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Cochrane Database of Systematic Reviews Protocol - Diagnostic

Point of care rapid test for diagnosis of syphilis infection in men and nonpregnant women

Authors' declarations of interest

Version published: 25 May 2018 Version history

https://doi.org/10.1002/14651858.CD013036
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Abstract

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows:

To determine the diagnostic accuracy of rapid tests at point of care (POC) for detecting syphilis infection in men and nonpregnant women of reproductive age, as verified with the combination of both reactive non‐treponemal and treponemal test as the reference standard.

Background

Target condition being diagnosed

Syphilis is a complex, curable sexually‐transmitted infection caused by the Treponema pallidum bacterium that has a variable clinical course (CDC 2014). It is a cause of acute illness and serious medical and psychological consequences in a small proportion of people infected with the bacteria. Syphillis is also the cause of long‐term disability
and death of thousands of men, women and infants (Saloojee 2004). The Center for Disease Control (CDC) defines syphilis as: Syphilis, primary: A stage of infection characterised by one or more ulcerative lesions (e.g. chancre); Syphilis, secondary:
a stage of infection characterised by localised or diffuse mucocutaneous lesions (e.g. rash such as non‐pruritic macular, papular, or pustular lesions), often with generalised lymphadenopathy; Syphilis, early latent: a person without clinical signs or symptoms of syphilis when the initial infection has occurred within the previous 12 months; Syphilis, late latent: a person without clinical signs or symptoms of syphilis when the
initial infection has occurred >12 months previously; Syphilis, late, with clinical manifestations; and Syphilis, Congenital (CDC 2014 a).

Syphilis is the most common disease during the years of peak sexual activity. In 2012, the estimated global prevalence was 0.5% (0.4% to 0.6%) in women aged 15 to 49 years and 0.48% (0.3% to 0.7%) in men (Newman 2015). These figures correspond to an estimated 6 million new cases of syphilis (4 to 8 million) each year worldwide. Prevalence and incidence estimates varied by region and sex.For syphilis in women, the infection with the most robust available data, the prevalence of infection decreased as average country income increased (Newman 2015).

Current diagnostic strategies

Diagnosis of syphilis is based on a combination of clinical history, symptom presentation, and serologic test results. There are two types of diagnostic tests, treponemal and non‐treponemal (PAHO 2015).

The non‐treponemal tests such as Venereal Disease Research Laboratory (VDRL) or rapid plasma reagin (RPR) measure the host's response to non‐treponemal antigens such as cardiolipin and lecithin released from the damaged host cells, as well as lipoprotein‐like material released from the treponema. These non‐treponemal tests are generally considered to be sensitive in early syphilis, but their disadvantage being false‐positive reactions due to cross‐reactivity with autoimmune diseases, collagen diseases and infections such as pian and leprosy. They also have false‐negative reactions due to its reduced sensitivity in primary syphilis and late latent syphilis, (sensitivity: primary syphilis 78% to 86% compared with dark‐field confirmed cases (Creegan 2007)), secondary syphilis 100%, latent syphilis 96% to 98%, late syphilis 71% to 73%; specificity 98% in all stages, compared with Treponema pallidum Haemagglutination (TPHA) test (Naidu 2012), and the potential for false‐negative results due to prozone phenomenon (Liu 2014). The result of the non‐treponemal test is given in titres, with a result of 1:8 titres very suggestive of recent/active infection. The treponemal tests such as fluorescent treponemal antibody absorbed (FTA‐ABS), Treponema pallidum particle agglutination (TP‐PA), enzyme immunoassay (EIA), chemiluminescence immunoassay (CIA) or equivalent serologic methods have high sensitivity for all the stages of disease other than very early primary syphilis (sensitivity 84% to 96%, specificity 98% in all stages). These tests detect human serum/plasma antibodies to Treponema pallidum by means of an indirect hemagglutination method. The results of these tests are given in a dichotomy method, being "positive" or "negative" the possible results (Naidu 2012).

