

-55y.o.M

anpo

strenaltransplant

day23presen

tedwith

abdo

minalpain,

macular

rash

andabno

rmalliver

functio

ntest.

+NA

–-VZV

pneumon

itis,he

patitis

-Riskof

airborne

transm

ission

ofVZ

Viseviden

t,espe

ciallywhe

nviralload

ishigh

.-Im

mun

ocom

prom

ised

patientsare

vulnerableto

serio

usinfection.

-Needforpre-transplant

vaccination.

Level3

-61y.o.M

anpo

strenaltransplantday25presen

ted

with

4days

fever,vesicularrash

andabno

rmal

liver

functio

n.

+NA

+-VZV

hepatitis.

-Diedon

day6admission

(3days

inICU)

Chh

abra

P,et

al.(2017)[51]

-33y.o.M

an,3

yearspo

st-transplant,had

severe

epigastricpain

for7days.

+NA

–-Varicellapancreatitisand

hepatitis

–Level3

Mom

aniH

,et

al.(2017)[52]

-One

patient

develope

dvaricella

-Detailsun

available

+NA

–-Varicellapn

eumon

itis

–Level3

NANot

available


(Table 3). Collectively, there were nineteen deaths re-ported from the studies. Errasti, et al. reported four pa-tients in which two died; both patients had significantcomplications (one with fulminant hepatitis, one had en-cephalitis) and multiorgan failure [19]. On the other hand,two other patients that had no complications survived theinfection. Ishikawa, et al. reported two patients with dis-seminated intravascular coagulation [20]. Fehr et al. re-ported four cases in which all survived while their reviewof the literature revealed overall varicella mortality rates tobe 34% [5]. Other deaths from varicella in ESRD were due

to respiratory failures (one from pneumonia, one frompneumonitis), multiorgan failure (two cases), nervous sys-tem neuropathy (one case) and hepatitis (one case) [13,21–25]. Length of stay has been reported to vary from 2 to40 days. Other reported complications were pancreatitis,retinal necrosis, secondary bacterial infection, acute kidneyinjury, myocarditis, microangiopathy, Darrier’s disease, andeven Guillain-Barre syndrome.Most of the studies revealed that infected with pri-

mary varicella were treated with intravenous acyclovir.Standard dose of 10 mg/kg 8hourly (eight to fourteen

Table 4 Immunogenicity of varicella vaccination

Reference Number ofpatients studied

Number ofdose of VZV vaccine

Seroconversion rate/response rate

Main conclusions Study quality

CrespoJF, et al. (2002) [16]

17 2 -94.1% after second dose of VZVvaccination.

-Vaccination protocol is effective inseroconverting.

Level 2

Geel AL, et al.(2006) [17]

11 2 -64% seroconverted after twodoses of VZV vaccine.

-64% seroconversion was lesser thanpost-licensurestudies.-Impaired immune system wasresponsible for less ability tomount antibody titres andmaintaining it over time.

Level 2

Kho MM, et al.(2016) [32]

52 2 -40 responders (77%)found (AUC > 0.9) VZVspecific antibody (Ab) at 3 months.-At one year, 67% still have positiveVZV Ab.-At two years,45.8% have positiveVZV Ab

-Two-dose vaccination before kidneytransplantation regime is safe andeffective in adults with CKD, resultingat least 77% seroconversion in VZVIgG and VZV-specific T cellmemory.

Level 2

Table 5 Safety on varicella vaccination

Reference No of patient studied Complications of vaccine Main conclusions Study quality

Crespo JF,et al. (2002) [16]

-17 seronegative patientscompleted vaccinationprotocol.

-No secondary effect of vaccinationdetected.-None of the subsequentlyseroconverted patients whoreceived kidney transplantpresented with VZV disease (up to18 months post renal transplant).

-Systematic vaccination prior totransplantation could prevent severevaricella.

Level 2

Scanlon-Kohlroser CA,et al.(2002) [28]

-A single case of 51yowoman at 6 months post-renal transplant developeda mild rash.-She had daily householdcontact with 15-month oldtwins vaccinated 40 days ago.

