Received:16June2022 Accepted:26August2022
DOI:10.1111/jebm.12494
GUIDELINE
Clinicalguidelineforthediagnosisandtreatmentofcutaneous
warts(2022)
PeiyaoZhu
1,2,3,4
Rui-QunQi
1,2,3,4
Yang Yang
1,2,3,4
WeiHuo
1,2,3,4
YuqingZhang
5
LiHe
6
GangWang
7
JinhuaXu
8
FurenZhang
9
RongyaYang
10
PingTu
11
LinMa
12
QuanzhongLiu
13
Yuzhen Li
14
HengGu
15
BoCheng
16
XiangChen
17
AijunChen
18
ShengxiangXiao
19
HongzhongJin
20
JunlingZhang
21
ShanshanLi
22
ZhirongYao
23
WeihuaPan
24
HuilanYang
25
ZhuShen
26
HaoCheng
27
PingSong
28
LingyuFu
29
HongxiangChen
30
SongmeiGeng
31
KangZeng
32
JianjianWang
33
JuanTao
30
YaolongChen
33,34,35
XiuliWang
36
Xing-HuaGao
1,2,3,4
1
DepartmentofDermatology,TheFirstHospitalofChinaMedicalUniversity,HepingDistrict,Shenyang,P.R.China
2
NHCKeyLaboratoryofImmunodermatology,ChinaMedicalUniversity,HepingDistrict,Shenyang,P.R.China
3
KeyLaboratoryofImmunodermatology,ChinaMedicalUniversity,MinistryofEducation,HepingDistrict,Shenyang,P.R.China
4
NationalandLocalJointEngineeringResearchCenterofImmunodermatologicalTheranostics,HepingDistrict,Shenyang,P.R.China
5
DepartmentofClinicalEpidemiologyandEvidence-BasedMedicine,TheFirstHospitalofChinaMedicalUniversity,HepingDistrict,Shenyang,P.R.China
6
DepartmentofDermatology,FirstAffiliatedHospitalofKunmingMedicalUniversity,Kunming,P.R.China
7
DepartmentofDermatology,XijingHospital,FourthMilitaryMedicalUniversity,Xi’an,Shaanxi,P.R.China
8
DepartmentofDermatology,HuashanHospital,FudanUniversity,Shanghai,P.R.China
9
ShandongProvincialHospitalforSkinDiseases&ShandongProvincialInstituteofDermatologyandVenereology,ShandongFirstMedicalUniversity&Shandong
AcademyofMedicalSciences,Jinan,P.R.China
10
DepartmentofDermatology,GeneralHospitalofBeijingMilitaryCommandofPLA,DongchengDistrict,Beijing,P.R.China
11
DepartmentofDermatologyandVenerology,PekingUniversityFirstHospital,Beijing,P.R.China
12
DepartmentofDermatology,BeijingChildren’sHospital,CapitalMedicalUniversity,NationalCenterforChildren’sHealth,Beijing,P.R.China
13
DepartmentofDermatology,TianjinMedicalUniversityGeneralHospital,Tianjin,P.R.China
14
DepartmentofDermatology,SecondAffiliatedHospitalofHarbinMedicalUniversity,Harbin,P.R.China
15
InstituteofDermatology,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Nanjing,P.R.China
16
DepartmentofDermatology,TheFirstAffiliatedHospitalofFujianMedicalUniversity,Fuzhou,P.R.China
17
DepartmentofDermatology,XiangyaHospital,CentralSouthUniversity,Changsha,P.R.China
18
DepartmentofDermatology,TheFirstAffiliatedHospitalofChongqingMedicalUniversity,Chongqing,P.R.China
19
DepartmentofDermatology,TheSecondAffiliatedHospital,SchoolofMedicine,Xi’anJiaotongUniversity,Xi’an,P.R.China
20
DepartmentofDermatology,PekingUnionMedicalCollegeHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,DongchengDistrict,
Beijing,P.R.China
21
DepartmentofDermatology,TianjinAcademyofTraditionalChineseMedicineAffiliatedHospital,Tianjin,P.R.China
22
DepartmentofDermatology,TheFirstHospitalofJilinUniversity,Changchun,JilinProvince,P.R.China
23
DepartmentofDermatology,XinhuaHospital,ShanghaiJiaoTongUniversitySchoolofMedicine,Shanghai,P.R.China
24
DepartmentofDermatology,ShanghaiKeyLaboratoryofMolecularMedicalMycology,SecondAffiliatedHospitalofNavalMedicalUniversity,Shanghai,P.R.China
PeiyaoZhu,RuiQunQi,andYangYangcontributedequally.
?2022ChineseCochraneCenter,WestChinaHospitalofSichuanUniversityandJohnWiley&SonsAustralia,Ltd.
JEvidBasedMed.2022;1–18. wileyonlinelibrary.com/journal/jebm 1
2 ZHU ET AL.
25
DepartmentofDermatology,GeneralHospitalofSouthernTheatreCommandofPLA,Guangzhou,P.R.China
26
DepartmentofDermatology,InstituteofDermatologyandVenereology,SichuanAcademyofMedicalSciencesandSichuanProvincialPeople’sHospital,Chengdu,
P.R.China
27
DepartmentofDermatologyandVenereology,SirRunRunShawHospital,SchoolofMedicine,ZhejiangUniversity,Hangzhou,P.R.China
28
DepartmentofDermatology,Guang’anmenHospital,ChinaAcademyofChineseMedicalSciences,Beijing,P.R.China
29
DepartmentofClinicalEpidemiologyandEvidence-BasedMedicine,TheFirstHospitalofChinaMedicalUniversity,HepingDistrict,Shenyang,P.R.China
30
DepartmentofDermatology,UnionHospital,TongjiMedicalCollege,HuazhongUniversityofScienceandTechnology,Wuhan,P.R.China
31
DepartmentofDermatology,TheSecondAffiliatedHospitalofXi’anJiaotongUniversity,Xi’an,Shaanxi,P.R.China
32
DepartmentofDermatology,NanfangHospital,SouthernMedicalUniversity,Guangzhou,P.R.China
33
Evidence-BasedMedicineCenter,SchoolofBasicMedicalSciences,LanzhouUniversity,Lanzhou,P.R.China
34
WorldHealthOrganizationCollaboratingCenterforGuidelineImplementationandKnowledgeTranslation,Lanzhou,P.R.China
35
GINAsia,Lanzhou,P.R.China
36
InstituteofPhotomedicine,ShanghaiSkinDiseaseHospital,SchoolofMedicine,TongjiUniversity,Shanghai,P.R.China
Correspondence
XinghuaGao,DepartmentofDermatology,
TheFirstHospitalofChinaMedicalUniversity,
155NanjingBeiStreet,Shenyang110001,P.R.
China.
Email:gaobarry@hotmail.com
XiuliWang,InstituteofPhotomedicine,
ShanghaiSkinDiseaseHospital,Schoolof
Medicine,TongjiUniversity,Shanghai200050,
China.
Email:wangxiuli_1400023@tongji.edu.cn
YaolongChen,Evidence-BasedMedicine
Center,SchoolofBasicMedicalSciences,
LanzhouUniversity,Lanzhou730000,China.
Email:chenyaolong@lzu.edu.cn
Abstract
Aim:Cutaneouswartscausedbyhumanpapillomavirusarebenignproliferativelesions
that occur at any ages in human lives. Updated, comprehensive and systematic
evidence-basedguidelinestoguideclinicalpracticeareurgentlyneeded.
Methods: We collaborated with multidisciplinary experts to formulate this guideline
based on evidences of already published literature, focusing on 13 clinical questions
elected by a panel of experts. We adopted Grading of Recommendations Assessment,
Development and Evaluation (GRADE) system to form classification of recommenda-
tions as well as the improved Delphi method to retain respective recommendations
withaconsensusdegreeofover80%.
Results: Our guideline covered aspects of the diagnosis and treatment of cutaneous
warts such as diagnostic gold standard, transmission routes, laboratory tests, treat-
mentprinciple,clinicalcurecriterion,definitions,andtreatmentsofcommonwarts,flat
warts, plantar warts, condyloma acuminatum, and epidermodysplasia verruciformis.
Recommendationsaboutspecialpopulationsuchaschildrenandpregnantwomenare
alsolisted.Intotal,49recommendationshavebeenobtained.
Conclusions: It is a comprehensive and systematic evidence-based guideline and we
hope this guideline could systematically and effectively guide the clinical practice of
cutaneouswartsandimprovetheoveralllevelsofmedicalservices.
KEYWORDS
commonwart,condylomaacuminatum,epidermodysplasiaverruciformis,flatwart,plantarwart
1 INTRODUCTION
Cutaneous warts are proliferative diseases caused by human papillo-
mavirus(HPV)infectionofkeratinocytes.Viralwartsarecommonwith
a prevalence rate of 7–12%.
1,2
HPV is a double-stranded DNA virus
withmorethan200typesbeingidentified.HPVscanbegrosslydivided
into high-risk types and low-risk types for their carcinogenic poten-
tials. The life cycle of HPV is closely associated with the proliferation
anddifferentiationofepithelium.Cutaneous HPVinfectioncommonly
manifests as warts including flat warts (verruca plana, on hands and
face),commonwarts(verrucavulgaris),plantawarts(verrucaplantaris,
on soles of feet), and condyloma acuminatum (anogenital warts, on
genitalia, anus or perianal area).