Currently, there are two common approaches to the diagnosis of syphilis using serological tests: the traditional algorithm and the reverse algorithm. The CDC recommends the traditional algorithm (CDC 2014). This algorithm begins the screening with a non‐treponemal test and confirms a positive result with a treponemal test (CDC 2014; PAHO 2015; WHO 2003). However, the treponemal‐based tests remain positive for life and cannot distinguish between recent, active infection and previously treated or old, non‐contagious infection (PAHO 2015). A reverse testing algorithm utilises a treponemal primary screening assay followed by a non‐treponemal test if the primary treponemal assay is positive. If the secondary, non‐treponemal test is reactive, then active syphilis is confirmed (CDC 2008). In the literature, it is considered as active syphilis if a positive treponemal test and a non‐treponemal test is reactive with different thresholds, with a non‐treponemal test at any titre, more than two dilutions or more than four dilutions (Kay 2014).

The presence of a hard chancre in genitals is suggestive of syphilis, and its treatment is considered in the syndromic approach of genital ulcers, because the treponemal test and the non‐treponemal test initially can both be negative. The reactive syphilis test in combination with a typical clinical sign of syphilis such a chancre, skin ulcer, or rash is highly suggestive of the disease (PAHO 2015). In the absence of symptoms, a combination of both reactive non‐treponemal and treponemal test indicates the possibility of contagious syphilis infection, and
supports the need for treatment of the individual and any sex partners (PAHO 2015).

The treponemal tests are expensive, laboratory‐based, require a continuous supply of electricity, reagents and trained staff, and are rarely available outside of reference laboratories. (Peeling 2004) As a result in many countries, treatment is based on non‐treponemal tests results, which are cheaper and have more availability, leading to over‐treatment of patients, due to false‐positive results, besides when the patient has a non‐treponemal positive test, the treponemal test is requested for confirmation, and if the patient could not return to the healthcare facility, the opportunity for treatment is lost (Jafari 2013).

Index test(s)

In resource‐limited settings, access to screening is limited and the risk of patients lost to follow‐up is high (Taylor 2017). So, syphilis rapid tests to be applied at point of care (POC), which detect antibodies to Treponema pallidum antigen or anticardiolipin antibodies, have become popular in those settings due to their advantages: the quickness in giving results, the possibility of giving treatment immediately, are performed with minimal technical training in non‐laboratory settings, and detect the disease at the clinical setting (PAHO 2015; Peeling 2004). In addition, as the test results are obtained on the same day, expressed in a qualitative way (detected or not detected) and treatment can be provided right away.The risk of over‐treatment given by false positives is less dangerous than the secondary risk of not treating the infection, so every patient with positive result must be given treatment (Jafari 2013).

In order to define the ideal characteristics of a rapid and POC test for the detection of sexually transmitted infections, the WHO Sexually Transmitted Diseases Diagnostic Initiative (SDI) established the ASSURED criteria: the test has to be Affordable, Sensitive, Specific, User‐friendly, Rapid and Robust, Equipment‐free and Delivered to end users. The setting of these criteria has the potential to make an impact in averting congenital syphilis in primary healthcare settings (Mabey 2012; Peeling 2006; Peeling 2010).

There are two types of POC test: non‐treponemal and treponemal. There is a device which offers the ability to provide the antibody detection of both tests. The treponemal tests have two variants: inmunochromatographic or agglutinant. The second type of POC, non‐treponemic test, is useful because it indicates an active infection. The combined test detects treponemal and non treponemal antibodies. In a high‐prevalence setting, the combined test may significantly reduce over‐treatment (Greer 2008). Another type of test combines the diagnosis of syphilis and HIV, this test HIV/syphilis Duo test, is a method of qualitative detection that uses as method the inmunochromatography to detect immunoglobulin (Ig) IgG, IgM and IgA antibodies for specific‐HIV antigens and the Treponema pallidum recombinant antigen in serum (Bristow 2014). Currently there are numerous commercial trades for POC tests, being the most commonly used the Abbott Determine, Omega Visitect, Qualpro Syphicheck, Standard Bioline and Trinity Syphilis Health Check (Mabey 2006)

In a recent meta‐analysis the sensitivity of treponemal POC tests varied from 74.26% to 90.04% and specificity from 94.15% to 99.58% (Jafari 2013). The combined test has a sensitivity of 98.4% when the standard is a non‐treponemal test (RPR) greater than 1:8 dilutions. but it has been seen that sensitivity falls to 88% when the RPR is negative (Singh 2015). Nevertheless, these recent meta‐analysis are founded in the background of stored samples, with serologic status previously known, which may introduce biases in the outcomes, resulting in high sensitivities and specificities. Our review will look for studies with fresh samples.