-Characteristic popular and vesicularrash over the face, trunk,extremities. No dissemination.Confirmed with positive VZV IgG2 weeks later.

-Transmission from those vaccinated tosusceptible individuals are rare andtypically occurs only if these patientsdevelop a rash.- Contact cases develop a subclinicalinfection or mild illness; suggestingvaccine virus remains attenuatedwhen vaccinated.

Level 3

Geel AL, et al.(2006) [17]

-11 seronegative patientshave been vaccinated withtwo doses VZV vaccine.

- No side effects, no fever, or skinlesions among all vaccinatedpatients.

-Vaccination should be performed in thisgroup of patients in view of potentiallylethal complications of primary varicellainfection.

Level 2

Kho MML, et al.(2016) [32]

-52 seronegative patientsgiven two doses of VZV vaccine.

-No severe vaccine-related adverseevents were reported.- One had pain at injection site.-Two had zoster (3 months and9 years post vaccination)-One patient developed mildvaricella (18 days post vaccination).

Level 2


days) were described in most cases (12 studies), renaladjusted dose were mentioned in seven reports, no doseof intravenous acyclovir was given in two reports, andin one study [9], all patients were given regimen of twoweeks of intravenous acyclovir followed by threemonths of oral acyclovir was administered. One casewas treated with three months of oral acyclovir. Onecase was treated with intravenous valaciclovir [26].Intravenous ganciclovir was given in two cases [5, 9].Cessation and reduction of immunosuppressant d rugswere described in four cases [5, 21, 25, 27, 28] and twostudies [5, 9] respectively. Adjunctive antibiotics wereinitiated in five cases [5, 25, 27, 29, 30]. Foscarnet wasgiven in one case following failure of initial treatment

[23]. Immunoglobulins were administered in eight cases[13, 20, 31].

Immunogenicity and safety of varicella vaccinationThree studies examined the seroconversion rate or postvaccination after administration of two doses of varicellavaccine. All three studies have limited number of patients.Crespo, et al. [16] reported a highly encouraging responserate of 94% while Geel, et al. [17] and Kho, et al. [32]found that the response rate to be around 64–77%. Table 4summarises the seroconversion rates of selected studies.As far as safety is concerned, Crespo, et al. and Geel,

et al. found no secondary effect of vaccination [16, 32].None of their vaccinated patients developed the

Fig. 1 Details of article selection process in the literature search


varicella-zoster disease. Kho, et al. followed up 52patients post-vaccination for complications and foundone to have primary varicella and two to have herpeszoster [32]. Only one reported pain at injection site, nocellulitis or skin infection was reported. Interestingly,Scanlon-Kohlroser, et al. reported a case where transmis-sion of varicella took place from two infants that werevaccinated to a post-renal transplant patient [28]. Table 5summarises the complications of the vaccine.

DiscussionSummary of findingsIn this review, the prevalence of seronegativity amongvaricella-infected ESRD adults was found to be signifi-cantly alarming at 42 to 100% [9, 13–15]. Nineteen deathswere reported in 23 studies that reported the varicella in-fections. At least 52 patients were reported to have com-plications from varicella infections. Efficacy of vaccination(measured by seroconversion rate after two doses of VZVvaccine) was found to be around 64–74%. Safety of vac-cines showed that adverse effects or complications fromvaccinations were zero in a cohort of fewer than twentypersons [16, 17]. Four adverse effects from vaccinationswere reported in a study of 52 patients [32].Varicella has been recognised as a potentially fatal dis-

ease among adults even though it has been largelyregarded as a benign disease of childhood [33]. Althoughaccounting for only 5% of reported cases of varicella,adults in general population contributed to 35% of allvaricella deaths [34]. Furthermore, varicella is a more se-vere threat to adult patients with ESRD the myriad oforgan and system-complications described. This dis-misses the general perception of acute varicella being aself-limiting disease.In the general population (adults and paediatrics),