3
Most cutaneous HPV infection leads
to benign proliferative lesions, while rarely develops into cutaneous
cancers such as squamous cell carcinoma.
4
Appropriate measures for
prevention, diagnosis, treatment, and long-time management of cuta-
neous HPV infection are mandatory for dermatologists, pediatricians,
urinologists,gynecologists,andgeneralpractitioners.
ZHU ET AL. 3
Albeitthereareseveralmajorguidelinesorconsensusforcutaneous
warts,
5–13
a comprehensive and systematically produced guidance for
managementofcutaneousHPVinfectionincludingflatwarts,common
warts, plantar warts, and anogenital warts is missing. We summa-
rized the recent clinical progress and incorporated recommendations
based on evidence and expert consensus, dedicated to provide a gen-
eral guideline for the prevention, diagnosis, treatment, and long-term
managementofcutaneouswarts.
2 METHODS
2.1 Scope and registration of the guideline
The target population of this guideline are patients with cutaneous
warts including common warts, flat warts, plantar warts, condyloma
acuminatum (CA), and epidermodysplasia verruciformis (EV) , caused
by HPV infection. The content covers aspects such as screening, diag-
nosis, treatment, and prevention. Special populations such as children
and pregnant women are also taken into account. The guidelines are
applicable to medical institutions at all levels. Target implementing
agenciesaremedicalinstitutionsandhealthmanagementdepartments
that provide health care services to the target population. The main
usersoftheguidelinesaremedicalworkersinthedepartmentsofDer-
matologyandVenereology,ObstetricsandGynecology,andPreventive
Health Care. Proctologists and infectiologists are practitioners of this
guidelineaswell.
This guideline has been bilingually registered on the International
PracticeGuidelinesRegistryPlatform(http://www.guidelines-registry.
cn)withregistrationnumberIPGRP-2020CN078onJune9,2020.
2.2 Guideline working group
This guideline was launched and formulated by the Chinese Society of
Dermatology on June 1, 2020. Methodological support was provided
by the WHO Collaborating Centre for Guideline Implementation and
Knowledge Translation, GRADE China Center, and Evidence-Based
Medicine Center of Lanzhou University. The guideline working group
consisted of five groups: (I) a guideline steering committee, consisted
of 9 senior clinical experts and methodologists; (II) a consensus expert
group,consistedof32panelistsfromprofessionalfieldofdermatology;
(III)asecretarialgroup,whowasfullyresponsibleforthecoordination
and management of the guide, the collection and sorting of evidence
and data, the arrangement and recording of various tasks, the con-
tactandcommunicationofrelevantexperts,andallissuesnotcovered
by other working groups; (IV) an evidence evaluation group consisted
of 33 members, which was responsible for finding, collecting, evaluat-
ing and synthesizing relevant evidence, and applying GRADE grading
system,
14
making decision tables, and preparing for expert consensus;
and (V) an external review group consisted of 10 members, which was
mainlyresponsibleforreviewingthefirstdraftoftheguideline,putting
forward comments and suggestions, and its work was intended to be
completedbeforetheguidelinewasofficiallyreleased.
2.3 Collection and determination of clinical
questions
We used predesigned questionnaires to collect clinical questions. The
responders of the survey were clinical doctors in dermatology. Mean-
while, by referring to the relevant guidelines and systematic reviews
ofHPV-relatedskindiseases,wecollectedpotentialclinicalquestions.
Wedistributedoriginalquestionnairesto20dermatologistsinthefirst
round and modified questionnaires to 50 dermatologists in the sec-
ondroundofthesurveywithboth100%responseratios.Throughtwo
roundsofquestionnairesurveys,basedonthescoringresultsbyorder
of importance of the clinical issues, 13 clinical questions were finally
includedinthisguideline.
2.4 Evidence collection
This guideline collected evidence from systematic reviews, meta-
analysis, and network meta-analysis. The search terms included
“Warts” or “Condylomata Acuminata” or “Epidermodysplasia Verru-
ciformis” or “verruca vulgaris” or “verruca plantaris” in both Chinese
and English respectively from 2010 to 2020, in the order of title
or abstract. Search databases included Medline, Embase, Cochrane
Library, Epistemonikos, China Biology Medicine (CBM), Wanfang, and
China National Knowledge Infrastructure (CNKI). In cases where no
systematic reviews or meta-analysis were available, we systematically
searched the database, generating a systematic review according to
the originalresearchdataorincorporatingitintotheoriginalresearch
toconstructanevidencebody.Aflowchartofliteraturescreeningwas
shown in Figure 1. Among the 49 recommendations of the 13 clin-
ical questions, 43 recommendations were based on existing reviews
while 6 recommendations were based on newly generated reviews
or evidence bodies of original research. A total of 29 new reviews
were generated for this guideline. The information from the included
research papers was extracted according to the predesigned data
extractiontable.Thescreeningandinformationextractionofeachdoc-
ument was done independently by two groups of members. A third
partywasconsultediftherewerediscrepancies.
2.5 Evidence assessment and grading
We used the systematic review bias risk assessment tool, A MeaSure-
ment Tool to Assess systematic Reviews (AMSTAR) scale, to evaluate
the bias risk of the included systematic reviews, meta-analysis, and
network meta-analysis.
15
We also used the Cochrane risk of bias
(ROB) assessment tool (for randomized controlled trials), diagnos-
tic accuracy research quality assessment tool (Quality Assessment of
Diagnostic Accuracy Studies, QUADAS-2, for diagnostic tests), and
Newcastle-Ottawa Scale (NOS, for cohort studies and case-control
studies) for methodological quality evaluation of respective types of
original research.
16–18
The evaluation process was completed by two
members independently and if there was a disagreement, they would
discuss it together or consult a third party to resolve it. The GRADE
4 ZHU ET AL.
FIGURE1 Flowchartofliteraturescreening
Resultsofsearching:Medline(n=4687),Embase(n=3312),CochraneLibrary(n=1313),Epistemonikos(n=215),CBM(n=8334),Wanfang
(n=8768),andCNKI(n=3709)
method (Table 1) was used to evaluate the quality of the evidence, and
the quality of the evidence was divided into four levels: high, moder-
ate, low, and very low.
14,19,20
They had been presented in an evidence
summarytable.
2.6 Formulation of recommendations
After four to five rounds of revisions, 60 relevant recommenda-
tions and the supporting materials for recommendations were initially
determined. The secretary group made the GRADE decision-making
table and reached a consensus on recommendations through 2–3
rounds of surveys using the improved Delphi method.
21
Upon evalua-
tionby27expertpanelsandafterconsideringthepatient’spreferences
and values, and the costs, benefits, and harms of the interventions,
49 recommendations were finally formed with a consensus degree of
over 80% and the corresponding recommendation basis was included.
We referenced Reporting Items for Practice Guidelines in Healthcare
(RIGHT) to write this guideline. The expert panel approved a diagram
of management of patients with cutaneous warts (Figure 2). Plan for
updates on recommendations of this guideline will be initiated around
2025accordingtotherequirementbytheinternationalguide.
22,23
3 RESULTS
Question 1: What is the gold standard for the diagnosis of
skin/mucosalHPVinfection?
Recommendation:
1. Typical viral warts can be diagnosed by clinical visual examination.
PathologicalexaminationandHPVgenotypingarerecommendedin
ZHU ET AL. 5
FIGURE2 Adiagramofthediagnosisandtreatmentofcutaneouswarts
6 ZHU ET AL.
TABLE 1 Strengthofrecommendationsandlevelsofevidences
Item Definition
Strengthofrecommendations
Strong(1) Itclearlyshowsthattheinterventiondoesmore
harmthangoodordoesmoregoodthan
harm.
Weak(2) Thebenefitsandharmsareuncertainorthe
qualityoftheevidenceshowscomparable
benefitsandharms.
Levelsofevidences
High(A) Weareveryconfidentthattheobservedvalue
isclosetothetruevalue.
Moderate(B) Wehavemoderateconfidenceintheobserved
value:theobservedvalueislikelytobeclose
tothetruevalue,butitmightbesubstantially
different.
Low(C) Wehavelimitedconfidenceintheobserved
value:theobservedvaluemaybe
substantiallydifferentfromthetruevalue.
Verylow(D) Wehavelittleconfidenceintheobservedvalue:
theobservedvaluecanbesubstantially
differentfromthetruevalue.
casesofatypicallesions(suspectedprecancerouslesionsorcancer)
andincaseswherethediagnosisisuncertain.(1C)
2. A 3?5% acetowhite test is suggested in the diagnosis of HPV
infectioninthegenitalmucosa.(2C)
Summaryoftheevidence:
Viralwartsaregenerallydiagnosedbyvisualrecognition.However,the
identification of atypical skin lesions should be evaluated by patholog-
ical examination and HPV genotype testing. For early genital mucosa
viralwarts,theapplicationof3–5%aceticacidcanhelpinthedetection
ofsubclinicalskinlesions.
5–8,24
A case series study
25
which examined 51 suspected men with CA
bypathologicalexaminationandcolposcopyshowedthattheaccuracy
of histopathological examination in the diagnosis of CA was higher
than that of colposcopy (95.60% vs. 88.20%). A case series described
that infection by different HPV types contributed to varied histologi-
cal patterns in association with clinical types.