Series that compare syphilis POC tests with the combination of treponemal and non‐treponemal tests, have shown a concordance with approximately 90.6%, with a specificity greater than 95% and a sensitivity between 60% to 100% depending on the test (Gaydos 2014). The implementation of rapid testing must be accompanied by quality assurance systems and technical competence (Benzaken 2014).

Clinical pathway

The improvement in access to appropriate diagnosis and treatment for infectious diseases can reduce the burden of disease (Taylor 2017). Although some infections can be managed syndromically without the need for diagnostic tests, this is not appropriate for asymptomatic infectious diseases in which a positive diagnostic test is needed before treatment can be given (Peeling 2010). In many situations, it is not possible to perform or to wait for the results of laboratory tests, because the delay represents opportunities lost for treatment, which can spread the infection of the STD, therefore diagnosis depends on the availability of POC tests (Peeling 2010). POC tests for STI would provide the ability to offer immediate testing and treatment in a single encounter to mitigate further spread of the disease (Singh 2015).

The POC test for syphilis can be implemented by clinicians, health services or auxiliary personnel in diverse places without laboratory support, under different scenarios regardless of healthcare systems levels, covering a broad patient spectrum, especially in high‐risk populations. The clinical pathway for this diagnostic approach can be summarised into two clinical presentations. The first one is the presence of an asymptomatic patient in which the lack of an opportune diagnostic test will be reflected in an absence of an appropriate treatment increasing in consequence, the burden of the condition and serious and deleterious sequelae. Examples for this scenario could be a pregnant woman with syphilis (CDC 2006; Larson 2014), people in developing countries, peripheral health facilities, or remote rural populations that do not have access to laboratory services (Bien 2015; Peeling 2010), people in resource‐limited settings (Gaydos 2014), in high‐risk populations (v.g. sexual workers and LGBTI population (lesbian, gay, bisexual, transgender and intersex) or drug users) (Gaydos 2014), or in syphilis‐control programs for female, male and transgender sex workers (Chen 2012; Gupte 2011).

The second clinical scenario where the POC test could be used is in the case of symptomatic patients. In this population, the syphilis infection can be suspected by unspecific signs of infection, such as hard chancre, inguinal adenopathies, exanthema or condylomata lata. For these patients, the prompt confirmation accompanied by the immediate treatment of the disease could relieve the infection and break the chain of transmission, decreasing the infection rates (Gaydos 2014).

Rationale

Considering the burden and economic costs associated with the condition, even in settings with low prevalence (Larson 2014), it is highly desirable to undertake a critical appraisal of the available evidence of the diagnostic accuracy of the different syphilis rapid POC tests. There is therefore, a need for high‐quality systematic reviews to improve the diagnosis of syphilis. This systematic review will facilitate the synthesis of the current evidence, and recognise the strengths and weaknesses, address the uncertainty of the current knowledge, and make it possible to assess the effectiveness and safety of this intervention.

Knowing the performance, advantages and limitations of the POC test, could facilitate the decision‐making process at individual, organisational, and healthcare systems levels (Larson 2014). The formulation of public health policy focused on early diagnostic and treatment of the infected patient, eliminating the treatment delays and cutting the infection spread, even in clinical settings can help to reduce the burden of syphilis (Singh 2015).

Objectives

To determine the diagnostic accuracy of rapid tests at point of care (POC) for detecting syphilis infection in men and nonpregnant women of reproductive age, as verified with the combination of both reactive non‐treponemal and treponemal test as the reference standard.

