Syphilis in the Americas: a protocol for a systematic review of syphilis prevalence and incidence in four high-risk groups, 1980–2016
Kitayama et al. Systematic Reviews
Syphilis in the Americas: a protocol for a systematic review of syphilis prevalence and incidence in four high-risk groups, 1980-2016
Ken Kitayama 0 3
Eddy R. Segura 1 2
Jordan E. Lake 7
Amaya G. Perez-Brumer 6
Catherine E. Oldenburg 5
Bethany A. Myers 4
Paria Pourjavaheri 2
Chinomnso N. Okorie 9
Robinson L. Cabello 8
Jesse L. Clark 2
0 Department of Medicine, Division of Infectious Diseases, UCLA South American Program in HIV Prevention Research (SAPHIR), David Geffen School of Medicine at UCLA , 10833 Le Conte Ave, CHS 37-121, Los Angeles, CA 90095 , USA
1 Escuela de Medicina, Universidad Peruana de Ciencias Aplicadas , Lima , Peru
2 Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine at UCLA , Los Angeles, CA , USA
3 Department of Medicine, Division of Infectious Diseases, UCLA South American Program in HIV Prevention Research (SAPHIR), David Geffen School of Medicine at UCLA , 10833 Le Conte Ave, CHS 37-121, Los Angeles, CA 90095 , USA
4 Louise M. Darling Biomedical Library at UCLA , Los Angeles, CA , USA
5 San Francisco School of Medicine, Francis I. Proctor Foundation for Research in Ophthalmology, Department of Ophthalmology, and Department of Epidemiology and Biostatistics, University of California , San Francisco, CA , USA
6 Columbia University Mailman School of Public Health , New York, NY , USA
7 Department of Medicine, Division of Infectious Diseases, McGovern Medical School at the University of Texas Health Science Center at Houston , Houston, TX , USA
8 Asociación Civil Vía Libre , Lima , Peru
9 Department of Biology, San Francisco State University , San Francisco, CA , USA
Background: Syphilis infection has recently resurfaced as a significant public health problem. Although there has been a tremendous amount of research on the epidemiology of syphilis, there has been limited work done to synthesize the extensive body of research and systematically estimate patterns of disease within high-risk groups in the Americas. The purpose of this systematic review and meta-analysis is to (1) summarize recent patterns of syphilis infection in North and South America among four high-risk groups (MSM, transgender women, sex workers, and incarcerated individuals) from 1980 to 2016, (2) identify and differentiate regional geographic epidemiologic characteristics, and (3) compare the epidemics of the economically developed countries of North America from the developing countries and public health systems of Latin America and the Caribbean. Methods/design: Primary studies reporting syphilis prevalence and/or incidence in at least one of the four high-risk groups will be identified from Medline/PubMed, Embase, Lilacs, SciELO, The Cochrane Library, Web of Science, Scopus, ProQuest, CINAHL, Clase, and Periódica, as well as “gray” literature sources (conference abstracts, country reports, etc.). Studies published from 1980 through 2016 will be included. Data will be extracted from studies meeting inclusion and exclusion criteria and a random effects meta-analysis of prevalence and incidence estimates will be conducted. Heterogeneity, risk of bias, and publication bias will be assessed. Pooled prevalence and incidence estimates will be calculated for comparisons based on geographic region, risk factors, and time period. Discussion: Our systematic review and meta-analysis aims to contribute to an improved understanding of global epidemiologic patterns of syphilis infection in most-at-risk populations. Through systematic classification of the existing literature, and comparison of disease patterns across regional, temporal and socio-behavioral differences, we hope to improve public health surveillance and improve efforts to control the spread of disease across the Americas. Systematic review registration: PROSPERO CRD42016047306.
Syphilis; Prevalence; Incidence; Men who have sex with men; Transgender women; Sex workers; Incarcerated individuals; Systematic review; Meta-analysis; Protocol
Global burden of syphilis
Syphilis is a critical public health problem worldwide.
Although the incidence of syphilis infection in the USA
and Western Europe decreased after the introduction of
penicillin in the early 1940s [
], a resurgence in syphilis
transmission that began in the 1980s has now gained
substantial strength. Beginning in the 2000s, a growing
number of isolated syphilis outbreaks were reported in
North America, Europe, and Australia, primarily within
sexual networks of men who have sex with men (MSM),
and often associated with HIV co-infection or
]. Following the successful
introduction of biomedical approaches to HIV prevention, these
sporadic outbreaks have more recently grown in
frequency and size to mark a new era of syphilis
transmission. In contrast to the relatively more effective control
of disease in the USA and Western Europe, endemic
rates of syphilis transmission have been stubbornly
persistent in the resource-limited public health systems of
Latin America, Asia, and Africa [
]. Despite the
proliferation of epidemiologic reports on syphilis prevalence
and incidence, we are not aware of any comprehensive
synthesis of the available literature that can (i) summarize
recent patterns of syphilis infection and transmission, (ii)
identify and differentiate regional epidemiologic
characteristics, and (iii) compare the developing syphilis epidemics
of the economically developed countries of North America
with the endemic patterns of disease observed in Latin
America and the Caribbean.