26
A diagnostic accuracy
test
27
showed that the HPV-positive rate of the histopathologically
diagnosed CA was 95.00%. The sensitivity and specificity for the pre-
diction of HPV 6/11 by pathological examination were 43.60–46.60%
and64.70–71.70%,respectively.Acase-seriesstudy
28
showedthatall
116 hyperplastic warts were positive, and 57.70% of flat warts in the
moist area were positive, while those in the dry area were practically
negativewhen5%aceticacidwasapplied.Twoclinicalstudiesrevealed
that in patients with CA, the accuracy of 5% acetic acid white test was
55.30% while in patients with subclinical HPV infection, the sensitiv-
ity and specificity of the acetowhite test were 92.30% and 58.20%,
respectively.
29,30
Question2:WhatarethetransmissionroutesofHPVinfectionofskin
ormucosa?
Recommendation:
1. Sexual and mother-to-fetus vertical transmissions are the main
transmissionsrouteofHPVtocauseCA.(1C)
2. Virus transmission by skin contact, hand spreading, and contact
with underwear or inanimate objects are responsible for common
warts,planewarts,andplantarwarts.(2D)
3. High-temperature evaporation treatment, i.e., CO
2
lasers, pro-
duces smog from the destructed HPV containing lesions that could
transmitHPVs.(2B)
Summaryoftheevidence:
HPV has more than 200 types and causes multiple diseases includ-
ingcutaneousandanogenitalwarts,cervicalcancer,andanalcancerin
men and women. Understanding the transmission routes of HPV can
leadtobetterpreventionforit.
31
A cross-sectional study
32
found that 64.29% (169/263) couples,
of whom at least one person was infected and 42.01% of partners
harboredthesameHPVtype(95%CI[36,47]).Thehighdegreeofcon-
cordance suggests a high probability of sexual transmission. A cohort
study
33
showed that the mother-to-fetus vertical transmission rate
of HPV was 27.66%. There was no significant difference in infants’
HPV infection rate between vaginal delivery and cesarean delivery
(25.71%vs.28.81%).
A systematic review in 2020
34
showed that mucosa of the upper
respiratory tract (nose, mouth, pharynx) is a more common site with
warts in CO
2
laser users compared to the normal population, as well
as to those who don’t use LEEP (Loop Electrosurgical Excision Proce-
dure) or CO
2
lasers (0.60–3.40% vs. 5.10–12.90%) (OR = 5.75, 95%
CI [1.55, 21.38], p < 0.001). Therefore, local exhaust ventilation such
as smoke evacuators was recommended when performing laser or
electrosurgicaltreatmentsforpatientswithwarts.
35
Question3:Whatarethelaboratorytestsforcutaneouswarts?
Recommendation:
1. AcetowhitetestisrecommendedforthediagnosisofsubclinicalCA.
(1C)
2. In cases where identification of HPV types is required, noninva-
sive sampling by skin swabbing is recommended for HPV testing,
resection or clamping of the warty tissue may be necessary in the
case.(1C)
3. Dermoscopymayaidinthediagnosisofviralwarts.(2D)
4. For vulvar CA harboring high-risk HPVs, cervical HPV test is
suggested.(2B)
Summaryoftheevidence:
Albeit controversial for the recommendation of acetowhite test for
the diagnosis of CA, it is still clinically used as an economical and
convenient inspection method. Several studies
28–30,36
have shown
ZHU ET AL. 7
the efficacy of acetowhite test to detect CA, including those with
inconspicuousclinicalappearance.
A case-series study
37
reported that PCR detection from samples
of the resected wart and the wart swab yielded HPV-positive rates
of 92.00% and 88.00%, respectively (p > 0.05). Another case-series
study
38
showedthat25swabbedsamplespossessidenticalHPVtypes
to the biopsy counterpart with 96.00% sensitivity, a result validat-
ing that wart swabs can be reliably used for HPV typing sampling. A
self-controlledexperiment
39
showedthatbothtwosamplingmethods,
swabbingthesurfaceofthelesionandtakingashavebiopsy,reacheda
high agreement for detection of HPV DNA in CA (87.80% agreement)
and penile intraepithelial neoplasia (100% agreement). However, the
agreement in these two methods was low to moderate for detecting
mostindividualHPVtypes,thusacombinationofbiopsywithswabbing
mayprovideadditionalinformationforHPVgenotyping.
A case-series study
40
including 132 patients with a total of 220
suspected CA lesions showed that the positive rate of dermatoscopic
diagnosis was higher than that of a physician’s visual diagnosis. A
study
41
reported that dermoscopy provided a higher positive rate and
superiority in observing tiny warts than visual observation (p < 0.01).
This method possessed the advantages of high sensitivity, quick and
accuratediagnosis,andnoninvasiveness.However,ithaslimitationsfor
itsinaccessibilityindeepurethralorificeandskinwrinkles.
Twocohortstudies
42,43
showedahigherriskofcervicalcancer,CIN
(CervicalIntraepithelialNeoplasia),andcervicalcancerinsituinfemale
patients with CA. In 2012, a study
44
reported that the rate of cervical
high-riskHPVinfectionwassignificantlyhigherinwomenwithCAthan
inthegeneralpopulation.
Question4:Whatisthetreatmentprincipleforcutaneouswarts?
Recommendation:
1. Remove the wart as early as possible and eliminate the subclinical
infectionaroundthewartasmuchaspossibletoreduceorprevent
recurrence.(1C)
2. Superimposed infections and inflammation should be controlled
beforetreatingCAlesions.(1C)
3. Decision on the treatment of genital warts in pregnant women
should be based on the size of warts and the impact on the fetus.
(2D)
4. Precaution to avoid contact with flowing particles should be taken
duringtheevaporatingsurgicaltreatmentofwarts.(2C)
Summaryoftheevidence:
Theprimarygoaloftreatmentistoremovewartsandimprovethepre-
senting symptoms. According to the published guidelines,
5,13,45
most
patients’ warts disappear after treatment while the recurrences are
frequent. Genital warts may heal, remain unchanged, or increase in
number and size in untreated patients. Treatment may weaken the
infectivity of HPV, but may not necessarily eradicate HPV. A guideline
of the Chinese Society of Dermatology in 2021
9
suggested that vis-
ible genital warts should be treated. For subclinical infections, laser,
cryotherapy, topical imiquimod, photodynamic therapy (extending to
1cmaroundwarts)shouldbeappropriatelyimplementedtoreducethe
rateofrecurrence.
So far, there is no effective anti-HPV drug to clear HPV infection.
Surgery and physical therapy can remove visible warts. An expert
consensus in 2017 in China
46
indicated that cytological examination
should be performed before the treatment of vaginal and cervical CA.
And if necessary, colposcopic biopsy should be performed to exclude
theprecancerousandcancerouslesionsofthevaginaandcervix.
A guideline from the Chinese Society of Dermatology in 2015
47
stated that patients with CA may be complicated with other sexually
transmitted diseases. In such cases, the inflammation or other super-
imposed infections should be controlled first, to avoid spreading skin
lesionsaftertreatment.
The numbers and sizes of genital warts may increase with the
progress of the pregnancy. The safety profile of topical podophyllo-
toxin and imiquimod during pregnancy has not been established and
thus prohibited. Cryotherapy, surgery, and trichloracetic acid for gen-
ital warts are applicable to pregnant women. Pregnant women should
betreatedappropriatelytoensurethesafetyofthefetus.China’s2014
Guidelines for Diagnosis and Treatment of CA
10
and an expert con-
sensus in 2017
11
both recommended that pregnant women infected
with CA should be treated as early as possible. Genital warts rarely
affect delivery, and their spontaneous resolution was common during
the puerperium. In 2019, a guideline from the Infection and Sexual
Health Clinical Research Center of the Institute of Global Health,
University of London, UK
6
stated that for small, slow-growing warts
which did not affect pregnancy and delivery, the treatment of geni-
tal warts could be postponed until after childbirth. If there are warts
that might block the birth canal, pelvic outlet obstruction, or vaginal
delivery,ajointconsultationwithspecialistsinobstetricsandgynecol-
ogy, neonatology, and venerology isnecessary.
9
The spouse or partner
who had sexual contact with the patient should be examined and they
need to be treated if with lesions. Avoidance of intercourse is recom-
mended during treatment. Choices of treatment methods should be
based on considerations of the size, location, age, and other factors
of the skin lesions. Toxic drugs or methods prone to scarring were not
recommended.
During the surgical treatment of HPV-related lesions, especially
when using smoke-producing surgical treatment methods (laser or
electrosurgery),itwasrecommendedtocomplywithlasersafetyregu-
lations and hygiene guidelines to protect patients and physicians from
contactinginfectiousparticles.
5
Question5:Whatistheclinicalcriterionforthecureofwarts?