Secondary objectives

To assess the accuracy of rapid POC testing according to type (non‐treponemal and treponemal), infection stage (active versus inactive) and setting (low/middle‐income vs high‐income countries). In addition, we will to determine the diagnostic accuracy of POC test by brand without realize a formal comparison.

Methods

Criteria for considering studies for this review

Types of studies

We will include accuracy studies. Participants in included studies should have been enrolled under field conditions, prospectively and consecutively or through random sampling. Only studies reporting that all participants received the index test and the reference standard and presenting 2 × 2 data will be eligible for inclusion. We will exclude diagnostic case‐control studies because this is not an appropriate design for diagnostic test studies.

Participants

We will include men and nonpregnant women at reproductive age, recruited at primary‐ or secondary‐care facilities without previous diagnostic testing, who are attending an outpatient facility. We will not include pregnant women because there is another review with this population.

Index tests

Rapid tests at POC from whole blood, serum or plasma, regardless of the type of POC test (non‐treponemal or treponemal) or technique (Immunochromatographic, agglutination or any other technology).

Target conditions

Syphilis at any infection stage (active versus inactive).

Reference standards

A combination of both reactive non‐treponemal (positive at any titre) and treponemal test (positive result).

Search methods for identification of studies

We will develop a highly‐sensitive, systematic search strategy to identify as many relevant accuracy or validity studies, irrespective of their language, and publication status (published, unpublished, in press, and in progress). We will use both electronic searching in bibliographic databases and handsearching, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

The results of all searches will be downloaded and managed using Endnote bibliographic software. Duplicate records of the same study will be deleted.

Electronic searches

We contacted with the Information Specialist of the Cochrane Sexually Transmitted Infections (STI) Review Group in order to implement a comprehensive search strategy to capture as many relevant studies as possible in electronic databases. For this purpose, we will use a combination of exploded controlled vocabulary (MeSH, Emtree, DeCS) and free‐text terms (considering spelling variants, plurals, synonyms, acronyms and abbreviations) for the index tests (point‐of‐care test, point of care, point of care testing, point of care devices, point of care diagnostic, point of care laboratory, POC, POCT, rapid test, rapid test device, self testing, self test, patient self testing) and the target condition (syphilis, Treponema pallidum), with field labels, truncation, proximity operators and boolean operators. The search strategies and their results can be found in Appendix 1 (Electronic search strategies).

Specifically, we will search the following electronic databases.

  • MEDLINE, Ovid platform: inception to present.

  • MEDLINE In‐Process & Other Non‐Indexed Citations, Ovid platform: inception to present.

  • MEDLINE Daily Update, Ovid platform: inception to present.

  • Embase.com: inception to present.

  • Cochrane Central Register of Controlled Trials, Ovid platform: inception to present.

  • LILACS, iAHx interface: inception to present.

Searching other resources

We will attempted to identify additional relevant studies by using of the following methods.

  • Searching the Cochrane STI Review Group’s Specialized Register, which includes randomised controlled trials (RCTs) and controlled clinical trials (CCTs), from 1944 to 2014, located through the following.

    • Electronic searching in MEDLINE, EMBASE and CENTRAL.

    • Online handsearching in those journals not indexed in MEDLINE or Embase, according to the journals’ master list of the Cochrane STI Review Group.

  • Searching trials registers.

  • Searching in Web of Science®: inception to present.

  • Searching for grey literature in System for Information on Grey Literature in Europe “OpenGrey” (http://www.opengrey.eu/): inception to present.

  • Searching in Health Services Research Projects in Progress (HSRProj), and the Database of Abstracts of Reviews of Effect (DARE) for additional articles.

  • Handsearching of conference proceeding abstracts in the following events.

    • The International Society for Sexually Transmitted Diseases Research ‐ ISSTDR (http://www.isstdr.org/): 2007, 2009, 2011, 2013 and 2015.

    • The British Association for Sexual Health and HIV ‐ BASHH (http://www.bashh.org/): 2014 and 2015.