The global epidemiology of syphilis infection varies
significantly by geography. A 2015 systematic review based
on data from the 2012 Global AIDS Response Progress
Reporting (GARPR) system estimated there were
approximately 17,721,000 cases of syphilis among men
and women 15–49 years of age worldwide [
country-specific estimates were not provided, the study
authors noted differences in syphilis prevalence according
to World Bank economic classifications, with prevalence
estimates lowest for high-income countries, at 0.2%
overall, and ranging from 0.3% to 1.3% in middle- to
Syphilis in high-risk groups
Risks for syphilis infection among MSM, transgender
women (TW), and sex workers (SW) of all genders are
disproportionately high across geographic locations, but
there have been few comprehensive global estimates of
disease prevalence and incidence in these key
]. GARPR did not begin collecting
behavioral data on syphilis in adults until 2012, with a formal
roll out of reporting for all regions initiated in 2013 [
As a result, pre-2012 GARPR estimates of syphilis
infection among MSM and TW were based on extrapolations
from reported data on cases of maternal and congenital
syphilis, with the assumption that heterosexual
transmission would result in a 1:1 male to female ratio of syphilis
]. In Latin America and the Caribbean, a
2013 systematic review of syphilis data in MSM, TW,
SW, and clients of SW included 35 studies on syphilis
prevalence in MSM, with a prevalence > 4% in three
quarters of the estimates included and > 7.5% in half
]. Five of those studies included TW, with syphilis
prevalence ranging from 6.5% in El Salvador to 43.3% in
Brazil. The same review identified 49 studies with female
SWs, half of them with a syphilis prevalence > 5%, but
noted large variations between the populations sampled.
In addition to MSM and SW, the United Nations has
also identified incarcerated individuals as a group at
high-risk for syphilis and other sexually transmitted
infections (STIs), with frequencies of disease two to 10
times higher (and potentially 50 times greater) among
prisoners than in the general population worldwide [
A 2012 systematic review of incarcerated populations
calculated pooled syphilis prevalence estimates of 2.5%
in men and 6.1% in women, finding that the incidence of
infection among women was 2.7 times greater than in
men (95% CI 1.5–4.8) [
In order to improve the public health response to the
emerging syphilis epidemics in the Americas, detailed
knowledge of epidemiologic patterns of disease in
mostat-risk populations is needed. A systematic review and
analysis of the broad range of existing data will help to
establish a framework for understanding the parameters
of syphilis transmission across the region and help to
define target points for STI control efforts. Comparing
patterns of disease in Latin America and the Caribbean
with those seen in Canada and the USA will help to
illuminate how behavioral, biological, social, and structural
characteristics of syphilis transmission differ across
geographic, socioeconomic, and epidemiologic contexts, as
well as how they may have changed over time.
Ultimately, the improved understanding of the global
epidemiology of syphilis infection to be provided by our analysis
will help to define and allocate future public health
surveillance and control efforts. We plan to conduct a
systematic review and meta-analysis of data on syphilis
infection prevalence and incidence in four high-risk
groups (MSM, TW, SW, and incarcerated persons) within
Latin America, the Caribbean, and North America (USA
and Canada), in published studies and reports from 1980
Methods and design
This systematic review and meta-analysis protocol was
developed according to the Preferred Reporting Items
for Systematic Reviews and Meta-Analysis Protocols
(PRISMA-P) 2015 statement [
]. The protocol has been
published in the PROSPERO International Prospective
Register of systematic reviews (http://www.crd.york.ac.uk/
PROSPERO), registration number CRD42016047306.
Criteria for considering studies for review
1. Studies reporting primary, quantitative data on the
prevalence and/or incidence (cumulative incidence
or incidence rates) of active and/or lifetime syphilis
infection among at least one high-risk group (MSM,
TW, SW, and/or incarcerated persons) who reside
in countries and territories within the Americas and
who are from any race, ethnicity, socioeconomic
status, and/or level of education will be included.
