ReviewThe Oslo study of the natural history of untreated syphilis: An epidemiologic investigation based on a restudy of the Boeck-Bruusgaard material a review and appraisal
Abstract
Nowhere in the world is there a more unique opportunity to learn what happens when early syphilis goes untreated than from the files of Boeck of Oslo, Norway. His scientific conviction as to the inadequacies of the specific treatment of the day led him to withhold treatment from approximately 2,000 patients with primary and secondary syphilis during the twenty-year period, 1891–1910. Community protection from infection was aided by the hospitalization of these patients until all traces of the disease had disappeared (from 1 to 12 months, average 3.6 months). In 1929, his successor, E. Bruusgaard, reported on a follow-up study of 473 of these patients and provided information on the outcome of untreated syphilis, which has formed the basis for prognostic statements on syphilis for more than twenty-five years. Now, in the department of Bruusgaard's successor, Danbolt, the entire material has been restudied successfully by Gjestland.
This restudy represents a striking example of the application of the modern epidemiologic approach. In addition to the scientific contribution of this investigation, an outstanding illustration of international scientific cooperation has been demonstrated.
The remarkable degree of success in obtaining significant information on approximately 80 per cent of the study group, 1,404 Norwegian residents of Oslo of 1891–1910, was undoubtedly due to the careful planning which preceded the tracing efforts. This planning included: (a) a consideration of the nature, extent, and significance of the problem of untreated syphilis; (b) an appraisal of existing information on the subject; (c) the setting up of hypotheses to be tested and questions to be answered; and (d) a detailed outline for a practical experiment design. The pretracing experiment design comprised: the selection of the study group; the listing of possible sources of information; a plan for orderly tracing; a provision for the collection and recording of information; plans for “controls”; and an outline for the analysis of data. Of particular importance is that these features of detailed planning preceded actual data collection. This characteristic of the epidemiologic method is well illustrated by this study.
The study was undertaken with the ultimate objective of providing information on the “… natural course of syphilis according to as many indices as the material will allow. …”1 The questions originally asked of the material were: Among patients untreated for secondary syphilis and with no, some, or unknown subsequent treatment: 1. What are the frequencies of secondary relapse, of benign late syphilis, of late symptomatic syphilis, of life-long latency, and of spontaneous cure? 2. What are the effects on longevity, on causes of death and on mortality over that of nonsyphilitics? 3. Does age at time of infection influence outcome? 4. Does sex influence outcome? 5. What are the effects on the outcome of pregnancy at varying intervals following infection? 6. Is morbidity from conditions other than syphilis greater than among nonsyphilitics?
Analysis of this material provides useful information in reference to questions 1 to 4. Unfortunately, it was impossible to collect significant data for question 5 and the matter of congenital syphilis was postponed for future investigation on a more limited scale. Data relating to question 6 will be introduced in a subsequent publication22 if satisfactory inferences can be drawn about morbidity from an extensive mortality study. The data relating to the remaining four questions are summarized in the following paragraphs.
One of the significant contributions of this investigation is the information obtained on clinical secondary relapse: 23.6 per cent of these patients experienced this manifestation within five years of discharge from the hospital (males 22.7 per cent, females 24.0 per cent) and of these approximately one-fourth had multiple episodes.
Benign late syphilis occurred in 14.4 per cent of males and 16.7 per cent of females. It was observed as early as the first year after discharge and as late as the forty-sixth year, the majority developing by the fifteenth year. There was some evidence of earlier appearance in females than in males and some suggestion that the probability of development is greater among females.
Cardiovascular syphilis was observed to have developed in 13.6 per cent of males and 7.6 per cent of females, no cases occurring in those infected before the age of 15.
Neurosyphilis did develop in patients who were infected before the age of 15 but not in males infected after the age of 40. In neurosyphilis there was a 2 to 1 ratio of males to females (males 9.4 per cent and females 5.0 per cent).
The mortality from syphilis among males was twice that of females, but in neither sex was it an important cause of death. It was second as a cause of death in males and fifth in females, but approximately 90 per cent of deaths were from other causes. There was a definite excess mortality among these syphilitics as compared to the population group from which they came.
No evidence was found to support the idea of the prognostic importance of either clinical secondary relapse or benign late syphilis.