mortality rates were around 0.41 deaths per 1 millionthrough 1990–1994. This decreased drastically to 0.14deaths per 1 million during 1999 through 2001 [35, 36].Compared to general population, mortality rates of vari-cella among adult patients with ESRD is much higher;suggesting the vulnerability of this group of patients tovaricella infection.Varicella-related complications derived from the re-

view were no different from known complications ofvaricella infection [34]. Pneumonia, hepatitis, and en-cephalitis were found to be the leading complications.These complications may progress to multi-organ failurewith high mortality.Based on this review, seroconversion rates of 64–94%

are encouraging and reflecting high immunogenicitywhen administered. This is in keeping with findings oflive-attenuated varicella vaccinations being immunogenic,efficacious and safe in preventing varicella infections

[35, 37]. Besides that, there are no major adverse effects inthe cohort studies of vaccinated adult patients. This couldsuggest the positive role of vaccinating VZV seronegativepatients with ESRD in preventing varicella infection.In addition to the database search, we also searched

specifically for guidelines on varicella vaccinations. As forrecommendations for varicella vaccination in this group ofpatients; only a handful recommendations from publishedguidelines were found. The Advisory Committee onImmunization Practices (ACIP); Centres for Disease Controland Prevention (CDC) have recommended varicella vaccinefor ESRD patients, who meet age criteria and who do nothave contraindications to vaccine [38].The American Society of Transplantation and the

American Society of Transplant Surgeons recommendedpre-transplantation VZV serology checking. Seronegativeadults should receive one dose of varicella vaccine with sero-logic testing post vaccination. If seroconversion does notoccur, the dose may be repeated once if time permits [39].Similarly, the Korean Vaccination Society has recom-

mended varicella vaccination for the seronegative adults;and this should be completed at least one month beforetransplantation [40]. The 2013 Infectious Disease Societyof America (IDSA) Clinical Practice Guideline (CPG) forvaccination of the immunocompromised host advocatedthat varicella vaccine (VAR) should be given to immuno-competent patients without evidence of varicella im-munity if it can be administered at least four weeksbefore initiating immunosuppressive therapy [41].Both the US Department of Veterans Affairs and De-

partment of Defence (2014) on their Clinical PracticeGuideline for the Management of Chronic Kidney Dis-ease in Primary Care (strong recommendation); andPublic Health Agency of Canada (in their Canadian Im-munisation Guide 2016) have extended the recommen-dation to include patients with chronic kidney disease orchronic renal disease [42, 43]. The Kidney Disease: Im-proving Global Outcomes (KDIGO) and the NationalKidney Foundation’s Kidney Disease Outcome: QualityImprovement (KDOQI) have not specifically advocatedfor varicella vaccination post-transplant, the reason be-ing varicella vaccine is a live-attenuated vaccine [44, 45].At present, there is yet to be any recommendation byboth KDIGO and KDOQI on pre-transplant vaccinationsin general. While post-exposure prophylaxis with vari-cella immunoglobulin, and primary varicella treatmentwith acyclovir or valaciclovir has been recommended;they are still silent with regards to VZV immunisation asa preventive method [43, 45].

Clinical implicationsThere is a lack of guidelines in the Asia Pacific Regionon varicella vaccination in patients with ESRD. Sincemost patients with ESRD or advanced CKD are


managed by renal physicians and family physicians; itis critical to advocate, initiate planning, followed byimplementing policies on varicella vaccination amongthese susceptible patients. This is of increasing im-portance considering the increasing number of pa-tients developing ESRD in Asia.