    • International Congress on Infectious Diseases ‐ ICID (http://www.isid.org/): 2010, 2012 and 2014.

    • The International Union against Sexually Transmitted Infections ‐ IUSTI (http://www.iusti.org/): 2011, 2012, 2013, 2014 and 2015.

    • International Society for Infectious Diseases ‐ ISID (http://www.isid.org/): 2011, 2012, 2013, 2014 and 2015.

    • International Meeting on Emerging Diseases and Surveillance ‐ IMED (http://www.isid.org/): 2007, 2009, 2011, 2013 and 2014.

    • Interscience Conference on Antimicrobial Agents and Chemotherapy ‐ ICAAC (http://www.icaac.org/): 2011, 2012, 2013, 2014 and 2015.

    • The International Federation of Gynecology and Obstetrics ‐ FIGO (http://www.figo2012.org/home/): 2009, 2012 and 2015.

  • Handsearching within previous systematic reviews and other relevant publications on the same topic.

  • Handsearching within reference lists of all relevant studies identified by others methods. Finally, we will search the citation lists from reviewed articles.

Data collection and analysis

Selection of studies

Two review authors (NT‐M, LV‐V) will independently selecting the titles and abstracts of studies retrieved as a result of the search. Disagreements will be resolved through consensus or, if required, by consultation with a third review author (CFG‐A). We will retrieve the full text of a study if we have doubts about whether the study should be included or excluded. Two authors (EA‐M, JA‐G) will review independently the full text of selected articles in order to defined their inclusion. Disagreements will be resolved through consensus or, if required, by consultation with a third review author (CFG‐A).

Data extraction and management

We will design a data extraction form. For eligible studies, two review authors (EA‐M, JA‐G) will extract data independently using the form. Discrepancies will be resolved through consensus or, if required, by consultation with a third review author (CFG‐A). The data extraction form will include the following information.

  • Methods

    • Country of the study. Setting.

    • Basic study design.

    • Power calculation.

    • Number of participants and sampling of patients.

    • Ethical issues.

  • Participants

    • Inclusion and exclusion criteria. Participants in included studies should have been enrolled under field conditions.

    • Baseline information on participants: presentation at recruitment and characteristics (e.g. gender, symptoms, presence of risk factors, sociodemographic characteristics and infection stage).

    • Proportion of participants included in the analysis.

  • Index test

    • POC specimen: whole blood, serum or plasma.

    • POC type: single non‐treponemal, single treponemal or combined tests.

    • POC technology: inmunochromatographic, agglutinant or any other technology.

    • POC staff: trained technicians, nurses, social workers or others.

    • POC timing: before, after or simultaneously with the reference standard.

    • POC application: laboratory or field.

    • POC origin: fresh or frozen sample.

  • Reference standard

    • Reference standard specimen: whole blood, serum or plasma.

    • Reference standard technology: Immunochromatographic, agglutination or any other technology.

    • Reference standard type: Treponemal test (TPPA, TPHA, FTA‐Abs, other), non treponemal test (VDRL, RPR).

    • Reference standard timing: before, after or simultaneously with the POC.

    • Reference standard staff: trained technicians, nurses, social workers or others

  • Outcomes

    • True positives, false positives, false negatives, true negatives.

    • Sensitivity and specificity.

    • Acceptability of the test.

    • Cost‐effectiveness.

We will collate and present this information in 'Characteristics of included studies' tables. We will add the data to Review Manager 5.3 (Revman 2014), and two review authors (CFG‐A, JA‐G) will independently assess the accuracy of the data. Differences will be resolved through consensus or by evaluation by a third review author (EA‐M). When information regarding any of the above is unclear, we will contact the authors of the original reports to request further details.