The best definition of spontaneous cure is too rigid to permit quantitative evaluation. More practical is a consideration of the extent of disability during the lifetime of the persons involved. It was estimated that between 60 and 70 out of every 100 of these patients went through life with a minimum of inconvenience despite no treatment for early syphilis. This gives no encouragement to withhold treatment because the final outcome in any individual cannot be predicted, and, too, syphilis is still a transmissible disease when untreated and can cause serious difficulties among 30 to 40 out of each 100 who remain untreated.
This is probably the most comprehensive study of untreated syphilis that has yet been made, and the great mass of data that has been collected will provide the basis for additional contributions to our knowledge of syphilis infection. This brief review cannot do justice to this monumental piece of work comprising a monograph of some 500 pages, with 83 tables and 12 figures, and an annex of 70 pages with 30 tables and 2 figures. Gjestland's contribution will stand as a model of carefully planned and successfully executed field research and will provide the medical literature with the long awaited restudy of the Boeck-Bruusgaard material.
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Cited by (141)
Historical Trauma, Health Care Distrust, and the Legacy of Tuskegee: Implications for Nurse Practitioner Practice and Research
2024, Journal for Nurse PractitionersNurse practitioners (NPs) represent a strong cadre of healers and researchers active in a global quest to eliminate health disparities and create health equity. Barriers to health care result in a disproportionate burden of disease/disability on marginalized groups. Historical trauma results in or contributes to health care distrust manifested as a unique type of barrier with implications for nurse practitioners in research and practice. The legacy of Tuskegee is a reminder and a sentinel exemplar of how Black American male participants in “The Tuskegee Study of Untreated Syphilis in the Negro Male” (the United States Public Health Services Study at Tuskegee) experienced historical trauma and how intergenerational trauma is linked to negative health care outcomes.
Genomic epidemiology of syphilis in England: a population-based study
2023, The Lancet MicrobeSyphilis is a sexually transmitted bacterial infection caused by Treponema pallidum subspecies pallidum. Since 2012, syphilis rates have risen dramatically in many high-income countries, including England. Although this increase in syphilis prevalence is known to be associated with high-risk sexual activity in gay, bisexual, and other men who have sex with men (GBMSM), cases are rising in heterosexual men and women. The transmission dynamics within and between sexual networks of GBMSM and heterosexual people are not well understood. We aimed to investigate if whole genome sequencing could be used to supplement or enhance epidemiological insights around syphilis transmission.
We linked national patient demographic, geospatial, and behavioural metadata to whole T pallidum genome sequences previously generated from patient samples collected from across England between Jan 1, 2012, and Oct 31, 2018, and performed detailed phylogenomic analyses.
Of 497 English samples submitted for sequencing, we recovered 240 genomes (198 from the UK Health Security Agency reference laboratory and 42 from other laboratories). Three duplicate samples (same patient and collection date) were included in the main phylogenies, but removed from further analyses of English populations, leaving 237 genomes. 220 (92·8%) of 237 samples were from men, nine (3·8%) were from women, and eight (3·4%) were of unknown gender. Samples were mostly from London (n=118 [49·8%]), followed by southeast England (n=29 [12·2%]), northeast England (n=24 [10·1%]), and southwest England (n=15 [6·3%]). 180 (76·0%) of 237 genomes came from GBMSM, compared with 25 (10·5%) from those identifying as men who have sex with women, 15 (6·3%) from men with unrecorded sexual orientation, nine (3·8%) from those identifying as women who have sex with men, and eight (3·4%) from people of unknown gender and sexual orientation. Phylogenomic analysis and clustering revealed two dominant T pallidum sublineages in England. Sublineage 1 was found throughout England and across all patient groups, whereas sublineage 14 occurred predominantly in GBMSM older than 34 years and was absent from samples sequenced from the north of England. These different spatiotemporal trends, linked to demography or behaviour in the dominant sublineages, suggest they represent different sexual networks. By focusing on different regions of England we were able to distinguish a local heterosexual transmission cluster from a background of transmission in GBMSM.
These findings show that, despite extremely close genetic relationships between T pallidum genomes globally, genomics can still be used to identify putative transmission clusters for epidemiological follow-up. This could be of value for deconvoluting putative outbreaks and for informing public health interventions.
Wellcome funding to the Sanger Institute, UK Research and Innovation, National Institute for Health and Care Research, European and Developing Countries Clinical Trials Partnership, and UK Health Security Agency.