Recommendation:
1. The clinical criteria for cure of warts are complete clearance of
lesionsat4weeksandnorecurrenceforatleast6months.(1B)
Summaryoftheevidence:
According to the current literature, there has been no uniform def-
inition of clinical criteria for the cure of HPV infection. A system-
atic review published in 2017
48
referred that short-term complete
8 ZHU ET AL.
clearance referred to complete clearance of lesions at 4 weeks
(± 4 weeks) at the end of treatment (EOT), intermediate-term com-
plete clearance referred to complete clearance of lesions at 16 weeks
(± 8 weeks) at the EOT, and long-term clearance referred to com-
plete clearance of lesions at 12 months (± 6 months) at the EOT.
Intermediate-term recurrence referred to recurrence of lesions at
16 weeks (± 8 weeks) at EOT in patients who had a complete clear-
ance at 4 weeks (±4 weeks) at EOT. Long-term recurrence referred to
recurrenceoflesionsat12months(±6months)atEOTinpatientswho
had a complete clearance at 4 weeks (±4 weeks) at EOT. Another sys-
tematic review in 2017
49
reported that, in HIV-positive patients with
genital warts, short-term complete clearance referred to complete
clearance of lesions at 4 weeks (after EOT), intermediate-term com-
plete clearance referred to complete clearance of lesions at 24 weeks
(± 16 weeks) at EOT, and long-term clearance referred to complete
clearance of lesions at 12 months (± 2 months) at EOT. Intermediate-
term and long-term recurrence respectively referred to recurrence of
lesionsat24weeks(±16weeks)and12months(±2months)afterEOT
in patients who had a complete clearance at EOT. For other warts, an
RCT
50
in2020includingrecalcitrantcommonwartsandastudyproto-
col for a single-center randomized controlled trial
51
in 2020 including
commonwarts,plantarwarts,flatwarts,andfiliformwartsbothstated
thattherecurrenceratewasassessedat6monthsafterenrolment.
Question 6: How to define multiple, recurrent, and refractory cuta-
neouswarts?
Recommendation:
1. Multiple warts are defined as a patient with two or more than two
warts.(2D)
2. Recurrent warts are defined as warts that appear near the orig-
inal site of warts, which have been completely cleared. The
intermediate-term recurrence of warts is 4 months (± 2 months)
by the end of treatment, and the long-term recurrence is 12
months(±6months)bytheendoftreatment.(2B)
3. Refractory warts are defined as warts that last for at least 2 years
withpoorresponsetomorethantwotraditionaltreatmentoptions.
(2B)
Summaryoftheevidence:
There has been no uniform definition of multiple/generalized, recur-
rent, and refractory warts thus far. Clinicians mostly classify them
accordingtotheirunderstanding.
In a cohort study,
52
albeit the authors didn’t explicitly define mul-
tiple warts, the presumptive were those patients with more than one
wartylesion.Ina2016casereport,
53
thegeneralizedwartwasdefined
as diffuse cutaneous warts over 20 in number that is distributed in
morethanoneareaofthebody.
In 1989, a nonrandomized controlled study
54
indicated that recur-
rentwarts werethose thatappearednear the originalsiteswithwarts
thathadbeenclearedcompletely.Twosystematicreviewsin2017
48,49
showed that intermediate-term recurrence of genital warts was 4
months (± 2 months) after the EOT, and long-term recurrence was
12 months (± 6 months) after the EOT (the skin lesions were com-
pletely cleared at the EOT). Two Chinese expert consensuses in 2015
and2017
11,12
statedthattherecurrenceofCAmostlyoccurredin3–6
monthsaftertreatment,andmostoftenoccurredinthefirst3months.
If there were no recurrence 6 months after treatment, the chance of
recurrencewaslow.
In a nonrandomized controlled study,
55
refractory warts were
defined as those who failed to respond to two traditional treatments
or warts that lasted for over 2 years. A cohort study
56
showed warts
were more persistent and refractory to treatment in organ transplant
recipients. In an RCT in 2018,
57
the included refractory warts were
those that lasted for more than 2 years and failed response to more
than two treatment methods (laser surgery, electrosurgery, curettage,
liquid nitrogen freezing therapy, and topical salicylic acid treatment).
In an observational study,
58
refractory warts were those resistant to
conventional treatments and there was no improvement after trying
differentmethods.
Question 7: What are the recommended clinical treatment methods
forcommonwarts?
Recommendation:
1. Localinjectionswithbleomycin,5-Fluorouracil(5-FU),andcidofovir
are suggested for refractory and recurrent common warts. Local
adverse reactions of intralesional injection therapy include pain,
burning, itching, erythema during the procedures, and postinflam-
matorypigmentation.(2B)
2. Cryotherapy is recommended for common warts. However,
patients receiving cryotherapy need to tolerate treatment-related
pain and, may experience other side effects, such as posttreatment
scarringandhyper/hypopigmentation.(1B)
3. Thermotherapy is suggested for patients with common warts,
especially multiple warts, who cannot tolerate local injection and
cryotherapy. The recommended treatment temperature ison aver-
age at 44
?
C over the lesion, and the treatment time lasts for
30 min. Repeated treatments are required. Common adverse reac-
tions include burning sensation, occasional heat-induced blisters,
andpostinflammatorypigmentation.(2C)
Summaryoftheevidence:
Common warts are mostly caused by HPV type 2. Choices for their
treatmentshouldbebasedonspecificconditions.
59
A case-series study
60
showed that after an average of 2.61 treat-
mentcycleswithintralesionalinjectionofbleomycin(therapeuticdose
at 3 U/ml and treatment interval at 3–4 weeks), all of the 250 periun-
gualandsubungualwartsin80patientsofwhom26(32.50%)patients
were either with no response to or recurrence after previous treat-
ments were cleared and 65 (81.25%) patients experienced moderate
pain during the treatment sessions, 155 (62.00%) treatment sites had
transit dyspigmentation, and 3 (1.20%) treatment sites experienced
reversiblenecrosis.AnRCT
61
including42patientswithmultiplewarts
(commonwartsandplantarwarts)comparedthebleomycinmicronee-
dle patch treatment with cryotherapy and their effective rates were
ZHU ET AL. 9
respectively 55.71% and 55.85%, but patients were more tolerable to
microneedlepatchforlesserpainduringthetreatment.
A prospective study
62
reported that the cure rate of common
warts with the injection of 5-FU, lidocaine, and epinephrine mixture
(50 mg/ml 5-FU plus with lidocaine and epinephrine mixture at a ratio
of 4:1) was higher than that of saline control (64.70% vs. 35.30%,
p<0.05). There was no significant difference in the incidence of sys-
temic adverse reactions and treatment-related side effects between
the two groups. A case-series study
63
included 280 patients with mul-
tiple and recalcitrant cutaneous warts (common and mosaic warts)
and without any success, they had received at least two other treat-
ments for their lesions. The result showed that lesional injection with
15 mg/ml cidofovir once a month, on average of 3.2 sessions, cleared
relapsedandrefractorywartsin276of280patients.
An observational study on 90 patients
64
showed that the overall
success rate was 64.44% in treating warts on hands and feet with
cryotherapy.Theeffectivenessofliquidnitrogencryotherapyforcom-
mon warts depended on factors including the duration of warts, the
numberofwarts,andtherepeatedtimesoftreatments.Wartstreated
by cryotherapy once a week had faster recovery than once every 2–
3 weeks while the overall cure rate depended on the total repeated
times of treatments rather than the time interval. A meta-analysis on
one nonrandomized controlled trial
65
and two RCTs
61,66
showed that
the effectiveness of liquid nitrogen cryotherapy in the treatment of
common warts was significantly higher than noncryotherapy meth-
ods (I
2
= 90%, RR = 2.01, 95% CI [1.02, 3.97], p = 0.04), as topical
trichloroacetic acid and intralesional injection of Candida antigen. A
cohort study
67
concluded that shorter freezing time (10 s) and inter-
val (2 weeks) of cryotherapy was more effective than longer freezing
time (20 s) and intervals (4 weeks), for treating common viral warts on
handandfoot.
Acase-seriesstudy
68
performedlocalhyperthermia(onceadayfor
30 min, for 5 consecutive days, temperature applied was determined
bytoleranceofthepatients,onaverage,temperaturesappliedtohand
warts was 43.5
?
C, while that for foot warts was 45.3
?
C) on patients
with common warts who had not received local or systemic treatment
in the past 3 months. For patients with multiple lesions, only one tar-
getlesionwasselectedforlocalhyperthermia.Afterthetreatment,the
patients were followed up monthly. After 3 months of follow-up, the
totalcureratewas53.85%,andthecurerateforthefoot(65.22%)was
higher than the hand cure rate (37.50%). Treatment response was not
affectedbynumber,gender,andage.Allpatientshadtolerableburning
sensationsduringtreatment.
Question 8: What are the recommended clinical treatment meth-
ods for flat warts, including generalized, recurrent, and refractory
conditions?
Recommendation:
1. 10% 5-aminolevulinicacid photodynamic therapy (5-ALA-PDT) is
recommendedforthetreatmentofflatwarts.(1B)
2. Lasers and photodynamic therapy could be used to treat multiple
flatwarts.LasersincludeCO
2
laser,PDL(pulseddyelaser),andYAG
laser. Photodynamic therapy (PDT) includes 5-aminolevulinic acid
(ALA)or5-methylaminolevulinicacid(MAL)photodynamictherapy.