Assessment of methodological quality

We will assess the quality of included articles by using a modified version of the Quality Assessment of Diagnostic Accuracy Studies‐2 (QUADAS‐2) tool (Whiting 2011). Two review authors (JA‐G,EA‐M ) will independently perform the quality assessment using the four key domains to assess risk of bias and concerns regarding the applicability to the research question (patient selection, index test, reference standard, and flow‐timing domains). We will score the papers as having a ’low’, ’high’ or ’unclear’ risk of bias for each of four domains, and for the patient selection, index test and reference standard applicability. Studies classified at high or unclear risk of bias and/or high concern regarding applicability in at least one domain will be regarded as having low methodological design. In the case of disagreements, differences will be resolved through consensus or by consultation with a third review author (CFG‐A). The results will be presented in graphics according to each study an as a summary of all the studies.

Statistical analysis and data synthesis

We will to assess the accuracy of all POC available test for detecting syphilis infection regardless their type: treponemal or non‐treponemal. In this sense we plan to look at their accuracy grouped. On the other hand, because currently there are two common approaches to the diagnosis of syphilis using serological tests: the traditional algorithm (begins the screening with a non‐treponemal test and confirms a positive result with a treponemal test) and the reverse algorithm (utilises a treponemal primary screening assay followed by a non‐treponemal test if the primary treponemal assay is positive) we plan to report POC test accuracy using as gold standard both approaches grouped by type and sequence.

We will summarise diagnostic test accuracy by creating a 2 × 2 table for each study based on information retrieved directly from the papers. Each table will contain false‐positive, false‐negative, true‐positive, and true‐negative rates. Two review authors (CFG‐A, JA‐G) will independently enter the data into Revman 2014. Discrepancies will be resolved by consensus or, if required, by consultation with a third review author (EA‐M).

In the first instance, we will analyse in a descriptive way all data retrieved from the included studies. For this purpose and given that results of the POC are reported qualitatively (positive or negative), we will present the results by plotting their sensitivity and specificity (and their 95% confidence intervals) both in forest plots and in a scatter plot in receiver operating characteristic (ROC) space. For the meta‐analysis of diagnostic accuracy measures, we will use the bivariate model (Reitsma 2005). For studies with a common threshold, this model takes into account within‐study variation and between‐study variation and focuses on estimating a summary operating point (i.e. a summary value for sensitivity and specificity). In addition, we will estimate the 95% confidence region and the 95% prediction region around the summary operating point. We will perform these analyses using the command xtmelogit in STATA, according to the licenses available.

We will include a 'Summary of findings' table using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach to diagnostic test accuracy (Hsu 2011), using the template provided in the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy (DTA) (Bossuyt 2013). We will present this summary table to provide a more accessible perspective of diagnostic information to healthcare providers and other end users.

Investigations of heterogeneity

We will explore heterogeneity initially by performing visual inspection of forest plots of sensitivities and specificities and visual examination of the prediction region. We will formally assess the source of heterogeneity by examining differences in diagnostic accuracy between subgroups of studies. Again, we will use the bivariate method to analyse how the summary estimate of sensitivity and specificity varies according to study level covariates. For this purpose, we will create a factor variable with N categories and will generate an N‐1 dummy that will be entered into the bivariate model to test the effects of covariates on both sensitivity and specificity (Bossuyt 2013).

We will define the sources of heterogeneity a priori and will include the following factors: POC type (non‐treponemal and treponemal), infection stage (active versus inactive) and setting (low/middle‐income vs high‐income countries). In addition, we will to realize a subgroup analyses in order to determine the diagnostic accuracy of POC test by brand, without incurring a formal comparison.

Sensitivity analyses

We will perform sensitivity analysis for aspects of the review that might affect the results, such as risk of bias associated with the quality of included trials based on an overall 'Risk of bias' assessment (low versus unclear and high risk of bias) according to QUADAS‐2 patient selection, index test, reference standard, and flow‐timing domains.

Assessment of reporting bias

We will investigate publication bias if we find 10 or more studies for inclusion in this systematic review. We will investigate reporting bias by using the natural logarithm of the DOR (lnDOR) and plot it against its variance or SE. We will assess asymmetry visually, and if asymmetry is suggested by a visual assessment, we will perform exploratory analyses using Deeks’ test to investigate the asymmetry and using diagnostic odds ratio (DOR) as a measure of test accuracy (van Enst 2014).