Diagnostic Tools for Preventing and Managing Maternal and Congenital Syphilis: an Overview Rosanna W
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Diagnostic tools for preventing and managing maternal and congenital syphilis: an overview Rosanna W. Peeling1 & Htun Ye2 Abstract Syphilis is a major cause of adverse outcomes in pregnancy in developing countries. Fetal death and morbidity due to congenital syphilis are preventable if infected mothers are identified and treated appropriately by the middle of the second trimester. Most pregnant women with syphilis are asymptomatic and can only be identified through serological screening. Non-treponemal tests, such as the rapid plasma reagin (RPR) test, are sensitive, simple to perform, and inexpensive. However, they have often not been available at primary health-care settings because they required cold storage for reagents and electricity to operate a rotator. Additionally, as many as 28% of positive RPR results in pregnant women are biological false positives. Confirmatory assays are usually available only in reference laboratories. Technological advances have resulted in improved serodiagnostic tools for syphilis. New enzyme immunoassays are available for surveillance and for large-scale screening programmes. Decentralized antenatal screening with on-site confirmation is now possible since new RPR reagents that are stable at room temperature have become commercially available, as have solar-powered rotators and simple, rapid point-of-care treponemal tests that use whole blood and do not require electricity or equipment. These will be valuable tools for preventing or eliminating congenital syphilis. The development of a non-invasive rapid treponemal test that distinguishes between active and past infections remains a high priority in areas where syphilis is endemic. Keywords Syphilis, Congenital. Syphilis/diagnosis/therapy; Syphilis serodiagnosis/utilization; Immunoenzyme techniques/utilization; Treponema pallidum/isolation and purification; Prenatal diagnosis; Evaluation studies (source: MeSH, NLM). Mots clés Syphilis congénitale/diagnostic/thérapeutique; Séro-diagnostic syphilis/utilisation; Méthode immunoenzymatique/utilisation; Treponema pallidum/isolement et purification; Diagnostic prénatal; Etude évaluation (source: MeSH, INSERM). Palabras clave Sífilis congénita/diagnóstico/terapia; Serodiagnóstico de la sífilis/utilización; Técnicas para inmunoenzima/utilización; Treponema pallidum/aislamiento y purificación; Diagnóstico prenatal; Estudios de evaluación (fuente: DeCS, BIREME). Bulletin of the World Health Organization 2004;82:439-446. Voir page 444 le résumé en français. En la página 445 figura un resumen en español. Introduction Infants born to infected mothers are at risk of acquiring the infection in utero, resulting in serious perinatal morbidity Important advances in the diagnosis and treatment of syphilis and mortality (4–6). Congenital syphilis can be prevented if have been made since the causative organism, Treponema pal- infection in the mother is detected and treated by the time lidum, was discovered in 1905 by Schaudinn and Hoffmann. of the second trimester. Antenatal screening to prevent con- Despite these achievements, syphilis remains a major public genital syphilis has become the main focus of syphilis control health problem in many developing countries, and there has programmes. had a resurgence in developed countries (1, 2). In settings where there is limited or no access to diagnostic tools, WHO has recommended using a syndromic management Diagnostic tools approach whereby patients presenting with genital ulcer disease A wide range of diagnostic tools is available (Table 1). The under- (GUD) are treated for syphilis and chancroid (3). A significant lying principles and characteristics of these tests are well described relative decline in the prevalence of primary syphilis among pa- in laboratory manuals and guidelines and will not be discussed tients with GUD was documented in countries where syndromic here (7–11). This paper focuses on whether the diagnostic tools management was successfully implemented. However, because are adequate to control maternal syphilis and prevent congenital most individuals infected with syphilis do not have clinical symp- syphilis as well as on the problems associated with their use for toms, syphilis continues to be a serious public health problem surveillance (Table 2). We also briefly discuss what the future in areas where screening programmes are not in place. may hold in terms of new tests. 1 Manager, Sexually Transmitted Diseases Diagnostics Initiative (SDI), UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, Avenue Appia, 1211 Geneva 27, Switzerland. Correspondence should be sent to this author (email: [email protected]). 