(2C)
3. Injection of bleomycin or Candida albicans antigen is recommended
totreatflatwarts.(1B)
Summaryoftheevidence:
Flat warts mostly appear in facial areas of children or young adults. It
is commonly caused HPV type 3, 10, 28, and 41. There is no specific
antiviraltreatmentthusfar.
69
A2017systematicreview
70
showedthatcomparedwithCO
2
laser,
ALA-PDT had a lower recurrence rate, fewer adverse reactions, and a
betterprognosisfortreatingflatwarts(p<0.05).Comparedwithtopi-
calimiquimodcream,ALA-PDThadahighercurativeeffect,alsowitha
higherincidenceofadversereactions(p<0.05).Comparedwithliquid
nitrogen freezing, ALA-PDT had a better curative effect with a lower
recurrencerateandadversereactionrate(p<0.05).AnRCT
71
showed
that10%ALAwasmoreeffectivethan5%and20%ALAregardingthe
completeremissionrateafter12weeks(33.30%vs.14.30%vs.26.30%,
p < 0.05). The rate of hyperpigmentation after 12 weeks was in the
descending order of 33.30%, 15.60%, and 12.90% by use of 20%, 5%,
and10%ALA,respectively(p<0.05).
A systematic review in 2016
72
showed that CO
2
,PDL,andNd:
YAG are currently the most studied lasers for the treatment of non-
genital verrucae with a response rate of 50.00?100.00% for CO
2
laser,47.10?100.00%forPDL,and46.34?100.00%forNd:YAGlaser.
PDL was comparable in effectiveness to traditional therapies such as
cryotherapy and topical cantharidin. Combination of PDL with drugs
such as bleomycin and salicylic acid had higher success rates, PDL had
fewer adverse reactions compared with Nd: YAG or CO
2
laser in the
treatment of nongenital warts. In 2016, a case series study
73
showed
that long-pulse 532 nm LP Nd: YAG laser achieved 92.00% complete
removalofallwartsafteronecourseoftreatment.Lesionswithlonger
duration (over 2 years vs. fewer than 6 months) had lower clearance
rates(84.00%vs.98.00%,respectively).
The working panel of the guideline conducted a meta-analysis of
fourRCTs
74–77
showingthattheeffectiverateofintralesionalinjection
of Candida albicans antigen to treat flat warts was significantly higher
than those of other options such as oral isotretinoin, local injection of
5-FU and other microbial antigens (I
2
=77%, RR=0.80, 95% CI [0.24,
2.72], p<0.0001). While in one of the RCTs
77
, it showed that the cure
rateofbleomycininjectionwassignificantlyhigherthanthatofCandida
albicans antigen as well as 5-FU. Side effects included injection pain,
local erythema and edema for all, and a few cases of flu-like symptoms
inCandidaalbicansantigenrecipients.
Question 9: What are the recommended clinical treatment meth-
ods for plantar warts, including multiple, recurrent, and refractory
conditions?
Recommendation:
1. Local hyperthermia is suggested for patients with plantar warts.
(2B)
10 ZHU ET AL.
2. Cryotherapyissuggestedforpatientswithplantarwarts.(2B)
3. Long-pulsed 1064 nm Nd: YAG laser combined with topical mois-
turizing cream treatment or optimized CO
2
laser treatment is
recommended for plantar warts. Local injections of recombinant
human IL-2 in combination with CO
2
laser are recommended for
recalcitrantplantarwarts.(1B)
4. Local injections of bleomycin are recommended for the treatment
ofplantarwarts.(1B)
Summaryoftheevidence:
TheplantarwartisacommonviralskindiseaseinfectedmostlybyHPV
types 1, 2, 4, 27, and 57, which is challenging because of the frequent
recurrencesaftertreatment.
78
An RCT
79
applied local hyperthermia at 44
?
C for 30 min in a ses-
sion, in a protocol of application on day 1, 2, 3, 17, and 18, on a single
target lesion. The results showed that 53.57% of patients with plantar
warts and 11.54% of patients in the sham treatment group achieved
complete cure (χ
2
=10.718, p =0.001), 3 months after completion of
the treatment protocol. No recurrent case was reported in the study.
Additional benefits were the reduction to 80.00% of loading-bearing
pain after the treatment and the removal of lesions at distant sites in
successful cases. A cohort study
68
treated plantar warts at local tem-
peratures best tolerated by the patients which ranged from 43.5
?
Cto
47.5
?
C (average at 45.3
?
C). By the end of 3 months after the therapy,
15 of 23 (65.22%) cases were cured. The treatment response was not
correlatedwithwartnumber,sex,age,ortemperaturesapplied.
An RCT
80
showed that cryotherapy had a significantly higher com-
plete cure rate than the silver tape closure treatment (58.00% vs.
20.00% out of 50 patients in each group) in the scheduled 8 weeks of
study.Therewerenosignificantdifferencesinresponseineithergroup
in association with the duration of the disease. The selection of differ-
ent cryotherapy devices may affect efficacy. An RCT
81
concluded that
nitrous oxide freezing had a higher cure rate in the treatment of com-
monwartsandplantarwartsthantheothertwocommerciallyavailable
devices (dimethyl ether and propane freezing device and dimethyl
ether without or with metal nib device, 82.00%, 47.37%, and 52.78%,
respectively,p=0.001).Thepatientstreatedwerethosewithadisease
durationofnomorethan6months.
Acohortstudyon240patients
82
showedthattheuseofmoisturiz-
ingcreambeforelong-pulse1064nanometerNd:YAGlasertreatment
achieved a clearance rate of 97.08%, by an average treatment session
of1.3(range1–3),75.80%clearedbyonesessionoftreatment.
An RCT
83
on the treatment of recalcitrant warts showed that local
injection of recombinant human IL-2 combined with CO
2
laser treat-
ment had a higher effective rate 2 months after treatment and a
lower recurrence rate than CO
2
laser treatment, cryotherapy, topi-
cal fluorouracil ointment and local injection of recombinant human
IL-2 (94.00%, 78.00%, 56.00%, 32.00%, and 44.00%, respectively). An
RCT
84
showed that the effective rate of optimized CO
2
laser (out-
putting grid spot) treatment and traditional CO
2
laser treatment for
plantar warts were 95.71% and 81.54%, respectively (χ
2
= 6.858, p
<0.05),after6monthsoffollow-up.
An RCT
85
showed that the cure rate of intralesional bleomycin
treatment were 63.02%, superior to that of 48.82% by cryotherapy (p
<0.05).
Question10:Whataretherecommendedclinicaltreatmentmethods
forCA,includingmultiple,recurrent,andrefractoryconditions?
Recommendation:
1. Combination of 5% imiquimod with traditional physical therapy
(lasers,cryotherapy)isrecommendedtotreatCA.(1A)
2. Topical treatment is recommended for genital warts with single
lesion size less than 5 mm or confluent lesion size less than 10 mm,
oratotalnumberofwartslessthan15.(1B)
3. ALA-PDT alone is recommended to treat genital warts <5mmin
size.(1B)
4. ALA-PDT combined with traditional physical therapy is recom-
mendedtoreducetherateofrecurrence.(1B)
5. Surgery is recommended for CA with pedicle or large volumes or
recalcitrant.(1A)
6. Destructive physical therapy followed by immunomodulators
(imiquimod or recombinant human interferonα?2b) or photody-
namictherapyisrecommended.(1B)
7. Topical 5% imiquimodor photodynamic therapy is considered for
CAwithunderliningHIVinfection.(2C)
Summaryoftheevidence:
The current principle of treatment of CA is to remove warts as
early as possible, improve symptoms, eliminate subclinical infections
and latent infections around warts, and reduce recurrence.
11
The
treatment methods of CA are divided into self-application and office-
based treatment. Self-application is mainly topical drugs, including
podophyllotoxin and imiquimod. Office-based treatment includes tra-
ditional physical therapy (CO
2
laser, microwave, high-frequency elec-
tric therapy, and liquid nitrogen freezing), photodynamic therapy, and
trichloroacetic acid. Appropriate treatment methods should be based
ontheoverallconsiderationoftheconditionofwarts,patientselection,
treatmentcostandfeasibility,sideeffects,anddoctor’sexperience.
Traditionalphysicaltherapyhasaquickclinicaleffectonhyperplas-
tic lesions, but the effect of maintaining complete clearance is poor
and the risk of recurrence is high.
86
However, topical treatment with
5% imiquimod is helpful to achieve continuous clearance and reduce
recurrence.ThecombinationofthesetwocaneffectivelyclearCAand
reduce CA recurrence.
87
A systematic review in 2020
87
showed that
CO
2
laser combined with 5% imiquimod had a higher clearance rate
than CO
2
laser alone (12 weeks after treatment: RR = 1.53, 95% CI
[1.38, 1.71], I
2
= 46%; 24 weeks after treatment: RR = 1.90, 95% CI
[1.42, 2.53], I
2
= 73%). The clearance rate of wart by electrocautery
combined with 5% imiquimod was higher than that by electrocautery
alone (RR = 1.62, 95% CI [1.33, 1.97], I
2
= 0%). Microwave combined
with 5% imiquimod was better than microwave alone (RR = 2.20,
95% CI [1.26, 3.83], I
2
= 73%). 5% podophyllotoxin and 5% or 3.75%
imiquimod cream are the most commonly used topical drugs. 5%
podophyllotoxin tincture was topically applied twice a day for 3
ZHU ET AL. 11
consecutivedays,followedbywithdrawalfor4days,7daysasacourse
of treatment, with a maximum of 4 courses of treatment. In a net-
work systematic review in 2020,
88
six treatment options, including
podophyllotoxin, imiquimod, tea polyphenol ointment, 5-FU, cidofovir,
and interferon cream were evaluated, setting the outcome index as
completeremovalofwarts.0.5%podophyllotoxinointmentorsolution
was the most effective in clearing the wart and the least recurrent.