For the purpose of this study, “The Americas” refers
to all countries designated under this geographical
group by the World Health Organization [
2. Included studies must describe appropriate criteria
used for diagnosis of active syphilis infection,
including serologic assays (e.g., rapid plasma reagin
(RPR), venereal disease research laboratory test
(VDRL), treponema pallidum particle agglutination
assay (TPPA), microhemagglutination assay (MHA-TP),
treponema pallidum enzyme-linked immunosorbent
assay (TP-EIA)), dark-field microscopy, and/or clinical
diagnosis based on history and physical exam findings.
3. Articles published in English, Spanish, Portuguese,
or French or with sufficient information for data
abstraction from an English abstract will be considered
We plan to collect data from articles and reports
published from 1 January 1980 through 31 December
2016. This date range selection is based on the fact that
in the USA, the highest recorded incidence of syphilis
since 1950 was observed in the year 1982 [
rates initially declining, but peaking again in 1990–1991,
thought to be because of a new surveillance case
definition for congenital syphilis [
]. Syphilis infection rates
then declined thereafter in association with increased
public health efforts to prevent HIV/AIDS and reduce
AIDSrelated mortality [
] and subsequently followed by a
resurgence of syphilis infection among MSM beginning in
the late 1990s and early 2000s [
1. Studies or reports that include mixed prevalence or
incidence data on syphilis infection as a composite
outcome with another STI and that do not
specifically report data on syphilis infection alone.
2. Studies or reports that extrapolate syphilis
prevalence or incidence data in high-risk groups
from general population statistics or congenital
syphilis data without direct measurement of the
social or behavioral factors used for classification.
3. Publications that report the same data in multiple
sources. If the same data is published in more than
one article, report, or abstract, the publication
reporting the most complete version of the data
will be used.
4. Narrative reviews, opinion pieces, letters, or other
publications that do not report primary data and/or
do not provide sufficient description of the study
methodology. Case series and case reports, as well as
mathematical modeling studies based on previously
reported data, will be excluded.
Search strategy for identification of relevant studies
The search strategy will be composed of two stages:
Stage 1: bibliographic database review
Ten electronic databases (including MEDLINE/PubMed,
Embase, Lilacs, SciELO, The Cochrane Library, Web of
Science, Scopus, ProQuest, CINAHL, Clase, and Periódica)
will be searched for articles published from January 1, 1980,
through December 31, 2016. A list of search terms
including “syphilis” or “Treponema pallidum” or “T. pallidum” or
“pallidum” in addition to terms for each of the four
highrisk groups of interest (MSM, TW, SW, and incarcerated
persons) was generated based on strategies from previously
published systematic reviews [
]. When possible,
controlled search terms (MeSH) will be combined with text
words. Otherwise, text words alone will be searched.
Reference lists of all included articles will be hand-searched to
identify additional studies and reports to include in our
analysis. For the full search strategy, see Additional file 1.
Stage 2: gray literature search
The Google Scholar search engine will be used to identify
“gray” literature (documents not published by commercial
publishers such as agency reports, government articles, and
academic theses) as previously described [
]. As the Google
Scholar search string is limited to 256 characters, a separate
search will be conducted for each of the four high-risk
groups, and the first 100 results for each of the searches will
be reviewed. Conference abstract archives or abstract books
will be searched for the following conferences: International
AIDS Conference, IAS Conference on HIV Pathogenesis,
Treatment and Prevention, Conference on Retroviruses and
Opportunistic Infections, IDWeek, and the International
Society for Sexually Transmitted Diseases Research. GARPR
system country reports, Centers for Disease Control and the
Public Health Agency of Canada statistics reports will also
be searched. Additionally, we will also poll recognized
experts in the field for additional citations or references not
identified using other methods.
Selecting studies for inclusion Studies that are found
utilizing the search strategies described above will be
compiled with their titles and abstracts into EndNote X7
(Thomson Reuters). As EndNote’s ability to accurately
remove duplicates has been found to be sub-optimal
], de-duplication will be performed using Mendeley
(Elsevier), which has been found to report fewer false
negatives and similar false positives in its de-duplication
results when compared to EndNote .
The primary author (KK) will apply the inclusion and
exclusion criteria to the de-duplicated list of articles, and
a separate reviewer (CO) will conduct an independent
screen of a random selection of 10% of all titles.
Comparison of the two authors’ screen results will be used to
calculate an inter-rater reliability score using Cohen’s
kappa coefficient [
]. The initial screens will result in
the creation of three categories: (1) Included, (2)
Excluded, or (3) Pending (when the article initially appears
to incompletely fit exclusion and/or inclusion criteria).