Limitations and future researchThe first limitation is the heterogeneity of the popula-tion in the studies that were included. The aim of thisreview is to review the available literature of adult popu-lations with ESRD comprehensively. However, moststudies included only subset populations of ESRD;namely renal transplant recipients or patients on haemo-dialysis and therefore findings may not be fully represen-tative of the overall population of ESRD. Therefore,there is a real need for study varicella among patientswith ESRD without renal transplantation. To date,guidelines by the US Veterans’ Affairs and CanadianPublic Health Agency are the only two available ones toadvocate vaccination even, among chronic kidney dis-ease, while most of the published guidelines advocatevaccination among ESRD. Studies on varicella amongCKD patients (before progressing into ESRD) may helpto give insight whether vaccinating patients once theyare diagnosed with CKD of certain stages (before theirprogression to ESRD) may prevent this vulnerable groupof patients from contracting varicella.There is some heterogeneity in the reports of preva-

lence of varicella immunity among patients in ESRD.Three described the prevalence among ESRD patientswho yet to contract varicella [16–18]; while four de-scribed the prevalence in already infected ESRD patients[9, 13–15]. Despite the comprehensive search, the num-ber of available studies in the literature is low, they weresummarised together in Table 2.Another limitation is the design of the selected articles.

As varicella in adult patients with ESRD has not beenwidely studied, there are no large-scale observational stud-ies to date to give an impactful insight on the burden ofthe disease in this group of population. Most availablestudies are case reports and retrospective data collectionand therefore are prone to selective bias (reporting bias).Finally, future research on the cost-effectiveness on

vaccinating all patients with ESRD compared to screen-ing patients with ESRD for seronegativity before vaccin-ating them and monitoring will be helpful to guidenational guidelines on varicella vaccination in adultpatients with ESRD. This can be challenging and variesbetween countries depending on the robustness ofnational healthcare surveillance data on patients withESRD and cost of delivering and administrating vaccinesand serological tests.

ConclusionVaricella is a disease with great morbidity and mortalityin adult patients with ESRD. Preventing varicella infec-tion in ESRD patients is critical, and has been provensafe and reasonably efficacious in ESRD and chronickidney disease patients.

AbbreviationsAb: Antibody; AUC: Area under curve; CINAHL: Cumulative Index to Nursingand Allied Health Literature; CKD: Chronic kidney disease; CMV: Cytomegalovirus;DIC: Disseminated intravascular coagulation; ESRD: End stage renal disease;Ig G: Immunoglobulin G; Ig M: Immunoglobulin M; LOS: Length of stay;MeSH: Medical subject heading; NA: not applicable; RRT: Renal replacementtherapy; SORT: Strength of recommendation taxonomy; VZV: Varicella zoster virus;y.o.: years old

Availability of data and materialsThe datasets used and/or analysed during the current study are availablefrom the corresponding author on reasonable request but restrictions applyto the availability of these data.

Authors’ contributionsOCY and LLL formulated the search strategy. OCY and LSG, independentlyevaluated the articles for eligibility through screening of the title andabstract first, followed by full text. FFV adjudicated the evaluation of articles.OCY wrote the draft. All authors participated in the editing of themanuscript. All authors read and confirmed the final draft.

Ethics approval and consent to participateNo ethics approval or consent is needed based on institution’s guidelines.

Consent for publicationNot applicable.

Competing interestsAll authors declare that they have no competing interests.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.

Author details1Department of Family Medicine, Sengkang General Hospital, 110 SengkangEast Way, Singapore 544886, Singapore. 2Post-acute and Continuing Care,SingHealth Community Hospital (Sengkang), Singapore, Singapore.3SingHealth Duke-NUS Family Medicine Academic Care Program, Singapore,Singapore. 4Department of General Medicine, Sengkang General Hospital,Singapore, Singapore. 5Department of Renal Medicine, Singapore GeneralHospital, Singapore, Singapore. 6Department of Family Medicine andContinuing Care, Singapore General Hospital, Singapore, Singapore.

Received: 13 December 2017 Accepted: 28 June 2018

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https://doi.org/10.1136/bcr-2014-206655

https://www.cdc.gov/chickenpox/about/index.html

https://www.healthquality.va.gov/guidelines/CD/ckd/VADoDCKDCPG2014.pdf

http://www.phac-aspc.gc.ca/publicat/cig-gci/p04-vari-eng.php

http://www.phac-aspc.gc.ca/publicat/cig-gci/p04-vari-eng.php

varicella infections in patients with end stage renal

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