Meanwhile, in a network meta-analysis
89
in 2020, 0.5% podophyllo-
toxin(OR=1.94,95%CI[1.02,3.71])wassignificantlymoreefficacious
than5%imiquimodforlesionclearance
A 2019 systematic review
90
showed that topical 0.5% podophyllo-
toxinsolutionwassuperiorto5%imiquimodcreaminthetreatmentof
patients with genital warts (OR=0.07, 95% CI [0.001, 0.36]). In 2019,
asystematicreview
91
showedthatcomparedwiththetraditionaltinc-
ture form of podophyllotoxin, podophyllotoxin nanogel could increase
the cure rate (OR = 1.76, 95% CI [1.65,1.87], p < 0.00001), reduce
therecurrencerate(OR=?0.32, 95% CI [?0.36,0.28], p < 0.00001),
shorten the course of disease (95% CI [?9.41,9.14], p < 0.00001),
reduce the adverse reactions such as edema (OR = 0.26, 95% CI
[0.29, 0.22], p < 0.00001), erosion (OR = 0.25, 95% CI [0.34, 0.17], p
< 0.00001), pain (OR = 0.35, 95% CI [?0.42,0.28], p < 0.00001), and
effectively control HPV subclinical infection (OR=0.46, 95% CI [0.31,
0.67],p<0.00001).
Meta-analysis of two RCTs
92,93
showed that the effective rate of
topicalimiquimodinthetreatmentofCAwassignificantlyhigherthan
those of other intervention groups (I
2
= 74.00%, RR = 1.60, 95% CI
[1.35, 1.89], p = 0.009). In 2015, an RCT
94
studied the clinical effects
of 2.5% or 3.75% imiquimod cream in the treatment of male CA for 12
consecutive weeks. The results showed that the clearance rate (CR) of
3.75%imiquimodcreamwashigherthanthatof2.5%imiquimodcream
(CR:18.60%vs.14.30%,p<0.05)
Photodynamic therapy, as with ALA-PDT, was applied once a week.
ALA-PDT therapy had certain advantages in reducing the recurrence
rate due to its direct inhibition effect on virus replication.
95
A system-
aticreviewin2013
96
showedthattherecurrencerateofALA-PDTwas
lowerthanCO
2
laserandcryotherapywithliquidnitrogenforurethral
anogenitalwarts(AGW)(RR=0.25,95%CI[0.18,0.36],p<0.05).The
recurrencerateofcervicalcondylomainALA-PDTwaslowerthanthat
of CO
2
laser (RR = 0.28, 95% CI [0.12, 0.65], p < 0.05). A multicenter
RCT study
97
showed that after being followed up for 12 weeks, the
recurrencerateofAGWwassignificantlylowerintheALA-PDTgroup
(10.77% vs. 33.33%, respectively, p < 0.05) compared with CO
2
laser
group, and again in patients with urethral AGW the recurrence rate
waslowerinALA-PDTgroupthanCO
2
lasergroup(10.53%vs.36.36%,
respectively, p < 0.05). A multicenter retrospective study
98
treated
AGW patients using ALA-PDT (once a week for 3 weeks) and assessed
the efficacy after each treatment. The results showed increased clear-
ancerateswithmoretreatmentsessions.Clearanceratesafter1,2,and
3weeksoftreatmentwere68.12%,81.16%,and95.27%,respectively,
p<0.001).Smallwarts(<5mm)hadahigherclearanceratethanwarts
of >5 mm (97.74% vs. 88.73%, p < 0.001). The recurrence rates var-
ied at different locations of warts and perianal warts had the highest
recurrence rates while those at labia had the lowest ones (30.23% vs.
11.54%, respectively). The adverse reactions included redness, pain,
erosion, ulcer, and pigmentation, and the incidence rates were 7.72%,
8.10%, 2.26%, 0.94%, and 0.19%, respectively. There was no reported
case of urethral malformation and sexual dysfunction. One clinical
observation
99
showed that after treatment for 1, 2, and 3 weeks, the
clearance rate of warts with ALA-PDT was higher than cryotherapy
with liquid nitrogen at rates of 73.23% vs. 53.19% (at week 1), 85.83%
vs.63.83%(atweek2),and93.70%vs.70.21%(atweek3),allp<0.01.
After3monthsoffollow-up,therecurrencerateofALA-PDTwaslower
thancryotherapywithliquidnitrogen(10.17%vs.45.45%,p<0.01).
A systematic review in 2014
100
revealed that ALA-PDT combined
with liquid nitrogen cryotherapy had a higher cure rate (OR = 4.82,
95% CI [3.33, 7.00], p < 0.01) and lower recurrence rate (OR = 0.32,
95%CI[0.21,0.50], p<0.01)compared with the liquid nitrogen freez-
ing alone in patients with AGW. Two systematic review
96,101
showed
that the local application of ALA-PDT combined with CO
2
laser had
a lower recurrence rate than using CO
2
laser alone after a 12 weeks
follow-up (RR = 0.20, 95% CI [0.09, 0.44], p < 0.05) in 13 RCTs and
a 24 weeks follow-up (RR = 0.23, 95% CI [0.11, 0.51], p < 0.05) in 7
RCTs.What’smore,thecombinedtreatmenthadalowerincidenceand
severity of adverse reactions, and patients were well tolerated.
101
In
a single-arm clinical trial,
102
98 patients with warts were treated with
laser ablation and then applied to three sessions of ALA-PDT treat-
ments. The results showed that 92 cases (93.88%) were completely
cured. After 3 months of follow-up, 18 (18.37%) cases had relapsed
lesions near the treatment sites. A meta-analysis of six RCTs
103–108
showed that the cure rate of ALA-PDT combined with conventional
physical treatments was higher than those of conventional physical
treatment alone (I
2
=89%, RR=1.33, 95% CI [1.09, 1.63], p=0.005).
ALA-PDT combined with conventional physical treatments had lower
recurrence rates than those of conventional physical treatment alone,
in 1 month (I
2
= 0%, RR = 0.20, 95% CI [0.13, 0.32], p<0.00001), 2
months (I
2
= 0%, RR = 0.16, 95% CI [0.11, 0.22], p<0.00001), and 3
months(I
2
=0%,RR=0.25,95%CI[0.19,0.34],p<0.00001).
101,104,105
Surgical resection is suitable for the treatment of pedicled or mas-
sive warts, recalcitrant warts, and warts with repeated attacks in a
short time. In a network meta-analysis on anogenital warts in 2020,
88
surgical resection achieved the best effect in removing the lesions
(RR = 10.54, 95% CI [4.53, 24.52]), as compared with other methods
like5-FU, ablation,ablationand imiquimod,cidofovir,9%citricacid,or
CO
2
laser. A systematic review
90
published in 2019, in which the out-
comeindexwasnorecurrenceofCA,showedthatsurgeryhadthebest
effect in reducing recurrence risk after thorough removal of CA com-
pared with cryotherapy, 5% imiquimod cream, 0.5% podophyllotoxin
solution,and20–25%podophyllate.
PerianalCAisdifficulttoremoveandtherecurrencerateishigh.The
meta-analysis results of two RCTs
109,110
showed the effective rate of
the combined treatment group (recombinant human interferon α?2b
injection combined with liquid nitrogen cryotherapy or CO
2
)wassig-
nificantlyhigherthanthatofliquidnitrogencryotherapyorCO
2
group
alone (I
2
= 85%, RR = 1.47, 95% CI [1.04, 2.06], p = 0.03) and the
recurrence rate was lower (I
2
= 89%, RR = 1.33, 95% CI [1.09, 1.63],
p=0.005).
12 ZHU ET AL.
AGW concurrent with HIV infection is more prone to malignant
transformation and more difficult to treat. Traditional therapy such as
CO
2
laser,microwave,high-frequencyelectrictherapy,andliquidnitro-
gen freezing treatment often fails and the recurrence rate is high. An
RCT
111
compared the efficacy of ALA-PDT with topical 5% imiquimod
cream for AGW with HIV infections, along with standard anti-HIV
therapy during the trial. ALA-PDT had a higher cure rate (84.00% vs.