Diagnosis of neurosyphilis in HIV-negative patients with syphilis: development, validation, and clinical utility of a suite of machine learning models
2023, eClinicalMedicineThe ability to accurately identify the absolute risk of neurosyphilis diagnosis for patients with syphilis would allow preventative and therapeutic interventions to be delivered to patients at high-risk, sparing patients at low-risk from unnecessary care. We aimed to develop, validate, and evaluate the clinical utility of simplified clinical diagnostic models for neurosyphilis diagnosis in HIV-negative patients with syphilis.
We searched PubMed, China National Knowledge Infrastructure and UpToDate for publications about neurosyphilis diagnostic guidelines in English or Chinese from database inception until March 15, 2023. We developed and validated machine learning models with a uniform set of predictors based on six authoritative diagnostic guidelines across four continents to predict neurosyphilis using routinely collected data from real-world clinical practice in China and the United States (through the Dermatology Hospital of Southern Medical University in Guangzhou [659 recruited between August 2012 and March 2022, treated as Development cohort], the Beijing Youan Hospital of Capital Medical University in Beijng [480 recruited between December 2013 and April 2021, treated as External cohort 1], the Zhongshan Hospital of Xiamen University in Xiamen [493 recruited between November 2005 and November 2021, treated as External cohort 2] from China, and University of Washington School of Medicine in Seattle [16 recruited between September 2002 and April 2014, treated as External cohort 3] from United States). We included all these patients with syphilis into our analysis, and no patients were further excluded. We trained eXtreme gradient boosting (XGBoost) models to predict the diagnostic outcome of neurosyphilis according to each diagnostic guideline in two scenarios, respectively. Model performance was measured through both internal and external validation in terms of discrimination and calibration, and clinical utility was evaluated using decision curve analysis.
The final simplified clinical diagnostic models included neurological symptoms, cerebrospinal fluid (CSF) protein, CSF white blood cell, and CSF venereal disease research laboratory test/rapid plasma reagin. The models showed good calibration with rescaled Brier score of 0.99 (95% CI 0.98–1.00) and excellent discrimination (the minimum value of area under the receiver operating characteristic curve, 0.84; 95% CI 0.81–0.88) when externally validated. Decision curve analysis demonstrated that the models were useful across a range of neurosyphilis probability thresholds between 0.33 and 0.66 compared to the alternatives of managing all patients with syphilis as if they do or do not have neurosyphilis.
The simplified clinical diagnostic models comprised of readily available data show good performance, are generalisable across clinical settings, and have clinical utility over a broad range of probability thresholds. The models with a uniform set of predictors can simplify the sophisticated clinical diagnosis of neurosyphilis, and guide decisions on delivery of neurosyphilis health-care, ultimately, support accurate diagnosis and necessary treatment.
The Natural Science Foundation of China General Program, Health Appropriate Technology Promotion Project of Guangdong Medical Research Foundation, Department of Science and technology of Guangdong Province Xinjiang Rural Science and Technology（Special Commissioner）Project, Southern Medical University Clinical Research Nursery Garden Project, Beijing Municipal Administration of Hospitals Incubating Program.
Syphilis: A Modern Resurgence
2023, Infectious Disease Clinics of North AmericaSyphilis seroprevalence among HIV-infected males in Istanbul, Turkey
2020, Revista Argentina de MicrobiologiaCitation Excerpt :It is well known that syphilis may heal spontaneously. Hence, another reason for low RPR titers detected in some patients may be that these patients have healed spontaneously9. This study, in parallel with other studies carried out in different parts of the world, shows the high frequency of syphilis among HIV-infected patients in Turkey.
Syphilis has become a serious issue for human immunodeficiency virus (HIV)-infected patients worldwide in recent years; however, the studies related to HIV coinfection and syphilis reinfections in Istanbul, Turkey, are limited. Our objective was to determine the seroprevalence of syphilis among HIV-infected men in the city which has one of the highest HIV prevalence rates in Turkey. Two hundred and forty four (244) HIV-positive men were evaluated at Istanbul Medical Faculty, Department of Medical Microbiology from March to June 2018. Serum samples were screened for the presence of antibodies against Treponema pallidum using the chemiluminescent microparticle immunoassay (CMIA). Samples found to be positive were investigated with the rapid plasma reagin (RPR) test and the T. pallidum hemagglutination assay (TPHA). The patients completed a questionnaire for sociodemographic data. The mean age was found to be 41.8 years; 35.6% were men who have sex with men (MSM). The overall seroprevalence of syphilis among the patients was 19.3%. MSM had a significantly higher seroprevalence than heterosexual patients (28.7%). In Turkey, there is a high seroprevalence of syphilis in HIV-infected patients, MSM being the most affected group. Therefore, HIV-infected patients should be screened for syphilis at least annually and should be informed about sexually transmitted diseases (STDs).