Titles classified as “Pending” will be examined by a
separate author with specialized expertise in the clinical and
epidemiologic classification of syphilis infection (JLC)
who will make the final determination of inclusion or
exclusion. In the full text screen, two reviewers (KK and
PP) will independently review the full article texts and
apply the inclusion and exclusion criteria listed above.
Any disagreements in categorizations within the full-text
screen will be resolved by group adjudication. A PRISMA
flow diagram outlining the procedures described above
will be prepared for transparency and to provide a visual
overview of how the final list of articles for data collection
Data collection Two reviewers (KK and PP) will
independently extract and manage the data for the final set
of included studies. A customizable electronic data
extraction form will be created using form.io (Dallas, TX)
that will be piloted and edited through an iterative
process using feedback from the entire panel of authors.
Any disagreements in data extraction between KK and
PP will be discussed and resolved, with the senior author
(JLC) acting as arbiter in instances where disagreements
cannot be resolved.
Data items The following data will be extracted:
1. Publication details: year, title, first author, language,
type of publication.
2. Study design: study type (cross-sectional, cohort,
clinical trial, etc.), sampling method (probability
or non-probability sampling and specific type of
sampling), recruitment site type (for non-probability
3. Study participants: city and country where study
took place, study time frame, participants’ sex and/
or gender, mean/median age and age range, primary
(e.g., MSM, TW, SW, incarcerated) and secondary
(e.g., mobile app/Internet use to find sex partners,
IV drug use) risk-group characteristic(s), number
of persons surveyed or studied for per group, HIV
serostatus (when available), race, and ethnicity.
Diagnostic criteria used to define syphilis infection,
syphilis re-infection, and neurosyphilis (if applicable).
Number and frequency of syphilis cases, including stage
at diagnosis, number and frequency of cases of syphilis
re-infection, and number and frequency of cases of
neurosyphilis. Reported titers of diagnostic tests (e.g.,
RPR, VDRL) will be recorded when available.
4. Outcome measures: reported estimates (or, if
sufficient raw data is available, estimates calculated
by our study team) of the point prevalence, period
prevalence, cumulative incidence, and/or incidence
rate of active and/or lifetime syphilis in selected
areas. Lifetime syphilis will be defined within
extracted data as (1) any positive non-treponemal
test with confirmatory treponemal test or (2)
selfreported lifetime history of syphilis infection. Active
syphilis will be defined as (1) a four-fold increase in
non-treponemal test compared to previous results
with positive confirmatory treponemal test or (2) a
positive non-treponemal test (e.g., RPR or VDRL)
titer of 1:8 or greater with a positive confirmatory
treponema-specific test (e.g., TPPA or MHA-TP).
Critical appraisal of included studies
Quality assessment of the studies will be performed
using a nine-item critical appraisal tool to assess the validity
and rate the methodological quality of studies reporting
prevalence data [
]. Compared to other instruments
specifically designed to assess a narrower scope of study
designs, this tool is designed to qualify studies of varied
designs reporting prevalence data [
]. KK and PP will each
independently apply this quality assessment tool to all
included studies. Any disagreements will be resolved by
consensus discussion and in consultation with the senior
author (JLC). The final assessment of risk of bias for all
included publications will be presented in a table. Publication
bias will be assessed using funnel plots of the study
outcome against the sample size, as described by Egger et al.
]. Furthermore, GRADE guidelines for assessing
publication bias will be referred to for additional guidance [
We will prepare a narrative synthesis and quantitative
meta-analysis of the prevalence and incidence of active
and lifetime syphilis in the four previously defined
highrisk groups in the Americas, with all relevant data
presented in tables. Estimates from studies found to be
of sufficient quality will be pooled to estimate overall
prevalence and incidence of active syphilis infection and
overall prevalence and incidence of any syphilis
infection, presenting meta-analysis results with forest plots.
Data will be displayed graphically as needed to assist in
the interpretation of data not amenable to the
application of statistical tests for trends.
Because we anticipate elevated levels of heterogeneity
in our included studies in terms of study design,
outcome measurement, and follow-up (for incidence rates),
we will conduct meta-analyses using a DerSimonian and
Laird random effects model and will account for
heterogeneity of studies by including a parameter for inter-study
variation. We will combine the percentages of patients
with lifetime and/or active syphilis (as defined above) in
each individual study to calculate pooled prevalence
estimates along with 95% confidence intervals (CI), using a
double arcsine transformation of prevalence.