52.00%,p<0.05),lowerrecurrencerate(16.00%vs.48.00%,p<0.05),
andreducedincidenceofadversereactionsrelatedtoskinandmucosal
injury (p < 0.05), but the treatment-related pain was more severe (p
<0.05). A case-series study
112
observed the cure rate 20 weeks after
treatment with microwave therapy combined with imiquimod cream
topical application (topical application after 1 week of microwave
treatment)inAGWpatientsconcurrentwithHIVinfection.Theresults
showed that in patients with CD4
+
T lymphocyte number ≥350 ×
10
6
/L, the cure rate was 89.55%, and CD4
+
T lymphocyte below that
number was 72.09%. A cohort study
113
focusing on different methods
forthetreatmentofpatientswithanalCAcomplicatedwithHIVinfec-
tion showed that 1 year after treatment, the cumulative recurrence
rates were 6.15% (4/65, 95% CI [2, 15], error data in original study)
by electroresection, 11.11% (3/27, 95% CI [4, 28]) by infrared coagu-
lation,and11.11%(1/9,95%CI[2,44])byimiquimod.After10yearsof
follow-up, cumulative recurrence rates were 46.15% (95% CI [35, 58])
by electroresection, 55.56% (95% CI [37, 72]) by infrared coagulation,
55.56%(95%CI[27,81])byimiquimod,and50.00%(1case,95%CI[1,
91])bycryotherapy.
Question11:Whataretherecommendedclinicaltreatmentmethods
forepidermodysplasiaverruciformis(EV)?
Recommendation:
1. 1.5-FU and imiquimod could be used topically for early stage EV
withlesionsfewinnumbersandsmallinsize.(2D)
2. Tretinoic acids could be taken orally and topically when the lesions
spreadalloverthebody.(2D)
3. Refractory lesions could be treated with electrocautery and
cryotherapy.(2D)
4. Surgery removal is suggested for patients with severe keratinized
lesions,precancerouslesions,andsquamouscellcarcinoma.(2D)
5. All patients need sun protection education and guidance on sun
protection.(1D)
Summaryoftheevidence:
Verrucous epidermal dysplasia is a rare chronic disease characterized
bygeneticsusceptibilitytoHPV,manifestingashighlypleomorphicand
disseminated lesions. Solar keratosis frequently occurs after 30 years
of age, and half of them evolve into squamous cell carcinoma. There is
currently no specific treatment, and different treatment methods are
chosen according to the manifestations of the skin lesions. Above all,
sunprotectionisnecessarytopreventmalignanttransformation.
In a case report, two 23-year-old female patients with multiple flat
EV lesions on the face were topically applied 5-FU combined with
imiquimod once a day and three days per week, and the area and
numbersofwartswerereduced,whilerecurrentafter1year.
114
A40-
year-old female EV patient with generalized lesion was treated with
oral Isotretinoin combined with Tazarotene gel, and the lesions sub-
sided significantly (no long-term follow-up).
115
A 16-year-old female
patient with generalized skin lesions on the face and neck was treated
with systemic ganciclovir, BCG polysaccharide nucleic acid, and the
skin lesions were treated with electrocautery and cryotherapy. A pro-
portion of the lesions were removed while there were remaining ones
onseveralsitesofthebody.
116
A50-year-oldmalepatientwithsevere
hyperkeratotic plaques on the face and limbs was diagnosed with
clinical manifestation and HPV 51 DNA positivity. Surgical resection
removed the plaques over his hands. There was no recurrence in a
1-year follow-up.
117
A case report described a 56-year-old female
patient with brown flat verrucous papules all over the body for 40
years.ShedevelopedmultiplelesionshistologicallyconfirmedBowen’s
disease,whichwassurgicallyremoved.
118
Question 12: How should children (under the age of 18) with cuta-
neouswartsbetreated?
Recommendation:
1. Intralesional Candida antigen immunotherapy is suggested for chil-
drenwithrecalcitrantandmultiplewarts.(2C)
2. ChildrenwithCAcouldbetreatedwith5-ALA-PDTcombinedwith
high-frequencyelectrocautery.(2C)
3. ChildrenwithrecalcitrantCAaroundtheanuscouldbetreatedwith
localthermotherapy.(2D)
4. Children with common warts can be treated with 5% imiquimod
cream.(1B)
5. Monochloroacetic acid (MCA) is recommended for children with
plantarwarts.(1B)
Summaryoftheevidence:
Cutaneous warts are estimated to occur in up to 10% of children and
young adults, with the greatest incidence between 12 and 16 years of
age. Warts occur more frequently in girls than in boys. Common warts
represent 70% of skin warts and occur primarily in children, whereas
plantarandflatwartsoccuramongslightlyolderpopulations.
119
Thefirst-linetreatmentofskinwartsincludestopicaluseofsalicylic
acidand cryotherapy, butcryotherapy maycause painand blistersand
require repeated treatment, which limits its use in children. Intrale-
sional immunotherapy is a promising method for the treatment of
multiple or refractory warts in children, which can remove distant
wartswithminimalsideeffects,withcureratesof23.30–95.20%.
120
An RCT
121
compared the efficacy of MMR (measles, mumps, and
rubella)vaccine(n=15),Candidaantigenintralesioninjection(n=15),
and saline control (n = 10) in 40 cases of children with anogenital
warts. Of 15 patients in the treatment groups, 73.33% (MMR) and
80.00% (Candida antigen) achieved complete clearance, respectively,
comparedwithsalinecontrol(1outof10patients,10.00%).Therewas
no statistically significant difference between the MMR vaccine and
theCandidaantigengroup.Adversereactionsweremild,andtherewas
norecurrenceafter6monthsoffollow-up.
ZHU ET AL. 13
AnRCT
122
comparedtheefficacyofhigh-frequencyelectrocautery
combined with 5-ALA-PDT and high-frequency electrocautery alone
for treating CA in children. The result showed that the effective rates
were not statistically different between the two groups (90.91% vs.
88.89%, p > 0.05), while the combination method had a significantly
lower recurrence rate than the high-frequency electrocautery group
alone(13.64%vs.44.44%,p<0.05).
Acasereportshowed
123
thatlocalthermotherapyat44
?
Csuccess-
fully cured a 2.5-year-old child with multiple CA around the anus, who
failed several previous treatments. The treatment started once a day
for 3 consecutive days, each treatment for 30 min, plus two sessions
of treatment 2 weeks later. Then the treatment was conducted once a
week for 5 weeks when the volume of the body of the wart started to
decrease.Twomoreadditionaltreatmentsweregiven,andin4months,
allthelesionsdisappearedwithoutrecurrencethemonthstofollow.
An RCT
124
compared the effect of MCA and cryotherapy on com-
mon warts. The cure rates were 40/92(43.48%, 95% CI [34, 54]) for
MCA and 50/93 (53.76%, 95% CI [44, 64]) for cryotherapy (risk dif-
ference (RD): 10%, 95% CI [?25, 4.0], p = 0.16), at week 13th after
initiation of treatment. MCA could effectively replace cryotherapy,
which could avoid pain and reduce blisters during treatment but could
not avoid pain after treatment. In regard to plantar wart, cure rates
were 49/106 (46.23%, 95% CI [37, 56]) for MCA and 45/115(39.13%,
95% CI [31, 48]) for cryotherapy combined with self-daily applied
salicylic acid (RD 7.10%, 95%CI [?5.9, 20], p = 0.29).MCA had sim-
ilar efficacy but it could reduce the pain, blister, and burden of
treatment.
Question 13: How should pregnant women with cutaneous warts be
treated?
Recommendation:
1. Podophyllotoxin and imiquimod are not recommended for CA
duringpregnancy,buttrichloroaceticacidcanbeused.(1A)
2. CA during pregnancy could be treated by liquid nitrogen cryother-
apyorsurgery.(2C)
3. Cesarean section is recommended when large warts may block the
birthcanalorcausemassivebleeding.(1C)
4. CA during pregnancy could be treated with local thermotherapy.
(2C)
Summaryoftheevidence:
Compared with the nonpregnancy patient, CA during pregnancy has
rapid growth, a high recurrence rate and is easy to ulcerate and bleed,
possibly due to changes in hormone levels in pregnant women, a
genital environment conducive to HPV reproduction, limited clinical
medication,anddecreasedimmunefunction.
125
ChineseguidelinesforthediagnosisandtreatmentofCAin2014
10
and an expert consensus in 2017
11
recommended that pregnant
women with CA should be treated as early as possible. Podophyllo-
toxin and imiquimod were not recommended.
13
Podophyllotoxin and
imiquimod were prohibited during pregnancy because their fetal ter-
atogenic effect was grade C for pregnancy medication classified by
FDA.
126
However,acohortstudy
127
showedthattherewasnostatisti-
cal relationship between podophyllotoxin exposure and nonexposure
groups in birth defects, spontaneous abortion, preterm delivery, and
stillbirth. The study concluded that the use of podophyllotoxin during
pregnancy(thedoseofpodophyllotoxinwasnotspecifiedinthiscohort
study,andexposurewasbasedontheprescriptionofthedrug)didnot
increase the risk of adverse fetal outcomes. However, sufficient evi-
dence from RCT trials on podophyllotoxin use in pregnant women are
needed. Similarly, although medical reports
128–131
indicated that the
use of imiquimod during pregnancy did not show adverse fetal out-
comes, there was still a lack of large-scale human trials, so it was not
recommended as a first-line drug for pregnant women.
132
Acompar-
ative study
133
showed that by combination therapy of CO
2
laser and
85% trichloroacetic acid in treating 32 pregnant women with genital
condylomas, 96.88% patients (31/32) achieved successful eradication
with only maternal postoperative complications being pyelonephritis
(1/32, 3.13%). The differences in obstetric complications such as pre-
matureruptureofmembranes,prematureonsetoflabor,andcesarean
delivery between the case group (n = 32) and control group (n = 64)
werenotsignificant.