2 Medical officer, STI Surveillance, Department of HIV/AIDS, World Health Organization, Geneva, Switzerland. Ref No. 03-008086 (Submitted: 22 September 2003 – Final revised version received: 1 April 2004 – Accepted: 1 April 2004) Bulletin of the World Health Organization | June 2004, 82 (6) 439 Maternal and congenital syphilis Tools to prevent and manage maternal and congenital syphilis Rosanna W. Peeling et al. Identification of T. pallidum specific than darkfield microscopy, but it is technically demand- The direct identification of T. pallidum is not routinely used ing and more expensive. The sensitivity of both microscopy because most people who have syphilis are asymptomatic. Identi- techniques can be affected by the age or condition of the lesion fication of the treponeme is only possible in people presenting and whether the patient has been treated. with lesions of primary and secondary syphilis (Fig. 1). Since T. Nucleic acid-based amplification assays, such as the poly- pallidum cannot be cultured in the laboratory, darkfield micros- merase chain reaction (PCR), which can detect as few as 10 copy is used to identify the treponemes in a wet mount of lesion treponemes in lesions, placental tissue and other body tissues, material. The treponemes have a characteristic morphology and have greatly improved the sensitivity and specificity of direct motility. Darkfield microscopy has a sensitivity of 74–86% and detection methods (12, 13). A multiplex PCR assay which simul- a specificity approaching 97% depending on the expertise of the taneously detects T. pallidum, herpes simplex virus type 2 and reader (8, 9). Its sensitivity may be lowered if the lesion has been Haemophilus ducreyi has been used to provide an etiological wiped with an antiseptic. Direct fluorescent antibody–T. palli- diagnosis for patients with GUD as well as for validating syn- dum testing (DFA–TP) uses fluorescein-conjugated antibodies dromic management algorithms (14). Since PCR assays for to stain the organism in a smear or tissue section (7). DFA–TP syphilis are not commercially available, these assays have re- does not require motile organisms and is more sensitive and mained research tools. Table 1. Comparison of syphilis tests (7–9) For patients presenting For screening with an ulcer or lesion Criteria Darkfield Antigen DNA Non-treponemal tests Treponemal tests microscopy detection detection (DFA–TP) (PCR) RPR VDRL Rapid test EIA TPHA–TPPA FTA-ABS Sensitivity 74–86% 73–100% 91% 86–100% 78–100% 84–98% 82–100% 85–100% 70–100% Specificity 85–97% 89–100% 99% 93–98% 98% 94–98% 97–100% 98–100% 94–100% Ease of use Easy Moderate Complex Easy Easy Easy Moderate Complex Complex Where used Exam room, Intermediate Referral Exam room, Exam room, Exam room, Intermediate Referral lab Referral lab on-site lab lab, referral lab on-site lab on-site lab on-site lab lab, referral lab lab Equipment Light Fluorescence Microfuge Rotator Light None Incubator, Incubator, Fluores- needed microscope microscope centrifuge, microscope microwell microwell cence with thermal plate plate microscope darkfield cycler, washer and washer and condenser incubator, reader reader microwell plate reader Training Extensive Moderate Extensive Minimal Minimal Minimal Moderate Extensive Extensive needed Average US$ 0.40 US$ 3.00 US$ 14.00 US$ 0.50 US$ 0.50 US$ 0.55–3.00 US$ 3.00 US$ 3.00 US$ 3.00 cost (includes detection of Haemophilus. ducreyi and herpes simplex virus) Comments Requires live Does not Does not Most RPR Reagents Most tests Allows high Confirma- Confirma- organisms. require distinguish reagents require are stable throughput tory test. tory test. Specificity live between the require refrigeration at room screening Does not Does not may be organisms subspecies refrigeration temperature but does not distinguish distinguish compromised pallidum and for >6 distinguish between between by presence pertenue months. between active infec- active infec- of debris or Test does no active infec- tions and tions and endogenous distinguish tions and infections infections treponemes between infections treated in treated in active infec- treated in the past the past tions and the past infections treated in the past DFA–TP = direct fluorescent antibody–Treponema pallidum testing; PCR = polymerase chain reaction; RPR = rapid plasma reagin test; VDRL = Venereal Diseases Research Laboratory test; EIA = enzyme immunoassay; TPHA–TPPA = T. pallidum haemagglutination assay–T. pallidum particle agglutination test; FTA-ABS = fluorescent treponemal antibody absorption test. 440 Bulletin of the World Health Organization | June 2004, 82 (6) Maternal and congenital syphilis Rosanna W. Peeling et al. Tools to prevent and manage maternal and congenital syphilis Table 2. Tools for preventing and controlling maternal and congenital syphilis in different settings Tests for diagnosis