En los últimos años, la sífilis se ha convertido en un problema grave para los pacientes infectados por el virus de la inmunodeficiencia humana (HIV) en todo el mundo; sin embargo, los estudios relacionados con la coinfección por HIV y las reinfecciones por sífilis en Estambul, Turquía, son limitados. Nuestro objetivo fue determinar la seroprevalencia de la sífilis entre los hombres infectados por el HIV en Estambul, ciudad con las tasas de prevalencia del HIV más altas de Turquía. Se evaluaron 244 hombres con HIV entre marzo y junio de 2018 en la Facultad de Medicina de Estambul, Departamento de Microbiología Médica. Las muestras de suero se analizaron para detectar la presencia de anticuerpos contra Treponema pallidum con un inmunoensayo de micropartículas quimioluminiscentes (CMIA). Las muestras que resultaron positivas en dicha prueba se investigaron con la prueba de reagina plasmática rápida (RPR) y el ensayo de hemoaglutinación T. pallidum (TPHA). Los pacientes completaron un cuestionario de datos sociodemográficos. La media de la edad fue de 41,8 años; 35,6% eran hombres que tienen sexo con hombres (HSH). La seroprevalencia global de sífilis entre los pacientes fue del 19,3%. Los HSH tuvieron una seroprevalencia significativamente mayor que los pacientes heterosexuales (28,7%). En Turquía, existe una alta seroprevalencia de la sífilis en pacientes infectados por el HIV y los HSH son el grupo más afectado. Por lo tanto, los pacientes infectados por el HIV deben someterse a la detección de sífilis al menos una vez al año y deben ser informados sobre las enfermedades de transmisión sexual (ETS).
Early symptomatic neurosyphilis and ocular syphilis: A comparative study between HIV-positive and HIV-negative patients
2020, Medecine et Maladies InfectieusesCitation Excerpt :However there is no formal system for reporting ocular syphilis (OS) or neurosyphilis (NS). Historically in the Oslo study, of 1404 Scandinavian patients with early syphilis, 1.6% (23 patients) developed symptomatic early NS (with no data about OS) [7]. More recently from 2009 to 2015 in the USA, of 48,045 of the syphilis cases notified to CDC, 403 (0,8%) were NS [8].
Since the 2000s, there has been an increase in prevalence of neurosyphilis (NS) and ocular syphilis (OS). As data about symptomatic NS/OS is limited, this study aims to assess the characteristics of symptomatic NS/OS, according to HIV status.
We compared the clinical and biological presentation of early symptomatic NS/OS and its outcome in HIV-positive and HIV-negative patients.
Ninety-six patients (93% men, 49% HIV-positive) were included from 2000 to 2016 in two centers, with 67 (69%) having OS, 15 (16%) NS, and 14 (14%) both. HIV-positive patients were younger (P = 0.006) and more likely to be males having sex with males (P = 0.00048) or to have a history of syphilis (P = 0.01). Among 81 OS, there were 43 posterior uveitis (57%), and bilateral involvement was more common in HIV-positive patients (62% versus 38%, P = 0.045). Among 29 NS there were 21 cases of cranial nerve involvement (72%), seven meningitis (24%) and 11 paresthesia (38%). Involvement of the VIIIth cranial nerve was the most common (16 cases). Treponemal tests were more commonly found positive in cerebrospinal fluid in HIV-positive patients (88% versus 76%, P = 0.04). Visual acuity (VA) always improved after treatment (initial VA logMAR 0.8 ± 0.8 versus 0.1 ± 0.1 at 3 months), but 32% and 18% of the patients still had neurological or ocular impairment respectively six and 12 months after treatment. Non-treponemal serological reversion was observed in 43/50 patients (88%) at six months.
HIV infection has no consequence on the outcome of NS and OS. Sequelae are common, emphasizing the importance of prevention, and screening, and questioning enhanced treatment.