A retrospective study
134
showed that liquid nitrogen cryotherapy
combined with proanthocyanidins dressings (2–3 times a day for 1
week, 20 min for each dressing) cleared all visible CA in 46 pregnant
women,withtherecurrenceratesof2.17%in1monthand10.87%in3
months.
The existence of warts rarely changed the mode of production,
and cesarean section could be performed only when warts block the
birth canal. The only serious complication of transvaginal delivery was
respiratory papillomatosis in infants and young children, which was
relativelyrare(4/million).
135
Areport
136
applied hyperthermia at 44
?
C for 30 min a day, 3 days
in a row, and 2 sessions of treatment after a week. CA in two cases
of pregnant women had been cleared 4 and 5 weeks after the last
treatment,respectively.Noapparentsideeffectswerereportedexcept
slight burning pain. There was no recurrence during the 6-month
follow-up.
4 DISCUSSION
4.1 Summary
This guideline covers several main types of cutaneous and mucosal
HPV infectious diseases including common warts, flat warts, plantar
warts, genital warts, and EV. Treatment for the special population
such as children and pregnant women was also involved. Some clini-
calquestionshavebeenredefinedandexplained.Theguidelineaimsto
systematically and effectively guide the clinical management of warts,
achieve better clinical outcomes for patients with HPV infectious skin
diseases, improve the overall levels of medical services for skin warts,
andreducemedicalcostsandeconomicburden.
14 ZHU ET AL.
4.2 Dissemination, implementation, and
evaluation
Once the guideline is released, the guideline development team will
mainly disseminate and promote the guideline in the following ways:
(I) introduce it in relevant academic conferences; (II) organize guide-
linepromotionspecialsessionsinaplannedwaytoensurethatmedical
practitioners fully understand and correctly apply the guidelines; (III)
conduct research in the next 2 years to understand the dissemina-
tion of the guidelines and evaluate the impact of the implementation
of the guidelines on clinical decision-making and patient outcomes.
However, as a rule, the choice of a treatment method is decided on
consensus between the practitioner and the patient, as well as practi-
tioners’ evaluation of the specificity of a patient. The strength of the
recommendationandlevelsofevidencemayoffercertainhelp.
4.3 Strengths and limitations
The guidelines for HPV infectious skin diseases are formulated by
evidence-based methods. The guideline working groups have strictly
followed the standards and procedures of evidence-based guidelines
formulation required by international organizations, selected spe-
cific problems in the clinical practice of HPV infectious diseases,
and conducted a systematic search. The evidence body is formed
after a systematic search and assessment, and based on patient pref-
erences and values, as well as cost-benefit factors, combined with
the practical experience of multidisciplinary clinical experts. A high-
quality evidence-based guideline has been formulated with evidence-
based medicine support, patient-based, clinical problem-oriented
features.
Meanwhile, limitations exist such as low-level evidence support of
certain recommendations. Especially for EV, the included literature is
mainly case reports so recommendations are formulated restrictively
with less representativeness. For responders of the survey, specialists
at the Department of Obstetrics and Gynecology were not concluded
while they were also clinical practitioners of this guideline. Due to the
cross-disciplines nature, treatments of HPV infectious skin diseases
have not included HPV vaccines. Only literature in English and Chi-
nese were covered in the guideline and exclusion of literature in other
languagesmaycausebias.
5 CONCLUSIONS
This guideline covers aspects of the diagnosis and treatment of cuta-
neous warts such as diagnostic gold standard, transmission routes,
laboratory tests, treatment principle, clinical cure criterion, defini-
tions, and treatments of common warts, flat warts, plantar warts,
CA, and EV. Recommendations about special populations such as
children and pregnant women are listed. It is a comprehensive and
systematic evidence-based guideline and we hope this guideline could
systematically and effectively guide the clinical practice of cutaneous
warts and improve the overall levels of medical services. We will
updatethisguidelinearound2025accordingtotherequirementofthe
internationalguide.
ACKNOWLEDGMENTS
We thank Doc. Yan Wu, Doc. Yiping Zhao and Doc. Dongxin Shi
(Department of Dermatology, The First Hospital of China Medical
University) for team organization of evidence-based medicine course
study and submission material preparation. We appreciated instruc-
tionsofguidelinedevelopmentbyShouyuanWu,QiangqiangGuo,Hui
Lan,andJuanjuanZhang(SchoolofPublicHealth,LanzhouUniversity).
CONFLICT OF INTEREST
All members of this guideline working group have signed a conflict
of interest declaration form when determining to participate in the
guidelinework.Allauthorshaveconfirmedthattheyhavenopotential
conflictsofinterest.
ORCID
YaolongChen https://orcid.org/0000-0002-7338-4418
Xing-HuaGao https://orcid.org/0000-0001-8809-8564
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https://doi.org/10.1111/jebm.12494
APPENDIX
WORKINGTEAM
Steeringcommittee:XinghuaGao(TheFirstHospitalofChinaMedical
University), Yaolong Chen (Evidence-Based Medicine Center, School
of Basic Medical Sciences, Lanzhou University), Hongduo Chen (The
First Hospital of China Medical University), Wanqing Liao (Shanghai
Changzheng Hospital), Qianjin Lu (The Second Xiangya Hospital of
CentralSouthUniversity),JieZheng(RuijinHospital),JianzhongZhang
(Peking University People’s Hospital), Xuejun Zhang (Anhui Medical
University),andJingheLang(PekingUnionMedicalCollegeHospital).
Consensus expert group: Hao Cheng (Sir Run Run Shaw Hospital),
Lingyu Fu (The First Hospital of China Medical University), Xinghua
Gao(TheFirstHospitalofChinaMedicalUniversity),HengGu(Chinese
AcademyofMedicalSciencesandPekingUnionMedicalCollege),LiHe
(First Affiliated Hospital of Kunming Medical University), Hongzhong
Jin (Peking Union Medical College Hospital), Quanzhong Liu (Tianjin
MedicalUniversityGeneralHospital),LinMa(BeijingChildren’sHospi-
tal), Ruiqun Qi (The First Hospital of China Medical University), Youlin
Qiao (Peking Union Medical College), Yuping Ran (West China Hos-
pital), Zhu Shen (Sichuan Academy of Medical Sciences and Sichuan
ProvincialPeople’sHospital),PingSong(Guang’anmenHospital),Gang
Wang (Xijing Hospital), Xiuli Wang (Shanghai Skin Disease Hospital),
Yan Wu (The First Hospital of China Medical University), Shengxi-
ang Xiao (The Second Affiliated Hospital, School of Medicine, Xi’an
Jiaotong University), Jinhua Xu (Huashan Hospital), Huilan Yang (Gen-
eral Hospital of Southern Theatre Command of PLA), Rongya Yang
(General Hospital of Beijing Military Command of PLA), Furen Zhang
(Shandong Provincial Hospital for Skin Diseases & Shandong Provin-
cial Institute of Dermatology and Venereology), Kang Zeng (Nanfang
Hospital),PingTu(PekingUniversityFirstHospital),YuzhenLi(Second
AffiliatedHospitalofHarbinMedicalUniversity),XiangChen(Xiangya
Hospital),AijunChen(TheFirstAffiliatedHospitalofChongqingMed-
icalUniversity),JunlingZhang(TianjinAcademyofTraditionalChinese
Medicine Affiliated Hospital), Shanshan Li (The First Hospital of Jilin
University), Zhirong Yao (Xinhua Hospital), Weihua Pan (Second Affili-
atedHospitalofNavalMedicalUniversity),SongmeiGeng(TheSecond
Affiliated Hospital of Xi’an Jiaotong University), and Juan Tao (Union
Hospital, Tongji Medical College, Huazhong University of Science and
Technology).
Secretarial group: Peiyao Zhu, Yang Yang, Xu Han, Yiping Zhao,
Dongxin Shi, Yunqiu Gao (The First Hospital of China Medical Uni-
versity), Jianjian Wang, Qiangqiang Guo, Shouyuan Wu, Hui Lan, and
Juanjuan Zhang (Evidence-Based Medicine Center, School of Basic
MedicalSciences,LanzhouUniversity).
Evidence evaluation group: Xueli Niu, Yao Lu, Tianxin Cong, Yanjun
Li, Congcong He, Xinyun Fan, Ze Wu, Wenzhen Hu, Kangle Fu, Yining
Wang, Qu Qi, Donghong Sun, Xiaoxue Yang, Jiali Yin, Yifei Liu, Yiping
Zhao, Gaiyang Xu, Mingsui Tang, Chang Fu, Jingyi Li, Weibao Lu, Qixin
Han, Shuzhen Ren, Dongxin Shi, Sitong Liu, Meihui Shi, Weitong Yan,
Peihong Sun, Jing Zeng, Chengfei Zhuang, Jingyu Wang, Peiyao Zhu,
andXuHan(TheFirstHospitalofChinaMedicalUniversity).
External review group: Xing-Hua Gao, Rui-Qun Qi, Yang Yang and
Peiyao Zhu (The First Hospital of China Medical University), Yaolong
Chen, Jianjian Wang, Shouyuan Wu, Qiangqiang Guo, Hui Lan, and
Juanjuan Zhang (Evidence-Based Medicine Center, School of Basic
MedicalSciences,LanzhouUniversity).
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