We will conduct separate subgroup analyses of the
data extracted from all studies: (1) between-group analyses
of the four high-risk groups (MSM, TW, SW, prisoners)
by calculating estimates separately for each group and
investigating differences, (2) differences between geographic
sub-regions (Latin America and the Caribbean versus
North America), (3) changes in syphilis prevalence and
incidence over time, as stratified by 10-year intervals, (4)
estimates within specific subgroups according to HIV
serostatus; and (5) differences in estimates depending on a
diagnostic method (self-reported history, serologic testing
strategy). Heterogeneity will be assessed with I2 and τ2
statistics. Sources of heterogeneity between included studies
will be examined by stratifying data according to study
characteristics. All analyses will be conducted using Stata
14.0 (StataCorp, College Station, TX).
This systematic review and meta-analysis of syphilis in
the Americas will compile and analyze the available
epidemiologic literature, summarizing the burden of syphilis in
high-risk groups in Latin America, the Caribbean, the
USA, and Canada. We will collect prevalence and
incidence data on active and lifetime syphilis in four high-risk
groups (MSM, TW, SW, incarcerated persons), comparing
and contrasting geographic regions within the Americas
and across time periods from 1980 to 2016. We will also
aim to better characterize details and potential nuances of
the current epidemiology of syphilis transmission,
including the impact on disease incidence of new biomedical
prevention technologies like pre-exposure prophylaxis,
the use of Internet/mobile applications to find sex
partners, and rates of HIV co-infection.
Based on an informal, preliminary review of the
existing literature, we expect that there will be tremendous
diversity in the prevalence and incidence of syphilis
infection between high-risk groups in the USA and Canada as
compared with Latin America and the Caribbean. To guide
the analysis, we propose the following hypotheses: (1) The
prevalence and incidence of syphilis infection in Latin
America and the Caribbean will be significantly higher
than the prevalence/incidence of infection in the USA
and Canada; (2) The majority of syphilis cases reported
in the USA and Canada will be identified during primary
or secondary syphilis infection (diagnosed through
symptomatic illness or network tracing), while the majority of
cases in Latin America and the Caribbean will be
diagnosed as latent disease (asymptomatic cases identified
through serologic testing); and (3) In all regions, there will
be a close epidemiologic association between syphilis
infection and HIV acquisition and transmission.
Our systematic review and meta-analysis aims to
contribute to an improved understanding of global epidemiologic
patterns of syphilis infection in most-at-risk populations.
Through systematic classification of the existing literature
and comparison of disease patterns across regional,
temporal, and socio-behavioral differences, we hope to improve
public health surveillance and improve efforts to control
the spread of disease across the Americas. Understanding
the prevalence and incidence of syphilis within and between
these high-risk groups will help guide resource allocation
and educational efforts, particularly in resource-limited
settings in Latin America and the Caribbean.
Additional file 1: Search strategy. (DOCX 106 kb)
CI: Confidence interval; GARPR: Global AIDS Response Progress Report;
MHA-TP: Microhemagglutination assay; MSM: Men who have sex with men;
RPR: Rapid plasma reagin; STI: Sexually transmitted infections; SW: Sex
workers; TP-EIA: Treponema pallidum enzyme-linked immunosorbent assay;
TPPA: Treponema pallidum particle agglutination assay; TW: Transgender
women; VDRL: Venereal disease research laboratory test
During the elaboration of this project, KK was a research fellow in the
NIHfunded South American Program in HIV Prevention Research (SAPHIR) of the
David Geffen School of Medicine at UCLA and gratefully acknowledges the
support he received from the staff in both Lima and Los Angeles.
Availability of data and materials
The datasets analyzed during the current study will be made available from
the corresponding author on reasonable request.
JLC conceived of the study, drafted the manuscript, and provided critical
review of the manuscript. KK furnished the details of the study design,
developed the search strategy, conducted the pilot search, drafted the
manuscript, and provided the critical review of the manuscript. ERS and
CEO provided the statistical advice, participated in the data synthesis
design, and edited the manuscript. JEL contributed to the details of the
study design, drafted the manuscript, and provided the critical review of
the manuscript. AGPB contributed to the details of the study design and
edited the manuscript. BAM participated in the development of the search
strategy, assisted with the pilot search, and contributed to refining the
details of the study design. PP and CNO participated in the pilot search
and contributed to refining the details of the study design. RLC provided
specialist expertise and edited the manuscript. All authors read and
approved the final manuscript.
This research was supported by the National Institutes of Health grants R25
MHO87222 to JLC and K23AI110532 to JEL. The funders had no role in
protocol design, decision to publish, or preparation of the manuscript.
Ethics approval and consent to participate
Consent for publication
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